MedWorm.com provides a medical RSS filtering service. Over 6000 RSS medical sources are combined and output via different filters. This feed contains the latest items from the 'Trends in Biochemical Sciences' source. Thu, 09 Feb 2012 13:38:46 +0100 http://www.medworm.com/index.php?rid=5672259&cid=s_36134_60_f&fid=36134&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D22300815%26dopt%3DAbstract Authors: Kugel JF, Goodrich JA Abstract Non-coding RNAs (ncRNAs) are now recognized as active participants in controlling many biological processes. Indeed, these products of transcription can even control the process of transcription itself. In the past several years, ncRNAs have been found to regulate transcription of single genes, as well as entire transcriptional programs, affecting the expression of hundreds to thousands of genes in response to developmental or environmental signals. Compared to more classical protein regulators, the list of ncRNAs that regulate mRNA transcription in mammalian cells is still small; however, the rate at which new ncRNA transcriptional regulators are being discovered is rapid, suggesting that models for how gene expression is controlled will con... Trends in Biochemical Sciences journals http://www.medworm.com/rss/comments.php?id=5672259 Tue, 31 Jan 2012 05:00:00 +0100 5672259 http://www.medworm.com/index.php?rid=5655097&cid=s_36134_60_f&fid=36134&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D22285516%26dopt%3DAbstract Authors: Liu Y, Wilson SH Abstract The expansion of trinucleotide repeat (TNR) sequences in human DNA is considered to be a key factor in the pathogenesis of more than 40 neurodegenerative diseases. TNR expansion occurs during DNA replication and also, as suggested by recent studies, during the repair of DNA lesions produced by oxidative stress. In particular, the oxidized guanine base 8-oxoguanine within sequences containing CAG repeats may induce formation of pro-expansion intermediates through strand slippage during DNA base excision repair (BER). In this article, we describe how oxidized DNA lesions are repaired by BER and discuss the importance of the coordinated activities of the key repair enzymes, such as DNA polymerase β, flap endonuclease 1 (FEN1) and DNA ligase, in prev... Trends in Biochemical Sciences journals http://www.medworm.com/rss/comments.php?id=5655097 Fri, 27 Jan 2012 05:00:00 +0100 5655097 http://www.medworm.com/index.php?rid=5619099&cid=s_36134_60_f&fid=36134&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D22260999%26dopt%3DAbstract Authors: Wild T, Cramer P Abstract Gene transcription in the nucleus of eukaryotic cells is carried out by three related multisubunit RNA polymerases, Pol I, Pol II and Pol III. Although the structure and function of the polymerases have been studied extensively, little is known about their biogenesis and their transport from the cytoplasm (where the subunits are synthesized) to the nucleus. Recent studies have revealed polymerase assembly intermediates and putative assembly factors, as well as factors required for Pol II nuclear import. In this review, we integrate the available data into a model of Pol II biogenesis that provides a framework for future analysis of the biogenesis of all RNA polymerases. PMID: 22260999 [PubMed - as supplied by publisher] (Source: Trends in Bioc... Trends in Biochemical Sciences journals http://www.medworm.com/rss/comments.php?id=5619099 Tue, 17 Jan 2012 05:00:00 +0100 5619099 http://www.medworm.com/index.php?rid=5595360&cid=s_36134_60_f&fid=36134&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D22236506%26dopt%3DAbstract Authors: Mittler R, Finka A, Goloubinoff P Abstract In plants, the heat stress response (HSR) is highly conserved and involves multiple pathways, regulatory networks and cellular compartments. At least four putative sensors have recently been proposed to trigger the HSR. They include a plasma membrane channel that initiates an inward calcium flux, a histone sensor in the nucleus, and two unfolded protein sensors in the endoplasmic reticulum and the cytosol. Each of these putative sensors is thought to activate a similar set of HSR genes leading to enhanced thermotolerance, but the relationship between the different pathways and their hierarchical order is unclear. In this review, we explore the possible involvement of different thermosensors in the plant response to warming and hea... Trends in Biochemical Sciences journals http://www.medworm.com/rss/comments.php?id=5595360 Mon, 09 Jan 2012 05:00:00 +0100 5595360 http://www.medworm.com/index.php?rid=5544612&cid=s_36134_60_f&fid=36134&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D22196451%26dopt%3DAbstract Authors: Gangloff M Abstract TLR4 is unique among pathogen-recognition receptors in that it initiates different pathways in different cellular locations. Binding of a bridging factor, Mal, allows recruitment of an adapter protein, MyD88, at the plasma membrane, which leads to the production of proinflammatory cytokines. Upon internalization, TLR4 uses a different bridging factor, TRAM, to activate a MyD88-independent pathway that results in type I interferon expression. Interestingly, both Mal and TRAM are localised initially at the plasma membrane. In this Opinion, I suggest a possible mechanism by which endosomal acidification triggers the differential adaptor usage of TLR4. I discuss the evidence of the pH sensitivity of TLR4 and propose a new dimerisation mode for TLR4 based on... Trends in Biochemical Sciences journals http://www.medworm.com/rss/comments.php?id=5544612 Wed, 21 Dec 2011 05:00:00 +0100 5544612 http://www.medworm.com/index.php?rid=5526200&cid=s_36134_60_f&fid=36134&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D22178137%26dopt%3DAbstract Authors: Leung DC, Lorincz MC Abstract Retrotransposons, such as endogenous retroviruses (ERVs), have colonized the genomes of all metazoans. As retrotransposition can be deleterious, numerous pathways have evolved to repress the expression of these parasitic elements. For example, methylation of the fifth carbon of the cytosine base in DNA (5-methylcytosine, 5mC) is required for transcriptional silencing of ERVs in differentiated cells. However, this epigenetic mark is generally dispensable for ERV silencing during early stages of mouse embryogenesis and in mouse embryonic stem cells (mESCs). In this Opinion, we evaluate recent findings on the exceptional role of covalent modifications of histones in ERV silencing in these cell types. In addition, we discuss the potential role of ... Trends in Biochemical Sciences journals http://www.medworm.com/rss/comments.php?id=5526200 Thu, 15 Dec 2011 05:00:00 +0100 5526200 http://www.medworm.com/index.php?rid=5526199&cid=s_36134_60_f&fid=36134&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D22178138%26dopt%3DAbstract Authors: Becker T, Böttinger L, Pfanner N Abstract Mitochondria, the powerhouses of the cell, import most of their proteins from the cytosol. It was originally assumed that mitochondria imported precursor proteins via a general pathway but recent studies have revealed a remarkable variety of import pathways and mechanisms. Currently, five different protein import pathways can be distinguished. However, the import machineries cooperate with each other and are connected to other systems that function in the respiratory chain, mitochondrial membrane organization, protein quality control and endoplasmic reticulum-mitochondria junctions. In this Opinion, we propose that mitochondrial protein import should not be seen as an independent task of the organelle and that a network of coopera... Trends in Biochemical Sciences journals http://www.medworm.com/rss/comments.php?id=5526199 Thu, 15 Dec 2011 05:00:00 +0100 5526199 http://www.medworm.com/index.php?rid=5526201&cid=s_36134_60_f&fid=36134&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D22177323%26dopt%3DAbstract Authors: Basha E, O'Neill H, Vierling E Abstract The small heat shock proteins (sHSPs) and the related α-crystallins (αCs) are virtually ubiquitous proteins that are strongly induced by a variety of stresses, but that also function constitutively in multiple cell types in many organisms. Extensive research has demonstrated that a majority of sHSPs and αCs can act as ATP-independent molecular chaperones by binding denaturing proteins and thereby protecting cells from damage due to irreversible protein aggregation. As a result of their diverse evolutionary history, their connection to inherited human diseases, and their novel protein dynamics, sHSPs and αCs are of significant interest to many areas of biology and biochemistry. However, it is increasingly clear that no single mode... Trends in Biochemical Sciences journals http://www.medworm.com/rss/comments.php?id=5526201 Wed, 14 Dec 2011 05:00:00 +0100 5526201 http://www.medworm.com/index.php?rid=5526202&cid=s_36134_60_f&fid=36134&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D22154517%26dopt%3DAbstract Authors: Budhidarmo R, Nakatani Y, Day CL Abstract Ubiquitylation, the covalent modification of proteins by the addition of ubiquitin, relies on a cascade of enzymes that culminates in an E3 ligase that promotes the transfer of ubiquitin from an E2 enzyme to the target protein. The most prevalent E3 ligases contain a type of zinc-finger domain called RING, and although an essential role for the RING domain in ubiquitin transfer is widely accepted, the molecular mechanism by which this is achieved remains uncertain. In this review, we highlight recent studies that have suggested that the RING domain modulates the stability of the E2∼ubiquitin conjugate so that catalysis is promoted. We also review the role of RING dimerisation and emphasise the importance of studying RING domains ... Trends in Biochemical Sciences journals http://www.medworm.com/rss/comments.php?id=5526202 Fri, 09 Dec 2011 05:00:00 +0100 5526202 http://www.medworm.com/index.php?rid=5526204&cid=s_36134_60_f&fid=36134&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D22154230%26dopt%3DAbstract Authors: Bieniossek C, Imasaki T, Takagi Y, Berger I Abstract Protein complexes composed of many subunits carry out most essential processes in cells and, therefore, have become the focus of intense research. However, deciphering the structure and function of these multiprotein assemblies imposes the challenging task of producing them in sufficient quality and quantity. To overcome this bottleneck, powerful recombinant expression technologies are being developed. In this review, we describe the use of one of these technologies, MultiBac, a baculovirus expression vector system that is particularly tailored for the production of eukaryotic multiprotein complexes. Among other applications, MultiBac has been used to produce many important proteins and their complexes for their structur... Trends in Biochemical Sciences journals http://www.medworm.com/rss/comments.php?id=5526204 Wed, 07 Dec 2011 05:00:00 +0100 5526204 http://www.medworm.com/index.php?rid=5526203&cid=s_36134_60_f&fid=36134&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D22154231%26dopt%3DAbstract Authors: Zhou HX Abstract Association between signaling proteins and their cellular targets is generally thought to be highly specific (implicating a high association constant, K(a)) and, at the same time, transient or short-lived (corresponding to a high dissociation rate constant, k(d)). However, a combination of high K(a) and high k(d) would lead to a high association rate constant (k(a) = K(a)k(d)), which poses a problem because there is a limit to which k(a) can be increased, set by the diffusional approach to form the complex. In this Opinion article, I propose that having the signaling protein disordered before binding to the target provides a way out of this quandary. The intrinsic disorder of the signaling protein would decrease K(a) without sacrificing the specificity of ... Trends in Biochemical Sciences journals http://www.medworm.com/rss/comments.php?id=5526203 Wed, 07 Dec 2011 05:00:00 +0100 5526203 http://www.medworm.com/index.php?rid=5526205&cid=s_36134_60_f&fid=36134&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D22118811%26dopt%3DAbstract Authors: Grasby JA, Finger LD, Tsutakawa SE, Atack JM, Tainer JA Abstract Structure-specific 5'-nucleases form a superfamily of evolutionarily conserved phosphodiesterases that catalyse a precise incision of a diverse range of DNA and RNA substrates in a sequence-independent manner. Superfamily members, such as flap endonucleases, exonuclease 1, DNA repair protein XPG, endonuclease GEN1 and the 5'-3'-exoribonucleases, play key roles in many cellular processes such as DNA replication and repair, recombination, transcription, RNA turnover and RNA interference. In this review, we discuss recent results that highlight the conserved architectures and active sites of the structure-specific 5'-nucleases. Despite substrate diversity, a common gating mechanism for sequence-independent subst... Trends in Biochemical Sciences journals http://www.medworm.com/rss/comments.php?id=5526205 Wed, 23 Nov 2011 05:00:00 +0100 5526205 http://www.medworm.com/index.php?rid=5526207&cid=s_36134_60_f&fid=36134&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D22099186%26dopt%3DAbstract Authors: Silverman JS, Skaar JR, Pagano M Abstract In response to genotoxic stress, eukaryotic cells activate the DNA damage response (DDR), a series of pathways that coordinate cell cycle arrest and DNA repair to prevent deleterious mutations. In addition, cells possess checkpoint mechanisms that prevent aneuploidy by regulating the number of centrosomes and spindle assembly. Among these mechanisms, ubiquitin-mediated degradation of key proteins has an important role in the regulation of the DDR, centrosome duplication and chromosome segregation. This review discusses the functions of a group of ubiquitin ligases, the SCF (SKP1-CUL1-F-box protein) family, in the maintenance of genome stability. Given that general proteasome inhibitors are currently used as anticancer agents, a bet... Trends in Biochemical Sciences journals http://www.medworm.com/rss/comments.php?id=5526207 Wed, 16 Nov 2011 05:00:00 +0100 5526207 http://www.medworm.com/index.php?rid=5526206&cid=s_36134_60_f&fid=36134&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D22099187%26dopt%3DAbstract Authors: Fast W, Tipton PA Abstract N-Acyl-L-homoserine lactones (AHLs) are a major class of quorum-sensing signals used by Gram-negative bacteria to regulate gene expression in a population-dependent manner, thereby enabling group behavior. Enzymes capable of generating and catabolizing AHL signals are of significant interest for the study of microbial ecology and quorum-sensing pathways, for understanding the systems that bacteria have evolved to interact with small-molecule signals, and for their possible use in therapeutic and industrial applications. The recent structural and functional studies reviewed here provide a detailed insight into the chemistry and enzymology of bacterial communication. PMID: 22099187 [PubMed - as supplied by publisher] (Source: Trends in Biochemi... Trends in Biochemical Sciences journals http://www.medworm.com/rss/comments.php?id=5526206 Wed, 16 Nov 2011 05:00:00 +0100 5526206 http://www.medworm.com/index.php?rid=5526208&cid=s_36134_60_f&fid=36134&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D22088262%26dopt%3DAbstract Authors: Bibi E Abstract Integral membrane proteins (IMPs) are usually synthesized by membrane-bound ribosomes, and this process requires proper localization of ribosomes and IMP-encoding transcripts. However, the underlying molecular mechanism of the pathway has not yet been fully established in vivo. The prevailing hypothesis is that ribosomes and transcripts are delivered to the membrane together during IMP translation by the signal recognition particle (SRP) and its receptor. Here, I discuss an alternative hypothesis that posits that ribosomes and transcripts are targeted separately. Ribosome targeting to the membrane might be mediated by the SRP receptor, rather than by SRP, and IMP-encoding transcripts might be targeted to the membrane in a translation-independent manner. Acc... Trends in Biochemical Sciences journals http://www.medworm.com/rss/comments.php?id=5526208 Mon, 14 Nov 2011 05:00:00 +0100 5526208 http://www.medworm.com/index.php?rid=5412340&cid=s_36134_60_f&fid=36134&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D22079189%26dopt%3DAbstract Authors: Ditch S, Paull TT Abstract The ataxia-telangiectasia mutated (ATM) protein kinase is best known for its role in the DNA damage response, but recent findings suggest that it also functions as a redox sensor that controls the levels of reactive oxygen species in human cells. Here, we review evidence supporting the conclusion that ATM can be directly activated by oxidation, as well as various observations from ATM-deficient patients and mouse models that point to the importance of ATM in oxidative stress responses. We also discuss the roles of this kinase in regulating mitochondrial function and metabolic control through its action on tumor suppressor p53, AMP-activated protein kinase (AMPK), mammalian target of rapamycin (mTOR) and hypoxia-inducible factor 1 (HIF1), and how ... Trends in Biochemical Sciences journals http://www.medworm.com/rss/comments.php?id=5412340 Thu, 10 Nov 2011 05:00:00 +0100 5412340 http://www.medworm.com/index.php?rid=5376845&cid=s_36134_60_f&fid=36134&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D22018829%26dopt%3DAbstract Authors: Praefcke GJ, Hofmann K, Dohmen RJ Abstract In addition to being structurally related, the protein modifiers ubiquitin and SUMO (small ubiquitin-related modifier), share a multitude of functional interrelations. These include the targeting of the same attachment sites in certain substrates, and SUMO-dependent ubiquitylation in others. Notably, several cellular processes, including the targeting of repair machinery to DNA damage sites, require the sequential sumoylation and ubiquitylation of distinct substrates. Some proteins promote both modifications. By contrast, the activity of some enzymes that control either sumoylation or ubiquitylation is regulated by the respective other modification. In this review, we summarize recent findings regarding intersections between SUMO ... Trends in Biochemical Sciences journals http://www.medworm.com/rss/comments.php?id=5376845 Thu, 20 Oct 2011 04:00:00 +0100 5376845 http://www.medworm.com/index.php?rid=5376844&cid=s_36134_60_f&fid=36134&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D22019011%26dopt%3DAbstract Authors: Fritz G Abstract The receptor for advanced glycation end products (RAGE) is a central signaling molecule in the innate immune system and is involved in the onset and sustainment of the inflammatory response. RAGE belongs to a class of pattern recognition receptors that recognize common features rather than a specific ligand. Recent structural information on the extracellular portion (ectodomain) of RAGE shed new light on this unusual ability. X-ray crystallographic, NMR and biochemical data suggest that ligand binding is driven largely by electrostatic interactions between the positively charged surface of the ectodomain and negatively charged ligands. In this article, I propose a putative mechanism of RAGE ligand recognition of receptor activation. PMID: 22019011 [Pub... Trends in Biochemical Sciences journals http://www.medworm.com/rss/comments.php?id=5376844 Wed, 19 Oct 2011 04:00:00 +0100 5376844 http://www.medworm.com/index.php?rid=5376847&cid=s_36134_60_f&fid=36134&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D22014644%26dopt%3DAbstract Authors: Claypool SM, Koehler CM Abstract Cardiolipin, the signature phospholipid of mitochondria, is a lipid dimer that is important for a diverse range of mitochondrial activities beyond the process of ATP production. Thus not surprisingly, derangements in cardiolipin metabolism are now appreciated to contribute to an assortment of pathological conditions. A comprehensive inventory of enzymes involved in cardiolipin biosynthesis and remodeling was just recently obtained. Post-biosynthesis, the acyl chain composition of cardiolipin is modified by up to three distinct remodeling enzymes that produce either a homogeneous tissue-specific mature form of cardiolipin or alternatively 'bad' cardiolipin that has been linked to mitochondrial dysfunction. In this review, we initially focus ... Trends in Biochemical Sciences journals http://www.medworm.com/rss/comments.php?id=5376847 Mon, 17 Oct 2011 04:00:00 +0100 5376847 http://www.medworm.com/index.php?rid=5309314&cid=s_36134_60_f&fid=36134&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D21978892%26dopt%3DAbstract Authors: Walensky LD, Gavathiotis E Abstract BAX, the BCL-2-associated X protein, is a cardinal proapoptotic member of the BCL-2 family, which regulates the critical balance between cellular life and death. Because so many medical conditions can be categorized as diseases of either too many or too few cells, dissecting the biochemistry of BCL-2 family proteins and developing pharmacological strategies to target them have become high priority scientific objectives. Here, we focus on BAX, a latent, cytosolic and monomeric protein that transforms into a lethal mitochondrial oligomer in response to cellular stress. New insights into the structural location of BAX's 'on switch', and the multi-step conformational changes that ensue upon BAX activation, are providing fresh opportunities t... Trends in Biochemical Sciences journals http://www.medworm.com/rss/comments.php?id=5309314 Tue, 04 Oct 2011 04:00:00 +0100 5309314 http://www.medworm.com/index.php?rid=5309313&cid=s_36134_60_f&fid=36134&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D21978893%26dopt%3DAbstract Authors: Eichinger CS, Jentsch S Abstract All living organisms are vulnerable to DNA damage. Cells respond to this hazard by activating a complex network of checkpoint and repair proteins to preserve genomic integrity. The DNA-encircling, ring-shaped heterotrimeric 9-1-1 complex, a relative of the replication protein PCNA, is a central coordinator of these events. 9-1-1 is loaded to damaged sites where it serves as a platform for the selective recruitment of checkpoint and repair proteins. In this Opinion article, 9-1-1 and proliferating cell nuclear antigen (PCNA) are compared and discussed in light of their respective structures and functions. We propose that the interaction partners of 9-1-1 possess specific 9-1-1-interaction boxes, which discriminate between 9-1-1 and PCNA ther... Trends in Biochemical Sciences journals http://www.medworm.com/rss/comments.php?id=5309313 Tue, 04 Oct 2011 04:00:00 +0100 5309313 http://www.medworm.com/index.php?rid=5294092&cid=s_36134_60_f&fid=36134&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D21975038%26dopt%3DAbstract Authors: Karkhanis V, Hu YJ, Baiocchi RA, Imbalzano AN, Sif S Abstract Arginine methylation governs important cellular processes that impact growth and proliferation, as well as differentiation and development. Through their ability to catalyze symmetric or asymmetric methylation of histone and non-histone proteins, members of the protein arginine methyltransferase (PRMT) family regulate chromatin structure and expression of a wide spectrum of target genes. Unlike other PRMTs, PRMT5 works in concert with a variety of cellular proteins including ATP-dependent chromatin remodelers and co-repressors to induce epigenetic silencing. Recent work also implicates PRMT5 in the control of growth-promoting and pro-survival pathways, which demonstrates its versatility as an enzyme involved in ... Trends in Biochemical Sciences journals http://www.medworm.com/rss/comments.php?id=5294092 Mon, 03 Oct 2011 04:00:00 +0100 5294092 http://www.medworm.com/index.php?rid=5272874&cid=s_36134_60_f&fid=36134&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D21958687%26dopt%3DAbstract Authors: Medema RH, Lindqvist A Abstract Reversible protein phosphorylation is an essential aspect of mitosis and forms the basis of nuclear envelope breakdown, chromosome condensation and spindle assembly. Through global phosphoproteomic analysis, it has become clear that overall protein phosphorylation and phosphosite occupancy is most abundant during mitosis. At mitotic exit, this abundant phosphorylation must be reversed, and this process requires massive and rapid protein dephosphorylation. In addition to this global shift in protein phosphorylation, careful spatial control of protein (de)phosphorylation is equally important for spindle assembly, chromosome disjunction and chromosome alignment. In this review, we discuss the underlying mechanisms that enforce the dramatic glob... Trends in Biochemical Sciences journals http://www.medworm.com/rss/comments.php?id=5272874 Tue, 27 Sep 2011 04:00:00 +0100 5272874 http://www.medworm.com/index.php?rid=5272873&cid=s_36134_60_f&fid=36134&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D21958688%26dopt%3DAbstract Authors: Elbaz Y, Schuldiner M Abstract Membrane contact sites (MCS) are close appositions between two organelles that facilitate both signaling and the passage of ions and lipids from one cellular compartment to another. Despite the fact that MCS have been observed for over 50 years now, we still know very little about the molecular machinery required to create them or their structure, function and regulation. In this review, we focus on the three best-characterized contact sites to date: the nucleus-vacuole junction and mitochondria-ER and plasma membrane-ER contact sites. In addition, we discuss principles arising from recent research and highlight several unanswered questions in the field. PMID: 21958688 [PubMed - as supplied by publisher] (Source: Trends in Biochemical Sci... Trends in Biochemical Sciences journals http://www.medworm.com/rss/comments.php?id=5272873 Tue, 27 Sep 2011 04:00:00 +0100 5272873 http://www.medworm.com/index.php?rid=5240792&cid=s_36134_60_f&fid=36134&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D21930385%26dopt%3DAbstract Authors: Lee DH, Chowdhury D Abstract DNA-damage-induced phospho-signaling has been studied for decades, with a focus mainly on initiation of the signaling cascade, and the kinases activated by DNA lesions. It is widely accepted that the balance of phosphorylation needs to be restored and/or maintained by phosphatases, yet there have only been sporadic efforts to investigate the impact of phosphatases on DNA repair. Recent advances in phosphoproteomic strategies and implementation of large genetic screens indicate that these enzymes play pivotal roles in these signaling networks. Dephosphorylation of repair proteins is crucial for efficient DNA repair, and the recommencement of cell division post-repair. Here, we focus on serine/threonine phosphatases implicated in dephosphorylatio... Trends in Biochemical Sciences journals http://www.medworm.com/rss/comments.php?id=5240792 Sat, 17 Sep 2011 04:00:00 +0100 5240792 http://www.medworm.com/index.php?rid=5240791&cid=s_36134_60_f&fid=36134&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D21930386%26dopt%3DAbstract Authors: Maccallum JL, Tieleman DP Abstract The partitioning of amino acid sidechains into the membrane is a key aspect of membrane protein folding. However, lipid bilayers exhibit rapidly changing physicochemical properties over their nanometer-scale thickness, which complicates understanding the thermodynamics and microscopic details of membrane partitioning. Recent data from diverse approaches, including protein insertion by the Sec translocon, folding of a small beta-barrel membrane protein and computer simulations of the exact distribution of a variety of small molecules and peptides, have joined older hydrophobicity scales for membrane protein prediction. We examine the correlations among the scales and find that they are remarkably correlated even though there are large diff... Trends in Biochemical Sciences journals http://www.medworm.com/rss/comments.php?id=5240791 Sat, 17 Sep 2011 04:00:00 +0100 5240791 http://www.medworm.com/index.php?rid=5240793&cid=s_36134_60_f&fid=36134&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D21924917%26dopt%3DAbstract Authors: Chen CK, Chan NL, Wang AH Abstract The β-propeller is a highly symmetrical structure with 4-10 repeats of a four-stranded antiparallel β-sheet motif. Although β-propeller proteins with different blade numbers all adopt disc-like shapes, they are involved in a diverse set of functions, and defects in this family of proteins have been associated with human diseases. However, it has remained ambiguous how variations in blade number could alter the function of β-propellers. In addition to the regularly arranged β-propeller topology, a recently discovered β-pinwheel propeller has been found. Here, we review the structural and functional diversity of β-propeller proteins, including β-pinwheels, as well as recent advances in the typical and atypical propeller structures. ... Trends in Biochemical Sciences journals http://www.medworm.com/rss/comments.php?id=5240793 Thu, 15 Sep 2011 04:00:00 +0100 5240793 http://www.medworm.com/index.php?rid=5225810&cid=s_36134_60_f&fid=36134&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D21920759%26dopt%3DAbstract Authors: Canals M, Sexton PM, Christopoulos A Abstract G protein-coupled receptors (GPCRs) constitute the largest family of receptors in the genome and are the targets for at least 30% of current medicines. In recent years, there has been a dramatic increase in the discovery of allosteric modulators of GPCR activity and a growing appreciation of the diverse modes by which GPCRs can be regulated by both orthosteric and allosteric ligands. Interestingly, some of the contemporary views of GPCR function reflect characteristics that are shared by prototypical allosteric proteins, as encompassed in the classic Monod-Wyman-Changeux (MWC) model initially proposed for enzymes and subsequently extended to other protein families. In this review, we revisit the MWC model in the context of emer... Trends in Biochemical Sciences journals http://www.medworm.com/rss/comments.php?id=5225810 Tue, 13 Sep 2011 04:00:00 +0100 5225810 http://www.medworm.com/index.php?rid=5225809&cid=s_36134_60_f&fid=36134&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D21920760%26dopt%3DAbstract Authors: Cui J, Shao F Abstract Bacterial virulence often relies on secreted effectors that modulate eukaryotic signal transduction. Recent studies provide a collection of examples in which bacterial effectors carry out unprecedented posttranslational modifications of key signaling molecules or organize a new signaling network. OspF and YopJ families of effectors use novel modification activities to block kinase phosphoactivation. Targeting of the ubiquitin system by IpaH and Cif/CHBP families provides insights into host ubiquitin signaling. Manipulation of small GTPases by VopS/IbpA and SidM suggests previously underappreciated regulation of signaling. Several other effectors, including SifA and EspG, organize newly discovered signaling networks in membrane trafficking. Studies of... Trends in Biochemical Sciences journals http://www.medworm.com/rss/comments.php?id=5225809 Tue, 13 Sep 2011 04:00:00 +0100 5225809 http://www.medworm.com/index.php?rid=5225811&cid=s_36134_60_f&fid=36134&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D21917465%26dopt%3DAbstract Authors: Kusumi A, Suzuki KG, Kasai RS, Ritchie K, Fujiwara TK Abstract Based on recent single-molecule imaging results in the living cell plasma membrane, we propose a hierarchical architecture of three-tiered mesoscale (2-300nm) domains to represent the fundamental functional organization of the plasma membrane: (i) membrane compartments of 40-300nm in diameter due to the partitioning of the entire plasma membrane by the actin-based membrane skeleton 'fence' and transmembrane protein 'pickets' anchored to the fence; (ii) raft domains (2-20nm); and (iii) dimers/oligomers and greater complexes of membrane-associated proteins (3-10nm). The basic molecular interactions required for the signal transduction function of the plasma membrane can be fundamentally understood and convenientl... Trends in Biochemical Sciences journals http://www.medworm.com/rss/comments.php?id=5225811 Mon, 12 Sep 2011 04:00:00 +0100 5225811 http://www.medworm.com/index.php?rid=5215682&cid=s_36134_60_f&fid=36134&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D21903397%26dopt%3DAbstract Authors: van Hoof A, Wagner EJ Abstract Defective mRNAs are degraded more rapidly than normal mRNAs in a process called mRNA surveillance. Eukaryotic cells use a variety of mechanisms to detect aberrations in mRNAs and a variety of enzymes to preferentially degrade them. Recent advances in the field of RNA surveillance have provided new information regarding how cells determine which mRNA species should be subject to destruction and novel mechanisms by which a cell tags an mRNA once such a decision has been reached. In this review, we highlight recent progress in our understanding of these processes. PMID: 21903397 [PubMed - as supplied by publisher] (Source: Trends in Biochemical Sciences) Trends in Biochemical Sciences journals http://www.medworm.com/rss/comments.php?id=5215682 Tue, 06 Sep 2011 04:00:00 +0100 5215682 http://www.medworm.com/index.php?rid=5171242&cid=s_36134_60_f&fid=36134&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D21855348%26dopt%3DAbstract Authors: Lee AG Abstract Are lipid interactions with membrane proteins best described in terms of the physical properties of the lipid bilayer or in terms of direct molecular interactions between particular lipid molecules and particular sites on a protein? A molecular interpretation is more challenging because it requires detailed knowledge of the 3D structure of a membrane protein, but recent studies have suggested that a molecular interpretation is necessary. Here, the idea is explored that lipid molecules modify the ways that transmembrane α-helices pack into bundles, by penetrating between the helices and by binding into clefts between the helices, and that these effects on helix packing will modulate the activity of a membrane protein. PMID: 21855348 [PubMed - as supplie... Trends in Biochemical Sciences journals http://www.medworm.com/rss/comments.php?id=5171242 Wed, 17 Aug 2011 23:00:00 +0100 5171242 http://www.medworm.com/index.php?rid=5171243&cid=s_36134_60_f&fid=36134&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D21852138%26dopt%3DAbstract Authors: Liou YC, Zhou XZ, Lu KP Abstract Pin1 is a highly conserved enzyme that only isomerizes specific phosphorylated Ser/Thr-Pro bonds in certain proteins, thereby inducing conformational changes. Such conformational changes represent a novel and tightly controlled signaling mechanism regulating a spectrum of protein activities in physiology and disease; often through phosphorylation-dependent, ubiquitin-mediated proteasomal degradation. In this review, we summarize recent advances in elucidating the role and regulation of Pin1 in controlling protein stability. We also propose a mechanism by which Pin1 functions as a molecular switch to control the fates of phosphoproteins. We finally stress the need to develop tools to visualize directly Pin1-catalyzed protein conformational c... Trends in Biochemical Sciences journals http://www.medworm.com/rss/comments.php?id=5171243 Mon, 15 Aug 2011 23:00:00 +0100 5171243 http://www.medworm.com/index.php?rid=5138912&cid=s_36134_60_f&fid=36134&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D21840721%26dopt%3DAbstract Authors: Ehrensberger KM, Bird AJ The transition metals zinc, iron and copper are common constituents in a wide range of proteins. Although these metals are all essential for life, when present in excess, they are frequently toxic to cell growth and viability. Therefore, all organisms rely on sophisticated mechanisms to maintain optimal levels of each metal. Genes that encode metal transport or storage proteins are often regulated at the transcriptional level in response to changes in metal status. In this review, we focus on what is known about the transcription factors that mediate these metal-dependent changes. Specifically, we highlight recent advances in our understanding of the mechanisms by which these factors sense metal ions. PMID: 21840721 [PubMed - as supplied by publish... Trends in Biochemical Sciences journals http://www.medworm.com/rss/comments.php?id=5138912 Thu, 11 Aug 2011 23:00:00 +0100 5138912 http://www.medworm.com/index.php?rid=5147407&cid=s_36134_60_f&fid=36134&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D21816617%26dopt%3DAbstract Authors: Boguta M, Graczyk D The synthesis of tRNA by yeast RNA polymerase III (Pol III) is regulated in response to changing environmental conditions. This control is mediated by Maf1, the global negative regulator of Pol III transcription conserved from yeast to humans. Details regarding the molecular basis of Pol III repression by Maf1 are now emerging from recently reported structural and biochemical data on Pol III and Maf1. Efficient Pol III transcription, following the shift of cells from a non-fermentable carbon source to glucose, requires phosphorylation of Maf1. One of the newly identified Maf1 kinases is the chromatin-bound casein kinase II (CK2). Current studies have allowed us to propose an innovative mechanism of Pol III regulation. We suggest that CK2-mediated phosphoryl... Trends in Biochemical Sciences journals http://www.medworm.com/rss/comments.php?id=5147407 Mon, 01 Aug 2011 23:00:00 +0100 5147407 http://www.medworm.com/index.php?rid=5089884&cid=s_36134_60_f&fid=36134&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D21798744%26dopt%3DAbstract Authors: Almena M, Mérida I Diacylglycerol signals by binding and activating C1 domain-containing proteins expressed principally in neuronal and immune tissues. This restricted expression profile suggests that diacylglycerol-regulated signals are particularly relevant in cell-cell communication processes in which active endocytosis and exocytosis take place. Not surprisingly, various experimental approaches have demonstrated a crucial role for diacylglycerol effectors and metabolizing enzymes in the control of immune responses, neuron communication and phagocytosis. Current research delineates a scenario in which coordinated decoding of diacylglycerol signals is translated into complex biological responses such as neuronal plasticity, T cell development or cytolytic killing. Diacylgly... Trends in Biochemical Sciences journals http://www.medworm.com/rss/comments.php?id=5089884 Tue, 26 Jul 2011 23:00:00 +0100 5089884 http://www.medworm.com/index.php?rid=5089876&cid=s_36134_60_f&fid=36134&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D21798745%26dopt%3DAbstract Authors: Kersse K, Verspurten J, Berghe TV, Vandenabeele P The death-fold superfamily encompasses four structurally homologous subfamilies that engage in homotypic, subfamily-restricted interactions. The Death Domains (DDs), the Death Effector Domains (DEDs), the CAspase Recruitment Domains (CARDs) and the PYrin Domains (PYDs) constitute key building blocks involved in the assembly of multimeric complexes implicated in signaling cascades leading to inflammation and cell death. We review the molecular basis of these homotypic domain-domain interactions in light of their structure, function and evolution. In addition, we elaborate on three distinct types of asymmetric interactions that were recently identified from the crystal structures of three multimeric, death-fold complexes: the MyD... Trends in Biochemical Sciences journals http://www.medworm.com/rss/comments.php?id=5089876 Mon, 25 Jul 2011 23:00:00 +0100 5089876 http://www.medworm.com/index.php?rid=5089886&cid=s_36134_60_f&fid=36134&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D21782450%26dopt%3DAbstract Authors: Hardie DG, Carling D, Gamblin SJ AMPK is a ubiquitous sensor of cellular energy status in eukaryotic cells. It is activated by stresses causing ATP depletion and, once activated, maintains energy homeostasis by phosphorylating targets that activate catabolism and inhibit energy-consuming processes. Evidence derived from non-mammalian orthologs suggests that its ancestral role was in the response to starvation for a carbon source. We review recent findings showing that AMPK is activated by ADP as well as AMP, and discuss the mechanism by which binding of these nucleotides prevent its dephosphorylation and inactivation. We also discuss the role of the carbohydrate-binding module on the β subunit and the mechanisms by which it is activated by drugs and xenobiotics such as metfor... Trends in Biochemical Sciences journals http://www.medworm.com/rss/comments.php?id=5089886 Tue, 19 Jul 2011 23:00:00 +0100 5089886 http://www.medworm.com/index.php?rid=5089887&cid=s_36134_60_f&fid=36134&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D21778060%26dopt%3DAbstract Authors: Bulleid NJ, Ellgaard L Our concept of how disulfides form in proteins entering the secretory pathway has changed dramatically in recent years. The discovery of endoplasmic reticulum (ER) oxidoreductin 1 (ERO1) was followed by the demonstration that this enzyme couples oxygen reduction to de novo formation of disulfides. However, mammals deficient in ERO1 survive and form disulfides, which suggests the presence of alternative pathways. It has recently been shown that peroxiredoxin 4 is involved in peroxide removal and disulfide formation. Other less well-characterized pathways involving quiescin sulfhydryl oxidase, ER-localized protein disulfide isomerase peroxidases and vitamin K epoxide reductase might all contribute to disulfide formation. Here we discuss these various pathw... Trends in Biochemical Sciences journals http://www.medworm.com/rss/comments.php?id=5089887 Mon, 18 Jul 2011 23:00:00 +0100 5089887 http://www.medworm.com/index.php?rid=5039020&cid=s_36134_60_f&fid=36134&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D21764321%26dopt%3DAbstract Authors: Shukla AK, Xiao K, Lefkowitz RJ β-Arrestins, originally discovered to desensitize activated seven transmembrane receptors (7TMRs; also known as G-protein-coupled receptors, GPCRs), are now well established mediators of receptor endocytosis, ubiquitylation and G protein-independent signaling. Recent global analyses of β-arrestin interactions and β-arrestin-dependent phosphorylation events have uncovered several previously unanticipated roles of β-arrestins in a range of cellular signaling events. These findings strongly suggest that the functional roles of β-arrestins are much broader than currently understood. Biophysical studies aimed at understanding multiple active conformations of the 7TMRs and the β-arrestins have begun to unravel the mechanistic basis for the diver... Trends in Biochemical Sciences journals http://www.medworm.com/rss/comments.php?id=5039020 Thu, 14 Jul 2011 23:00:00 +0100 5039020 http://www.medworm.com/index.php?rid=5039021&cid=s_36134_60_f&fid=36134&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D21741842%26dopt%3DAbstract Authors: Wan G, Mathur R, Hu X, Zhang X, Lu X Faithful transmission of genetic material in eukaryotic cells requires not only accurate DNA replication and chromosome distribution but also the ability to sense and repair spontaneous and induced DNA damage. To maintain genomic integrity, cells undergo a DNA damage response using a complex network of signaling pathways composed of coordinate sensors, transducers and effectors in cell cycle arrest, apoptosis and DNA repair. Emerging evidence has suggested that miRNAs play a crucial role in regulation of DNA damage response. In this review, we discuss the recent findings on how miRNAs interact with the canonical DNA damage response and how miRNA expression is regulated after DNA damage. PMID: 21741842 [PubMed - as supplied by publisher]... Trends in Biochemical Sciences journals http://www.medworm.com/rss/comments.php?id=5039021 Wed, 06 Jul 2011 23:00:00 +0100 5039021 http://www.medworm.com/index.php?rid=5039022&cid=s_36134_60_f&fid=36134&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D21741246%26dopt%3DAbstract Authors: Stolz A, Hilt W, Buchberger A, Wolf DH Cdc48 is an essential, highly prominent ATP driven machine in eukaryotic cells. Physiological function of Cdc48 has been found in a multitude of cellular processes, for instance cell cycle progression, homotypic membrane fusion, chromatin remodeling, transcriptional and metabolic regulation, and many others. The molecular function of Cdc48 is arguably best understood in endoplasmic reticulum-associated protein degradation by the ubiquitin proteasome system. In this review, we summarize the general characteristics of Cdc48/p97 and the most recent results on the molecular function of Cdc48 in some of the above processes, which were found to finally end in proteolysis-connected pathways, either involving the proteasome or autophagocytosis-me... Trends in Biochemical Sciences journals http://www.medworm.com/rss/comments.php?id=5039022 Tue, 05 Jul 2011 23:00:00 +0100 5039022 http://www.medworm.com/index.php?rid=5039023&cid=s_36134_60_f&fid=36134&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D21723731%26dopt%3DAbstract Authors: Yébenes H, Mesa P, Muñoz IG, Montoya G, Valpuesta JM Chaperonins are ubiquitous chaperones found in Eubacteria, eukaryotic organelles (group I), Archaea and the eukaryotic cytosol (group II). They all share a common structure and a basic functional mechanism. Although a large amount of information has been gathered for the simpler group I, much less is known about group II chaperonins. Recent crystallographic and electron microscopy structures have provided new insights into the mechanism of these chaperonins and revealed important differences between group I and II chaperonins, mainly in the molecular rearrangements that take place during the functional cycle. These differences are evident for the most complex chaperonin, the eukaryotic cytosolic CCT, which highlights the u... Trends in Biochemical Sciences journals http://www.medworm.com/rss/comments.php?id=5039023 Wed, 29 Jun 2011 23:00:00 +0100 5039023 http://www.medworm.com/index.php?rid=4946569&cid=s_36134_60_f&fid=36134&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D21646023%26dopt%3DAbstract Authors: Stewart MP, Toyoda Y, Hyman AA, Muller DJ Atomic force microscopy (AFM) is a force sensing nanoscopic tool that can be used to undertake a multiscale approach to understand the mechanisms that underlie cell shape change, ranging from the cellular to molecular scale. In this review paper, we discuss the use of AFM to characterize the dramatic shape changes of mitotic cells. AFM-based mechanical assays can be applied to measure the considerable rounding force and hydrostatic pressure generated by mitotic cells. A complementary AFM technique, single-molecule force spectroscopy, is able to quantify the interactions and mechanisms that functionally regulate individual proteins. Future developments of these nanomechanical methods, together with advances in light microscopy imaging a... Trends in Biochemical Sciences journals http://www.medworm.com/rss/comments.php?id=4946569 Fri, 03 Jun 2011 23:00:00 +0100 4946569 http://www.medworm.com/index.php?rid=4946571&cid=s_36134_60_f&fid=36134&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D21641804%26dopt%3DAbstract Authors: Bremm A, Komander D Polyubiquitin chains are assembled via one of seven lysine (Lys) residues or the N terminus. The cellular roles of Lys48- and Lys63-linked polyubiquitin have been extensively studied; however, the cellular functions of Lys11-linked chains are less well understood. Recent insights into Lys11-linked ubiquitin chains have revealed their important function in cell cycle control. Additionally, Lys11 linkages have been identified in the context of mixed chains in many other cellular pathways. In this review, we introduce the specific enzymes that mediate Lys11-linked chain assembly and disassembly, and discuss the diverse cellular processes in which Lys11 linkages participate. Notably, mechanistic insights have revealed how the E2 ubiquitin-conjugating enzyme UBE... Trends in Biochemical Sciences journals http://www.medworm.com/rss/comments.php?id=4946571 Thu, 02 Jun 2011 23:00:00 +0100 4946571 http://www.medworm.com/index.php?rid=4946570&cid=s_36134_60_f&fid=36134&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D21641805%26dopt%3DAbstract Authors: Blow JJ, Ge XQ, Jackson DA Many replication origins that are licensed by loading MCM2-7 complexes in G1 are not normally used. Activation of these dormant origins during S phase provides a first line of defence for the genome if replication is inhibited. When replication forks fail, dormant origins are activated within regions of the genome currently engaged in replication. At the same time, DNA damage-response kinases activated by the stalled forks preferentially suppress the assembly of new replication factories, thereby ensuring that chromosomal regions experiencing replicative stress complete synthesis before new regions of the genome are replicated. Mice expressing reduced levels of MCM2-7 have fewer dormant origins, are cancer-prone and are genetically unstable, demonstr... Trends in Biochemical Sciences journals http://www.medworm.com/rss/comments.php?id=4946570 Thu, 02 Jun 2011 23:00:00 +0100 4946570 http://www.medworm.com/index.php?rid=4897769&cid=s_36134_60_f&fid=36134&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D21620710%26dopt%3DAbstract Authors: Fuxreiter M, Simon I, Bondos S Traditionally, specific DNA recognition is thought to rely on static contacts with the bases or phosphates. Recent results, however, indicate that residues far outside the binding context can crucially influence selectivity or binding affinity via transient, dynamic interactions with the DNA binding interface. These regions usually do not adopt a well-defined structure, even when bound to DNA, and thus form a fuzzy complex. Here, we propose the existence of a dynamic DNA readout mechanism, wherein distant segments modulate conformational preferences, flexibility or spacing of the DNA binding motifs or serve as competitive partners. Despite their low sequence similarity, these intrinsically disordered regions are often conserved at the structural ... Trends in Biochemical Sciences journals http://www.medworm.com/rss/comments.php?id=4897769 Tue, 24 May 2011 23:00:00 +0100 4897769 http://www.medworm.com/index.php?rid=4851290&cid=s_36134_60_f&fid=36134&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D21596569%26dopt%3DAbstract Authors: Heyd F, Lynch KW With recent advances in microarrays and sequencing it is now relatively straightforward to compare pre-mRNA splicing patterns in different cellular conditions on a genome-wide scale. Such studies have revealed extensive changes in cellular splicing programs in response to stimuli such as neuronal depolarization, DNA damage, immune signaling and cellular metabolic changes. However, for many years our understanding of the signaling pathways responsible for such splicing changes was greatly lacking. Excitingly, over the past few years this gap has begun to close. Recent studies now suggest notable trends in the mechanisms that link cellular stimuli to downstream alternative splicing events. These include regulated synthesis or degradation of splicing factors, dif... Trends in Biochemical Sciences journals http://www.medworm.com/rss/comments.php?id=4851290 Mon, 16 May 2011 23:00:00 +0100 4851290 http://www.medworm.com/index.php?rid=4851291&cid=s_36134_60_f&fid=36134&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D21565514%26dopt%3DAbstract Authors: Korotkov KV, Gonen T, Hol WG Secretins form megadalton bacterial-membrane channels in at least four sophisticated multiprotein systems that are crucial for translocation of proteins and assembled fibers across the outer membrane of many species of bacteria. Secretin subunits contain multiple domains, which interact with numerous other proteins, including pilotins, secretion-system partner proteins, and exoproteins. Our understanding of the structure of secretins is rapidly progressing, and it is now recognized that features common to all secretins include a cylindrical arrangement of 12-15 subunits, a large periplasmic vestibule with a wide opening at one end and a periplasmic gate at the other. Secretins might also play a key role in the biogenesis of their cognate secretion ... Trends in Biochemical Sciences journals http://www.medworm.com/rss/comments.php?id=4851291 Mon, 09 May 2011 23:00:00 +0100 4851291 http://www.medworm.com/index.php?rid=4851292&cid=s_36134_60_f&fid=36134&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D21550256%26dopt%3DAbstract Authors: Rein A, Datta SA, Jones CP, Musier-Forsyth K Retrovirus particles are constructed from a single virus-encoded protein, termed Gag. Given that assembly is an essential step in the viral replication cycle, it is a potential target for antiviral therapy. However, such an approach has not yet been exploited because of the lack of fundamental knowledge concerning the structures and interactions responsible for assembly. Assembling an infectious particle entails a remarkably diverse array of interactions, both specific and nonspecific, between Gag proteins and RNAs. These interactions are essential for the construction of the particle, for packaging of the viral RNA into the particle, and for placement of the primer for viral DNA synthesis. Recent results have provided some new insi... Trends in Biochemical Sciences journals http://www.medworm.com/rss/comments.php?id=4851292 Wed, 04 May 2011 23:00:00 +0100 4851292 http://www.medworm.com/index.php?rid=4798167&cid=s_36134_60_f&fid=36134&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D21546252%26dopt%3DAbstract Authors: Verstrepen L, Verhelst K, Carpentier I, Beyaert R The innate immune system senses and protects against invading microorganisms and endogenous danger signals by triggering inflammatory and antimicrobial responses. However, dysregulation of these pathways, which involve the transcription factors nuclear factor-κB (NF-κB) and interferon regulatory factor (IRF) 3, can lead to severe inflammatory diseases. Tax1-binding protein 1 (TAX1BP1) plays a key role in the negative regulation of NF-κB and IRF3 signaling by acting in concert with the ubiquitin-editing enzyme A20. In addition to regulating A20 function in anti-inflammatory and antiviral signaling pathways, TAX1BP1 also coordinates its antiapoptotic activities. Moreover, TAX1BP1 can also function as a transcriptional coactiva... Trends in Biochemical Sciences journals http://www.medworm.com/rss/comments.php?id=4798167 Tue, 03 May 2011 23:00:00 +0100 4798167 http://www.medworm.com/index.php?rid=4798168&cid=s_36134_60_f&fid=36134&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D21531565%26dopt%3DAbstract Authors: Mendoza MC, Er EE, Blenis J The Ras-extracellular signal-regulated kinase (Ras-ERK) and phosphatidylinositol 3-kinase-mammalian target of rapamycin (PI3K-mTOR) signaling pathways are the chief mechanisms for controlling cell survival, differentiation, proliferation, metabolism, and motility in response to extracellular cues. Components of these pathways were among the first to be discovered when scientists began cloning proto-oncogenes and purifying cellular kinase activities in the 1980s. Ras-ERK and PI3K-mTOR were originally modeled as linear signaling conduits activated by different stimuli, yet even early experiments hinted that they might intersect to regulate each other and co-regulate downstream functions. The extent of this cross-talk and its significance in cancer the... Trends in Biochemical Sciences journals http://www.medworm.com/rss/comments.php?id=4798168 Thu, 28 Apr 2011 23:00:00 +0100 4798168 http://www.medworm.com/index.php?rid=4798169&cid=s_36134_60_f&fid=36134&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D21514168%26dopt%3DAbstract Authors: Sanchez R, Zhou MM PHD (plant homeodomain) zinc fingers are structurally conserved modules found in proteins that modify chromatin as well as mediate molecular interactions in gene transcription. The original discovery of their role in gene transcription is attributed to the recognition of lysine-methylated histone H3. Recent studies show that PHD fingers have a sophisticated histone sequence reading capacity that is modulated by the interplay between different histone modifications. These studies underscore the functional versatility of PHD fingers as epigenome readers that control gene expression through molecular recruitment of multiprotein complexes of chromatin regulators and transcription factors. Moreover, they reinforce the concept that evolutionary changes in amino ac... Trends in Biochemical Sciences journals http://www.medworm.com/rss/comments.php?id=4798169 Tue, 19 Apr 2011 23:00:00 +0100 4798169 http://www.medworm.com/index.php?rid=4745329&cid=s_36134_60_f&fid=36134&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D21497095%26dopt%3DAbstract Authors: Bowzard JB, Davis WG, Jeisy-Scott V, Ranjan P, Gangappa S, Fujita T, Sambhara S Retinoic-acid-inducible gene-I (RIG-I) is an important component of the innate immune response to many RNA viruses that limits viral replication until adaptive immunity becomes available to clear the infection. Upon binding to the nucleic acid genomes and replication intermediates of these viruses, RIG-I undergoes a complex activation process that involves post-translational modifications and structural rearrangements. Once activated, RIG-I upregulates well-studied signal transduction pathways that lead to the production of type-I interferons (IFNs) and a large variety of antiviral IFN-stimulated genes. Thus, an effective antiviral response is dependent on the interaction between pathogen-derived l... Trends in Biochemical Sciences journals http://www.medworm.com/rss/comments.php?id=4745329 Wed, 13 Apr 2011 23:00:00 +0100 4745329 http://www.medworm.com/index.php?rid=4745330&cid=s_36134_60_f&fid=36134&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D21497094%26dopt%3DAbstract Authors: Ndlovu MN, Denis H, Fuks F DNA methylation was the first epigenetic modification discovered. Until recently, comprehensive coverage of the composition and distribution of methylated cytosines across the genome was lacking. Technological advances, however, are providing methylation maps that can reveal the genomic distribution of DNA methylation in different cell states or phenotypes. The emerging picture includes extensive gene body methylation that is highly conserved in eukaryotes, the presence of DNA methylation in previously unappreciated sequence contexts, and the discovery of another modified DNA base, 5-hydroxymethylcytosine. These new data point to the role of DNA methylation both in gene silencing and gene activation; reconciliation of these seemingly contradictory ro... Trends in Biochemical Sciences journals http://www.medworm.com/rss/comments.php?id=4745330 Tue, 12 Apr 2011 23:00:00 +0100 4745330 http://www.medworm.com/index.php?rid=4745331&cid=s_36134_60_f&fid=36134&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D21482118%26dopt%3DAbstract Authors: Woehlbier U, Hetz C The accumulation of unfolded proteins in the endoplasmic reticulum (ER) triggers the unfolded protein response (UPR) through the activation of specialized sensors including inositol-requiring enzyme-1α (IRE1α). IRE1α signals by assembling a dynamic protein platform referred to as the UPRosome, where different modulator and adaptor proteins assemble to regulate the kinetics and amplitude of UPR effector responses. Conversely, chronic ER stress can cause apoptosis. Recent evidence indicates that several apoptosis-related proteins interact with IRE1α, regulating its prosurvival activities and performing a dual function in the regulation of cell death and adaptation to stress. Based on the increasing relevance of ER stress to the occurrence of diverse patho... Trends in Biochemical Sciences journals http://www.medworm.com/rss/comments.php?id=4745331 Wed, 06 Apr 2011 23:00:00 +0100 4745331 http://www.medworm.com/index.php?rid=4693116&cid=s_36134_60_f&fid=36134&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D21458998%26dopt%3DAbstract Authors: Gabius HJ, André S, Jiménez-Barbero J, Romero A, Solís D Lectins are carbohydrate-binding proteins which lack enzymatic activity on their ligand and are distinct from antibodies and free mono- and oligosaccharide sensor/transport proteins. Emerging insights into the functional dimension of lectin binding to cellular glycans have strongly contributed to the shaping of the 'sugar code'. Fittingly, over a dozen folds and a broad spectrum of binding site architecture, ranging from shallow grooves to deep pockets, have developed sugar-binding capacity. A central question is how the exquisite target specificity of endogenous lectins for certain cellular glycans can be explained. In this regard, affinity regulation is first systematically dissected into six levels. Experimentally,... Trends in Biochemical Sciences journals http://www.medworm.com/rss/comments.php?id=4693116 Thu, 31 Mar 2011 23:00:00 +0100 4693116 http://www.medworm.com/index.php?rid=4635159&cid=s_36134_60_f&fid=36134&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D21420300%26dopt%3DAbstract Authors: Klaholz BP When the ribosome machinery reaches a stop codon in the mRNA, protein synthesis stops, and nascent polypeptide release is catalysed by class-I release factors (RFs); class-II RFs then promote the release of class-I RFs. Cryo electron microscopy structures of termination complexes and crystal structures of isolated factors have provided insights into key concepts such as bridging of active sites on the ribosome, and conformational changes that regulate the termination process. Recent crystal structures of the four possible functional ribosome complexes that contain the class-I RFs and the three stop codons have uncovered the molecular mechanisms by which RF1/RF2 (i) both recognise UAA, but discriminate specifically between UAG and UGA, and (ii) catalyse peptide relea... Trends in Biochemical Sciences journals http://www.medworm.com/rss/comments.php?id=4635159 Thu, 17 Mar 2011 00:00:00 +0100 4635159 http://www.medworm.com/index.php?rid=4635160&cid=s_36134_60_f&fid=36134&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D21411326%26dopt%3DAbstract Authors: Fändrich M, Schmidt M, Grigorieff N The formation of amyloid fibrils, protofibrils and oligomers from the β-amyloid (Aβ) peptide represents a hallmark of Alzheimer's disease. Aβ-peptide-derived assemblies might be crucial for disease onset, but determining their atomic structures has proven to be a major challenge. Progress over the past 5years has yielded substantial new data obtained with improved methodologies including electron cryo-microscopy and NMR. It is now possible to resolve the global fibril topology and the cross-β sheet organization within protofilaments, and to identify residues that are crucial for stabilizing secondary structural elements and peptide conformations within specific assemblies. These data have significantly enhanced our understanding of the ... Trends in Biochemical Sciences journals http://www.medworm.com/rss/comments.php?id=4635160 Mon, 14 Mar 2011 00:00:00 +0100 4635160 http://www.medworm.com/index.php?rid=4571834&cid=s_36134_60_f&fid=36134&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D21388813%26dopt%3DAbstract Authors: Greaves J, Chamberlain LH S-palmitoylation is a reversible post-translational modification that occurs on diverse cellular proteins. Palmitoylation can affect proteins in many different ways, including regulating membrane attachment, intracellular trafficking, and membrane micro-localisation. Intracellular palmitoylation reactions are mediated by a family of recently identified aspartate-histidine-histidine-cysteine (DHHC) palmitoyl transferases. More than 20 DHHC proteins are encoded by mammalian genomes, and there is now a major effort to identify DHHC-substrate pairings and to determine how interaction specificity is encoded. Recent studies have highlighted how DHHC proteins regulate cell function and influence physiology and pathophysiology. PMID: 21388813 [PubMed - as... Trends in Biochemical Sciences journals http://www.medworm.com/rss/comments.php?id=4571834 Mon, 07 Mar 2011 00:00:00 +0100 4571834 http://www.medworm.com/index.php?rid=4571836&cid=s_36134_60_f&fid=36134&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D21353780%26dopt%3DAbstract Authors: Baker BM, Haynes CM Mitochondrial dysfunction has long been associated with the aging process and the onset of numerous diseases. Regulation of the complex protein-folding environment within the organelle is essential for maintaining efficient metabolic output. Over time, dysregulation of protein homeostasis arises through stress induced by the accumulation of reactive oxygen species and mutations in the mitochondrial genome introduced during replication. To preserve organelle function during biogenesis, remodeling and stress, quality control of mitochondrial proteins must be monitored by molecular chaperones and proteases stationed in the four compartments of the organelle. Here, we review mitochondrial protein quality control with a focus on organelle biogenesis and aging. ... Trends in Biochemical Sciences journals http://www.medworm.com/rss/comments.php?id=4571836 Thu, 24 Feb 2011 00:00:00 +0100 4571836 http://www.medworm.com/index.php?rid=4571835&cid=s_36134_60_f&fid=36134&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D21353781%26dopt%3DAbstract Authors: Weinfeld M, Mani RS, Abdou I, Aceytuno RD, Glover JN The termini of DNA strand breaks induced by internal and external factors often require processing before missing nucleotides can be replaced by DNA polymerases and the strands rejoined by DNA ligases. Polynucleotide kinase/phosphatase (PNKP) serves a crucial role in the repair of DNA strand breaks by catalyzing the restoration of 5'-phosphate and 3'-hydroxyl termini. It participates in several DNA repair pathways through interactions with other DNA repair proteins, notably XRCC1 and XRCC4. Recent studies have highlighted the physiological importance of PNKP in maintaining the genomic stability of normal tissues, particularly developing neural cells, as well as enhancing the resistance of cancer cells to genotoxic therapeuti... Trends in Biochemical Sciences journals http://www.medworm.com/rss/comments.php?id=4571835 Thu, 24 Feb 2011 00:00:00 +0100 4571835 http://www.medworm.com/index.php?rid=4517675&cid=s_36134_60_f&fid=36134&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D21345680%26dopt%3DAbstract Authors: Doncheva NT, Klein K, Domingues FS, Albrecht M The study of individual amino acid residues and their molecular interactions in protein structures is crucial for understanding structure-function relationships. Recent work has indicated that residue networks derived from 3D protein structures provide additional insights into the structural and functional roles of interacting residues. Here, we present the new software tools RINerator and RINalyzer for the automatized generation, 2D visualization, and interactive analysis of residue interaction networks, and highlight their use in different application scenarios. PMID: 21345680 [PubMed - as supplied by publisher] (Source: Trends in Biochemical Sciences) Trends in Biochemical Sciences journals http://www.medworm.com/rss/comments.php?id=4517675 Mon, 21 Feb 2011 00:00:00 +0100 4517675 http://www.medworm.com/index.php?rid=4517676&cid=s_36134_60_f&fid=36134&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D21315607%26dopt%3DAbstract Authors: Kato S, Yokoyama A, Fujiki R Members of the nuclear steroid/thyroid hormone receptor (NR) gene superfamily are DNA-binding transcription factors that regulate target genes in a spatiotemporal manner, depending on the promoter context. In vivo observations of ligand responses in NR-mediated gene regulation led to the identification of ligand-dependent coregulators that directly interact with NRs. Functional dissection of NR coregulators revealed that their transcriptional coregulation was linked to histone acetylation. However, recent work in the fields of reversible histone modification and chromatin remodeling indicates that histone-modifying enzymes, including histone methylases and chromatin remodelers, are potential transcriptional coregulators that interact directly and i... Trends in Biochemical Sciences journals http://www.medworm.com/rss/comments.php?id=4517676 Wed, 09 Feb 2011 00:00:00 +0100 4517676 http://www.medworm.com/index.php?rid=4517677&cid=s_36134_60_f&fid=36134&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D21269834%26dopt%3DAbstract Authors: Greenspan NS A major focus of modern biochemical, biophysical and cell biological research is the attribution of function to elements of structure: gene products, genes and higher-order cellular structures. Misunderstandings and controversies can arise in connection with such assignments, in part because of the logical complexity inherent in the relating of structure to function and the failure to distinguish clearly among the different senses in which function can be imputed to elements of structure. I explore distinct ways in which functions are connected to structures and factors that contribute to the context-dependence of such associations so that the multiple senses of function can be made explicit. PMID: 21269834 [PubMed - as supplied by publisher] (Source: Trends i... Trends in Biochemical Sciences journals http://www.medworm.com/rss/comments.php?id=4517677 Mon, 24 Jan 2011 00:00:00 +0100 4517677 http://www.medworm.com/index.php?rid=4517678&cid=s_36134_60_f&fid=36134&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D21256032%26dopt%3DAbstract We present a survey of the historical and modern phases of research in this area, focusing on the common and differing aspects of protein adenylylation. PMID: 21256032 [PubMed - as supplied by publisher] (Source: Trends in Biochemical Sciences) Trends in Biochemical Sciences journals http://www.medworm.com/rss/comments.php?id=4517678 Wed, 19 Jan 2011 00:00:00 +0100 4517678 http://www.medworm.com/index.php?rid=4393505&cid=s_36134_60_f&fid=36134&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D21242088%26dopt%3DAbstract Authors: Gilbert WV Ribosomes are highly conserved macromolecular machines that are responsible for protein synthesis in all living organisms. Work published in the past year has shown that changes to the ribosome core can affect the mechanism of translation initiation that is favored in the cell, which potentially leads to specific changes in the relative efficiencies with which different proteins are made. Here, I examine recent data from expression and proteomic studies that suggest that cells make slightly different ribosomes under different growth conditions, and discuss genetic evidence that such differences are functional. In particular, I argue that eukaryotic cells probably produce ribosomes that lack one or more core ribosomal proteins (RPs) under some conditions, and that co... Trends in Biochemical Sciences journals http://www.medworm.com/rss/comments.php?id=4393505 Sat, 15 Jan 2011 00:00:00 +0100 4393505 http://www.medworm.com/index.php?rid=4393506&cid=s_36134_60_f&fid=36134&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D21239176%26dopt%3DAbstract Authors: Smith HC APOBEC3G (A3G) is an effective cellular host defense factor under experimental conditions in which a functional form of the HIV-encoded protein Vif cannot be expressed. Wild-type Vif targets A3G for proteasomal degradation and when this happens, any host defense advantage A3G might provide is severely diminished or lost. Recent evidence cast doubt on the potency of A3G in host defense and suggested that it could, under some circumstances, promote the emergence of more virulent HIV strains. In this article, I suggest that it is time to recognize that A3G has the potential to act as a double agent. Future research should focus on understanding how cellular and viral regulatory mechanisms enable the antiviral function of A3G, and on the development of novel research reag... Trends in Biochemical Sciences journals http://www.medworm.com/rss/comments.php?id=4393506 Fri, 14 Jan 2011 00:00:00 +0100 4393506 http://www.medworm.com/index.php?rid=4393507&cid=s_36134_60_f&fid=36134&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D21227701%26dopt%3DAbstract Authors: Kaneko T, Sidhu SS, Li SS An important question in modular domain-peptide interactions, which play crucial roles in many biological processes, is how the diverse specificities exhibited by different members of a domain family are encoded in a common scaffold. Analysis of the Src homology (SH) 2 family has revealed that its specificity is determined, in large part, by the configuration of surface loops that regulate ligand access to binding pockets. In a distinct manner, SH3 domains employ loops for ligand recognition. The PDZ domain, in contrast, achieves specificity by co-evolution of binding-site residues. Thus, the conformational and sequence variability afforded by surface loops and binding sites provides a general mechanism by which to encode the wide spectrum of specific... Trends in Biochemical Sciences journals http://www.medworm.com/rss/comments.php?id=4393507 Mon, 10 Jan 2011 00:00:00 +0100 4393507 http://www.medworm.com/index.php?rid=4393508&cid=s_36134_60_f&fid=36134&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D21216149%26dopt%3DAbstract Authors: Anthis NJ, Campbell ID Integrins are essential adhesion receptors found on the surfaces of all metazoan cells. As regulators of cell migration and extracellular matrix assembly, these membrane-spanning heterodimers are critical for embryonic development, tissue repair and immune responses. Signals transmitted by integrins from outside to inside the cell promote cell survival and proliferation, but integrin affinity for extracellular ligands can also be controlled by intracellular cues. This bidirectional signaling is mediated by the short cytoplasmic tails of the two integrin subunits. Recent structural and functional studies of various integrin fragments and complexes between the cytoplasmic tails and intracellular proteins, such as talin, have provided new insight into the s... Trends in Biochemical Sciences journals http://www.medworm.com/rss/comments.php?id=4393508 Thu, 06 Jan 2011 00:00:00 +0100 4393508 http://www.medworm.com/index.php?rid=4311303&cid=s_36134_60_f&fid=36134&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D21146412%26dopt%3DAbstract Authors: Davey NE, Travé G, Gibson TJ Viruses, as obligate intracellular parasites, are the pathogens that have the most intimate relationship with their host, and as such, their genomes have been shaped directly by interactions with the host proteome. Every step of the viral life cycle, from entry to budding, is orchestrated through interactions with cellular proteins. Accordingly, viruses will hijack and manipulate these proteins utilising any achievable mechanism. Yet, the extensive interactions of viral proteomes has yielded a conundrum: how do viruses commandeer so many diverse pathways and processes, given the obvious spatial constraints imposed by their compact genomes? One important approach is slowly being revealed, the extensive mimicry of host protein short linear motifs (S... Trends in Biochemical Sciences journals http://www.medworm.com/rss/comments.php?id=4311303 Thu, 09 Dec 2010 00:00:00 +0100 4311303 http://www.medworm.com/index.php?rid=4246831&cid=s_36134_60_f&fid=36134&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D21130657%26dopt%3DAbstract Authors: Soto C Forty-three years have passed since it was first proposed that a protein could be the sole component of the infectious agent responsible for the enigmatic prion diseases. Many discoveries have strongly supported the prion hypothesis, but only recently has this once heretical hypothesis been widely accepted by the scientific community. In the past 3 years, researchers have achieved the 'Holy Grail' demonstration that infectious material can be generated in vitro using completely defined components. These breakthroughs have proven that a misfolded protein is the active component of the infectious agent, and that propagation of the disease and its unique features depend on the self-replication of the infectious folding of the prion protein. In spite of these important disc... Trends in Biochemical Sciences journals http://www.medworm.com/rss/comments.php?id=4246831 Fri, 03 Dec 2010 00:00:00 +0100 4246831 http://www.medworm.com/index.php?rid=4182537&cid=s_36134_60_f&fid=36134&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D21075636%26dopt%3DAbstract Authors: Kim GW, Yang XJ Recent proteomic studies reveal that 5-10% of mammalian and bacterial proteins undergo lysine acetylation, a post-translational modification that adds an acetyl group to the ɛ-amino group of lysine residues. Many of these proteins are not canonical targets, such as histones and transcription factors, suggesting that this modification plays a much wider role than previously appreciated. These studies also suggest that lysine acetylomes are at least comparable with (if not larger than) phosphoproteomes. Although many of the newly identified acetylation events still require validation, they constitute an important framework for further research and the development of new drugs useful in treating a variety of pathologies. Herein, we summarize these proteomic studi... Trends in Biochemical Sciences journals http://www.medworm.com/rss/comments.php?id=4182537 Fri, 12 Nov 2010 00:00:00 +0100 4182537 http://www.medworm.com/index.php?rid=4146568&cid=s_36134_60_f&fid=36134&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D21055949%26dopt%3DAbstract Authors: Kang HJ, Baker EN The recent discovery of intramolecular isopeptide bonds formed between lysine and asparagine residues in certain bacterial cell-surface proteins represents a new component in nature's toolbox for stabilising proteins. Although isopeptide bonds are well known as intermolecular crosslinks in processes such as ubiquitylation, these intramolecular isopeptide bonds form autocatalytically during protein folding, as the reacting groups are brought together in a hydrophobic environment. First identified in the Ig-like pilin subunits of Gram-positive bacterial pili, these internal crosslinks provide stabilisation against chemical, thermal and mechanical stress and provide new opportunities for applications in biotechnology. The crucial role of structural biology and m... Trends in Biochemical Sciences journals http://www.medworm.com/rss/comments.php?id=4146568 Wed, 03 Nov 2010 00:00:00 +0100 4146568 http://www.medworm.com/index.php?rid=4121752&cid=s_36134_60_f&fid=36134&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D21030261%26dopt%3DAbstract Authors: Peel S, Macheboeuf P, Martinelli N, Weissenhorn W Endosomal sorting complexes required for transport (ESCRT) have been implicated in topologically similar but diverse cellular and pathological processes including multivesicular body (MVB) biogenesis, cytokinesis and enveloped virus budding. Although receptor sorting at the endosomal membrane producing MVBs employs the regulated assembly of ESCRT-0 followed by ESCRT-I, -II, -III and the vacuolar protein sorting (VPS)4 complex, other ESCRT-catalyzed processes require only a subset of complexes which commonly includes ESCRT-III and VPS4. Recent progress has shed light on the pathway of ESCRT assembly and highlights the separation of tasks of different ESCRT complexes and associated partners. The emerging picture suggests that amo... Trends in Biochemical Sciences journals http://www.medworm.com/rss/comments.php?id=4121752 Tue, 26 Oct 2010 00:00:00 +0100 4121752 http://www.medworm.com/index.php?rid=4107093&cid=s_36134_60_f&fid=36134&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D20971646%26dopt%3DAbstract Authors: Taylor SS, Kornev AP Eukayotic protein kinases evolved as a family of highly dynamic molecules with strictly organized internal architecture. A single hydrophobic F-helix serves as a central scaffold for assembly of the entire molecule. Two non-consecutive hydrophobic structures termed "spines" anchor all the elements important for catalysis to the F-helix. They make firm, but flexible, connections within the molecule, providing a high level of internal dynamics of the protein kinase. During the course of evolution, protein kinases developed a universal regulatory mechanism associated with a large activation segment that can be dynamically folded and unfolded in the course of cell functioning. Protein kinases thus represent a unique, highly dynamic, and precisely regulated set... Trends in Biochemical Sciences journals http://www.medworm.com/rss/comments.php?id=4107093 Thu, 21 Oct 2010 23:00:00 +0100 4107093 http://www.medworm.com/index.php?rid=4075246&cid=s_36134_60_f&fid=36134&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D20947357%26dopt%3DAbstract Authors: Flynn RL, Zou L The integrity of the genome is constantly challenged by intrinsic and extrinsic genotoxic stresses that damage DNA. The cellular responses to DNA damage are orchestrated by DNA damage signaling pathways, also known as DNA damage checkpoints. These signaling pathways play crucial roles in detecting DNA damage, regulating DNA repair and coordinating DNA repair with other cellular processes. In vertebrates, the ATM- and Rad3-related (ATR) kinase plays a key role in the response to a broad spectrum of DNA damage and DNA replication stress. Here, we will discuss the recent findings on how ATR is activated by DNA damage and how it protects the genome against interference with DNA replication. PMID: 20947357 [PubMed - as supplied by publisher] (Source: Trends in B... Trends in Biochemical Sciences journals http://www.medworm.com/rss/comments.php?id=4075246 Mon, 11 Oct 2010 23:00:00 +0100 4075246 http://www.medworm.com/index.php?rid=4061155&cid=s_36134_60_f&fid=36134&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D20934340%26dopt%3DAbstract Authors: Guan KL, Xiong Y Extensive studies during the past four decades have identified important roles for lysine acetylation in the regulation of nuclear transcription. Recent proteomic analyses on protein acetylation uncovered a large number of acetylated proteins in the cytoplasm and mitochondria, including most enzymes involved in intermediate metabolism. Acetylation regulates metabolic enzymes by multiple mechanisms, including via enzymatic activation or inhibition, and by influencing protein stability. Conversely, non-nuclear NAD(+)-dependent sirtuin deacetylases can regulate cellular and organismal metabolism, possibly through direct deacetylation of metabolic enzymes. Furthermore, acetylation of metabolic enzymes is highly conserved from prokaryotes to eukaryotes. Given the f... Trends in Biochemical Sciences journals http://www.medworm.com/rss/comments.php?id=4061155 Wed, 06 Oct 2010 23:00:00 +0100 4061155 http://www.medworm.com/index.php?rid=4061156&cid=s_36134_60_f&fid=36134&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D20926298%26dopt%3DAbstract Authors: Fussner E, Ching RW, Bazett-Jones DP Eukaryotic genomes must be folded and compacted to fit within the restricted volume of the nucleus. According to the current paradigm, strings of nucleosomes, termed 10nm chromatin fibers, constitute the template of transcriptionally active genomic material. The majority of the genome is maintained in a silenced state through higher-order chromatin assemblies, based on the 30nm chromatin fiber, which excludes activating regulatory factors. New experimental approaches, however, including chromatin conformation capture and cryo-electron microscopy, call into question the in situ evidence for the 30nm chromatin fiber. We suggest that the organization of the genome based on 10nm chromatin fibers is sufficient to describe the complexities of nuc... Trends in Biochemical Sciences journals http://www.medworm.com/rss/comments.php?id=4061156 Sun, 03 Oct 2010 23:00:00 +0100 4061156 http://www.medworm.com/index.php?rid=4040664&cid=s_36134_60_f&fid=36134&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D20888775%26dopt%3DAbstract Authors: Bolanos-Garcia VM, Blundell TL The multidomain protein kinases BUB1 and BUBR1 (Mad3 in yeast, worms and plants) are central components of the mitotic checkpoint for spindle assembly (SAC). This evolutionarily conserved and essential self-monitoring system of the eukaryotic cell cycle ensures the high fidelity of chromosome segregation by delaying the onset of anaphase until all chromosomes are properly bi-oriented on the mitotic spindle. Despite their amino acid sequence conservation and similar domain organization, BUB1 and BUBR1 perform different functions in the SAC. Recent structural information provides crucial molecular insights into the regulation and recognition of BUB1 and BUBR1, and a solid foundation to dissect the roles of these proteins in the control of chromosom... Trends in Biochemical Sciences journals http://www.medworm.com/rss/comments.php?id=4040664 Wed, 29 Sep 2010 23:00:00 +0100 4040664 http://www.medworm.com/index.php?rid=4025444&cid=s_36134_60_f&fid=36134&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D20880711%26dopt%3DAbstract Authors: Washburn MP Proteomic analysis of biological samples plays an increasing role in modern research. Although the application of proteomics technologies varies across many disciplines, proteomics largely is a tool for discovery that then leads to novel hypotheses. In recent years, new methods and technologies have been developed and applied in many areas of proteomics, and there is a strong push towards using proteomics in a quantitative manner. Indeed, mass spectrometry-based, quantitative proteomics approaches have been applied to great success in a variety of biochemical studies. In particular, the use of quantitative proteomics provides new insights into protein complexes and post-translational modifications and leads to the generation of novel insights into these important b... Trends in Biochemical Sciences journals http://www.medworm.com/rss/comments.php?id=4025444 Sun, 26 Sep 2010 23:00:00 +0100 4025444 http://www.medworm.com/index.php?rid=4025447&cid=s_36134_60_f&fid=36134&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D20870410%26dopt%3DAbstract Authors: Bunney TD, Katan M Phosphoinositide-specific phospholipase C (PLC) enzymes are common signalling components linked to the activation of most cellular receptors. All PLC families are complex, modular, multi-domain proteins and together cover a broad spectrum of regulatory interactions, including direct binding to G protein subunits, small GTPases from Rho and Ras families, receptor and non-receptor tyrosine kinases and lipid components of cellular membranes. Recent structural determinations of PLC components and their complexes with regulatory proteins and direct mechanistic studies, together with earlier work, have provided the foundation to propose molecular mechanisms that stringently regulate PLC activity. PMID: 20870410 [PubMed - as supplied by publisher] (Source: Tren... Trends in Biochemical Sciences journals http://www.medworm.com/rss/comments.php?id=4025447 Thu, 23 Sep 2010 23:00:00 +0100 4025447 http://www.medworm.com/index.php?rid=4025446&cid=s_36134_60_f&fid=36134&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D20870411%26dopt%3DAbstract Authors: Worthington JJ, Klementowicz JE, Travis MA Transforming growth factor beta (TGFβ) controls numerous cellular responses, including proliferation, differentiation, apoptosis and migration. This cytokine is produced by many different cell types and has been implicated in the pathogenesis of many diseases, ranging from autoimmune disorders and infectious diseases to fibrosis and cancer. However, TGFβ is always produced as an inactive complex that must be activated to enable binding to its receptor and subsequent function. Recent evidence highlights a crucial role for members of the integrin receptor family in controlling the activation of TGFβ. These pathways are important in human health and disease, and new insights into the biochemical mechanisms that allow integrins t... Trends in Biochemical Sciences journals http://www.medworm.com/rss/comments.php?id=4025446 Thu, 23 Sep 2010 23:00:00 +0100 4025446 http://www.medworm.com/index.php?rid=4025445&cid=s_36134_60_f&fid=36134&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D20870412%26dopt%3DAbstract Authors: Pitson SM Bioactive sphingolipids, including ceramide, sphingosine and sphingosine 1-phosphate are important regulators of many cellular processes, including cell survival, proliferation, differentiation, migration and immune responses. Although the levels of these bioactive sphingolipids are regulated by complex pathways subject to spatial and temporal control, the sphingosine kinases have emerged as critical central regulators of this system and, as a consequence, they have received substantial recent attention as potential therapeutic targets for cancer and a range of other conditions. Deciphering the molecular mechanisms that regulate both the activity and subcellular localization of these enzymes is vital for understanding the control of bioactive sphingolipid generation ... Trends in Biochemical Sciences journals http://www.medworm.com/rss/comments.php?id=4025445 Thu, 23 Sep 2010 23:00:00 +0100 4025445 http://www.medworm.com/index.php?rid=4025448&cid=s_36134_60_f&fid=36134&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D20863707%26dopt%3DAbstract Authors: Verdin E, Hirschey MD, Finley LW, Haigis MC Sirtuins are a highly conserved family of proteins whose activity can prolong the lifespan of model organisms such as yeast, worms and flies. Mammals contain seven sirtuins (SIRT1-7) that modulate distinct metabolic and stress response pathways. Three sirtuins, SIRT3, SIRT4 and SIRT5, are located in the mitochondria, dynamic organelles that function as the primary site of oxidative metabolism and play crucial roles in apoptosis and intracellular signaling. Recent findings have shed light on how the mitochondrial sirtuins function in the control of basic mitochondrial biology, including energy production, metabolism, apoptosis and intracellular signaling. PMID: 20863707 [PubMed - as supplied by publisher] (Source: Trends in Bioche... Trends in Biochemical Sciences journals http://www.medworm.com/rss/comments.php?id=4025448 Sun, 19 Sep 2010 23:00:00 +0100 4025448 http://www.medworm.com/index.php?rid=3961477&cid=s_36134_60_f&fid=36134&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D20813532%26dopt%3DAbstract Authors: Jankowsky E RNA helicases are ubiquitous, highly conserved enzymes that participate in nearly all aspects of RNA metabolism. These proteins bind or remodel RNA or RNA-protein complexes in an ATP-dependent fashion. How RNA helicases physically perform their cellular tasks has been a longstanding question, but in recent years, intriguing models have started to link structure, mechanism and biological function for some RNA helicases. This review outlines our current view on major structural and mechanistic themes of RNA helicase function, and on emerging physical models for cellular roles of these enzymes. PMID: 20813532 [PubMed - as supplied by publisher] (Source: Trends in Biochemical Sciences) Trends in Biochemical Sciences journals http://www.medworm.com/rss/comments.php?id=3961477 Mon, 30 Aug 2010 23:00:00 +0100 3961477 http://www.medworm.com/index.php?rid=3961478&cid=s_36134_60_f&fid=36134&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D20810284%26dopt%3DAbstract Authors: Parekh AB A rise in cytosolic Ca(2+) concentration is used as a universal signalling mechanism to control biological processes as diverse as exocytosis, contraction, cell growth and cell death. Ca(2+) signals are often presented to cells in the form of Ca(2+) oscillations, with signalling information encoded in both amplitude and frequency of the Ca(2+) spikes. Recent studies have revealed that the sub-cellular spatial profile of the Ca(2+) oscillation is also important in activating cellular responses, thereby suggesting a new mechanism for extracting information from the ubiquitous Ca(2+) oscillation. PMID: 20810284 [PubMed - as supplied by publisher] (Source: Trends in Biochemical Sciences) Trends in Biochemical Sciences journals http://www.medworm.com/rss/comments.php?id=3961478 Sun, 29 Aug 2010 23:00:00 +0100 3961478 http://www.medworm.com/index.php?rid=3961479&cid=s_36134_60_f&fid=36134&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D20801044%26dopt%3DAbstract Authors: Málnási-Csizmadia A, Kovács M Actomyosin powers muscle contraction and various cellular activities, including cell division, differentiation, intracellular transport and sensory functions. Despite their crucial roles, key aspects of force generation have remained elusive. To perform efficient force generation, the powerstroke must occur while myosin is bound to actin. Paradoxically, this process must be initiated when myosin is in a very low actin-affinity state. Recent results shed light on a kinetic pathway selection mechanism whereby the actin-induced activation of the swing of myosin's lever enables efficient mechanical functioning. Structural elements and biochemical principles involved in this mechanism are conserved among various NTPase-effector (e.g. kinesin-m... Trends in Biochemical Sciences journals http://www.medworm.com/rss/comments.php?id=3961479 Wed, 25 Aug 2010 23:00:00 +0100 3961479 http://www.medworm.com/index.php?rid=3911436&cid=s_36134_60_f&fid=36134&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D20729089%26dopt%3DAbstract Authors: Tennen RI, Chua KF Saccharomyces cerevisiae Sir2 is an NAD(+)-dependent histone deacetylase that links chromatin silencing to genomic stability, cellular metabolism and lifespan regulation. In mice, deficiency for the Sir2 family member SIRT6 leads to genomic instability, metabolic defects and degenerative pathologies associated with aging. Until recently, SIRT6 was an orphan enzyme whose catalytic activity and substrates were unclear. However, new mechanistic insights have come from the discovery that SIRT6 is a highly substrate-specific histone deacetylase that promotes proper chromatin function in several physiologic contexts, including telomere and genome stabilization, gene expression and DNA repair. By maintaining both the integrity and the expression of the mammalian ge... Trends in Biochemical Sciences journals http://www.medworm.com/rss/comments.php?id=3911436 Thu, 19 Aug 2010 23:00:00 +0100 3911436 http://www.medworm.com/index.php?rid=3911435&cid=s_36134_60_f&fid=36134&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D20729090%26dopt%3DAbstract Authors: Cukkemane A, Seifert R, Kaupp UB Ion channels gated by cyclic nucleotides serve multiple functions in sensory signaling in diverse cell types ranging from neurons to sperm. Newly discovered members from bacteria and marine invertebrates provide a wealth of structural and functional information on this channel family. A hallmark of classical tetrameric cyclic-nucleotide-gated channels is their cooperative activation by binding of several ligands. By contrast, the new members seem to be uncooperative, and binding of a single ligand molecule suffices to open these channels. These new findings provide a fresh look at the mechanism of allosteric activation of ion channels. PMID: 20729090 [PubMed - as supplied by publisher] (Source: Trends in Biochemical Sciences) Trends in Biochemical Sciences journals http://www.medworm.com/rss/comments.php?id=3911435 Thu, 19 Aug 2010 23:00:00 +0100 3911435 http://www.medworm.com/index.php?rid=3911442&cid=s_36134_60_f&fid=36134&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D20728359%26dopt%3DAbstract Authors: Loenarz C, Schofield CJ Pioneering work in the 1960s defined prolyl and lysyl hydroxylations as physiologically important oxygenase-catalyzed modifications in collagen biosynthesis; subsequent studies demonstrated that extracellular epidermal growth factor-like domains were hydroxylated at aspartyl and asparaginyl residues. More recent work on the hypoxia-sensing mechanism in animals has shown that prolyl and asparaginyl hydroxylation of the hypoxia-inducible transcription factor play central roles in sensing hypoxia, by regulating protein-protein interactions in an oxygen-dependent manner. The collective results imply that protein hydroxylation is more common than previously perceived. Most protein hydroxylases employ Fe(II) as a cofactor, and 2-oxoglutarate and oxygen as co-... Trends in Biochemical Sciences journals http://www.medworm.com/rss/comments.php?id=3911442 Wed, 18 Aug 2010 23:00:00 +0100 3911442 http://www.medworm.com/index.php?rid=3911441&cid=s_36134_60_f&fid=36134&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D20728360%26dopt%3DAbstract Authors: Corcos D PMID: 20728360 [PubMed - as supplied by publisher] (Source: Trends in Biochemical Sciences) Trends in Biochemical Sciences journals http://www.medworm.com/rss/comments.php?id=3911441 Wed, 18 Aug 2010 23:00:00 +0100 3911441 http://www.medworm.com/index.php?rid=3911438&cid=s_36134_60_f&fid=36134&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D20728361%26dopt%3DAbstract Authors: Feige MJ, Hendershot LM, Buchner J PMID: 20728361 [PubMed - as supplied by publisher] (Source: Trends in Biochemical Sciences) Trends in Biochemical Sciences journals http://www.medworm.com/rss/comments.php?id=3911438 Wed, 18 Aug 2010 23:00:00 +0100 3911438 http://www.medworm.com/index.php?rid=3911437&cid=s_36134_60_f&fid=36134&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D20728362%26dopt%3DAbstract Authors: Scherz-Shouval R, Elazar Z Reactive oxygen species (ROS) are small and highly reactive molecules that can oxidize proteins, lipids and DNA. When tightly controlled, ROS serve as signaling molecules by modulating the activity of the oxidized targets. Accumulating data point to an essential role for ROS in the activation of autophagy. Be the outcome of autophagy survival or death and the initiation conditions starvation, pathogens or death receptors, ROS are invariably involved. The nature of this involvement, however, remains unclear. Moreover, although connections between ROS and autophagy are observed in diverse pathological conditions, the mode of activation of autophagy and its potential protective role remain incompletely understood. Notably, recent advances in the field o... Trends in Biochemical Sciences journals http://www.medworm.com/rss/comments.php?id=3911437 Wed, 18 Aug 2010 23:00:00 +0100 3911437 http://www.medworm.com/index.php?rid=3911443&cid=s_36134_60_f&fid=36134&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D20727772%26dopt%3DAbstract Authors: Chari A, Fischer U Molecular machines are supramolecular assemblies of biomolecules (proteins, RNA and/or DNA) that facilitate a diversity of biological tasks in the cells of all organisms. How these complex structures are built within the crowded cellular environment is, therefore, a central question in the biological sciences. Recent studies on spliceosomal uridine-rich small nuclear ribonucleoproteins (snRNPs) have unveiled cellular assembly strategies for RNA-protein complexes. snRNPs form in vivo by the coordinated action of an elaborate assembly line consisting of assembly chaperones, scaffolding proteins and catalysts. These newly discovered strategies exhibit similarities to those employed by protein complexes such as ribulose-1,5-bisphosphate-carboxylase (Rubisco) and... Trends in Biochemical Sciences journals http://www.medworm.com/rss/comments.php?id=3911443 Tue, 17 Aug 2010 23:00:00 +0100 3911443 http://www.medworm.com/index.php?rid=3911444&cid=s_36134_60_f&fid=36134&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D20724162%26dopt%3DAbstract Authors: Cross TA, Sharma M, Yi M, Zhou HX Membrane protein structures are stabilized by weak interactions and are influenced by additional interactions with the solubilizing environment. Structures of influenza virus A M2 protein, a proven drug target, have been determined in three different environments, thus providing a unique opportunity to assess environmental influences. Structures determined in detergents and detergent micelles can have notable differences from those determined in lipid bilayers. These differences make it imperative to validate membrane protein structures. PMID: 20724162 [PubMed - as supplied by publisher] (Source: Trends in Biochemical Sciences) Trends in Biochemical Sciences journals http://www.medworm.com/rss/comments.php?id=3911444 Mon, 16 Aug 2010 23:00:00 +0100 3911444 http://www.medworm.com/index.php?rid=3911445&cid=s_36134_60_f&fid=36134&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D20719516%26dopt%3DAbstract Authors: Stewart M The nuclear export of mRNA, in which Mex67-Mtr2 mediates movement of mature transcripts through nuclear pores, represents the culmination of the nuclear portion of the gene expression pathway. Nuclear export is closely integrated with transcription and processing, and is based on forming a messenger ribonucleoprotein (mRNP) export complex in the nucleus that is able to diffuse back and forth through the pores. Directionality is imposed by remodelling of the mRNP in the cytoplasm, thereby removing key transport-related proteins and preventing its return to the nucleus. The nuclear and cytoplasmic steps of this pathway, in which Mex67-Mtr2 and Nab2 are added and removed, are crucial, and both involve remodelling of the mRNP, which is mediated by DEAD-box helicases toge... Trends in Biochemical Sciences journals http://www.medworm.com/rss/comments.php?id=3911445 Sun, 15 Aug 2010 23:00:00 +0100 3911445 http://www.medworm.com/index.php?rid=3881970&cid=s_36134_60_f&fid=36134&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D20708406%26dopt%3DAbstract Authors: Hiller S, Abramson J, Mannella C, Wagner G, Zeth K The most abundant protein of the mitochondrial outer membrane is the voltage-dependent anion channel (VDAC), which facilitates the exchange of ions and molecules between mitochondria and cytosol and is regulated by interactions with other proteins and small molecules. VDAC has been studied extensively for more than three decades, and last year three independent investigations revealed a structure of VDAC-1 exhibiting 19 transmembrane beta-strands, constituting a unique structural class of beta-barrel membrane proteins. Here, we provide a historical perspective on VDAC research and give an overview of the experimental design used to obtain these structures. Furthermore, we validate the protein refolding approach and summarize t... Trends in Biochemical Sciences journals http://www.medworm.com/rss/comments.php?id=3881970 Tue, 10 Aug 2010 23:00:00 +0100 3881970 http://www.medworm.com/index.php?rid=3833606&cid=s_36134_60_f&fid=36134&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D20685123%26dopt%3DAbstract Authors: Barth TK, Imhof A Most multi-cellular organisms adopt a specific gene expression pattern during cellular differentiation. Once established, this pattern is frequently maintained over several cell divisions despite the fact that the initiating signal is no longer present. Differential packaging into chromatin is one such mechanism that allows fixation of transcriptional activity. Recent genome-wide studies demonstrate that actively transcribed regions are characterized by a specific modification pattern of histones, the main protein component of chromatin. These findings support the hypothesis that a histone code uses histone post-translational modifications to stably inscribe particular chromatin structures into the genome. Experiments on the dynamics of histone modifications ... Trends in Biochemical Sciences journals http://www.medworm.com/rss/comments.php?id=3833606 Sun, 01 Aug 2010 23:00:00 +0100 3833606 http://www.medworm.com/index.php?rid=3776779&cid=s_36134_60_f&fid=36134&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D20638285%26dopt%3DAbstract Authors: Kozlov MM, McMahon HT, Chernomordik LV Cellular membranes undergo continuous remodeling. Exocytosis and endocytosis, mitochondrial fusion and fission, entry of enveloped viruses into host cells and release of the newly assembled virions, cell-to-cell fusion and cell division, and budding and fusion of transport carriers all proceed via topologically similar, but oppositely ordered, membrane rearrangements. The biophysical similarities and differences between membrane fusion and fission become more evident if we disregard the accompanying biological processes and consider only remodeling of the lipid bilayer. The forces that determine the bilayer propensity to undergo fusion or fission come from proteins and in most cases from membrane-bound proteins. In this review, we conside... Trends in Biochemical Sciences journals http://www.medworm.com/rss/comments.php?id=3776779 Wed, 14 Jul 2010 23:00:00 +0100 3776779 http://www.medworm.com/index.php?rid=3758874&cid=s_36134_60_f&fid=36134&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D20621482%26dopt%3DAbstract Authors: Waksman G, Fronzes R In Gram-negative bacteria, type IV secretion (T4S) systems form ATP-powered complexes that span the entire cellular envelope and secrete a wide variety of substrates from single proteins to protein-protein and protein-DNA complexes. Recent structural data, namely the electron microscopy structure of the T4S core complex and the atomic-resolution structure of its outer-membrane pore, have profoundly altered our understanding of T4S architecture and mechanisms. PMID: 20621482 [PubMed - as supplied by publisher] (Source: Trends in Biochemical Sciences) Trends in Biochemical Sciences journals http://www.medworm.com/rss/comments.php?id=3758874 Thu, 08 Jul 2010 23:00:00 +0100 3758874 http://www.medworm.com/index.php?rid=3758873&cid=s_36134_60_f&fid=36134&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D20621483%26dopt%3DAbstract Authors: Wimmer R, Baccarini M The three-tiered Raf-MEK-ERK kinase module is activated downstream of Ras and has been traditionally linked to cellular proliferation. Mammals have three Raf, two Mek and two Erk genes. Recently, the analysis of protein-protein interactions in the pathway has begun to provide a rationale for the redundancy within each tier. New results show that the MEK-ERK-activating unit consists of Raf hetero- and homodimers; downstream of Raf, MEK1-MEK2 heterodimers and ERK dimers are required for temporal and spatial pathway regulation. Finally, C-Raf mediates pathway crosstalk downstream of Ras by directly binding to and inhibiting kinases engaged in other signaling cascades. Given the roles of these interactions in tumorigenesis, their study will provide new opport... Trends in Biochemical Sciences journals http://www.medworm.com/rss/comments.php?id=3758873 Thu, 08 Jul 2010 23:00:00 +0100 3758873 http://www.medworm.com/index.php?rid=3741623&cid=s_36134_60_f&fid=36134&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D20598891%26dopt%3DAbstract Authors: Sudol M, Harvey KF Metazoans have evolved several pathways to regulate the size of organs and ultimately that of organisms. One such pathway is known as Salvador-Warts-Hippo, or simply Hippo. Research on the Hippo pathway has grown exponentially during the past 8 years, revealing a complex signaling network. Intriguingly, within this complexity, there are levels of modularity. One level of modularity is represented by the unusually wide occurrence of the WW module in the Hippo core kinase cassette, the upstream regulatory components and the downstream nuclear proteins. We suggest that the prevalence of WW domain-mediated complexes in the Hippo pathway should facilitate its molecular analysis and aid prediction of new pathway components. PMID: 20598891 [PubMed - as supplied... Trends in Biochemical Sciences journals http://www.medworm.com/rss/comments.php?id=3741623 Wed, 30 Jun 2010 23:00:00 +0100 3741623 http://www.medworm.com/index.php?rid=3691190&cid=s_36134_60_f&fid=36134&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D20561791%26dopt%3DAbstract Authors: Gonçalves SA, Matos JE, Outeiro TF Several neurodegenerative diseases are characterized by the accumulation of misfolded and aggregated proteins, which lead to neurotoxicity. However, the nature of those toxic species is controversial. Developments in optical microscopy and live-cell imaging are essential in providing crucial insight into the molecular mechanisms involved. In particular, the technique of bimolecular fluorescence complementation (BiFC) represents a remarkable improvement for observing protein-protein interactions within living cells. Unlike other techniques, BiFC provides spatial and temporal resolution and can be carried out in a physiological environment. Among other applications, BiFC has been used to study molecular determinants of oligomerization in neu... Trends in Biochemical Sciences journals http://www.medworm.com/rss/comments.php?id=3691190 Wed, 16 Jun 2010 23:00:00 +0100 3691190 http://www.medworm.com/index.php?rid=3672802&cid=s_36134_60_f&fid=36134&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D20554446%26dopt%3DAbstract Authors: Daniel RM, Danson MJ The two established thermal properties of enzymes are their activation energy and their thermal stability, but experimental data do not match the expectations of these two properties. The recently proposed Equilibrium Model (EM) provides a quantitative explanation of enzyme thermal behaviour under reaction conditions by introducing an inactive (but not denatured) intermediate in rapid equilibrium with the active form. It was formulated as a mathematical model, and fits the known experimental data. Importantly, the EM gives rise to a number of new insights into the molecular basis of the temperature control of enzymes and their environmental adaptation and evolution, it is consistent with active site properties, and it has fundamental implications for enzym... Trends in Biochemical Sciences journals http://www.medworm.com/rss/comments.php?id=3672802 Sun, 13 Jun 2010 23:00:00 +0100 3672802 http://www.medworm.com/index.php?rid=3672801&cid=s_36134_60_f&fid=36134&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D20554447%26dopt%3DAbstract Authors: Hentze MW, Preiss T 'Classic' enzymes carry out the housekeeping functions of intermediary metabolism. The past decades have seen a steady trickle of reports of several of these enzymes 'moonlighting' as RNA-binding proteins. Although evidence for a physiological role for RNA binding is strong in a few individual examples, no systematic concept has been proposed for the overall phenomenon. We suggest that these diverse observations might herald the existence of currently hidden post-transcriptional regulatory networks between intermediary metabolism and gene expression based on RNA, enzyme and metabolite interactions. We briefly summarize the evidence in support of such networks and discuss how current approaches can be employed for systematic analyses and integration into our... Trends in Biochemical Sciences journals http://www.medworm.com/rss/comments.php?id=3672801 Sun, 13 Jun 2010 23:00:00 +0100 3672801 http://www.medworm.com/index.php?rid=3672803&cid=s_36134_60_f&fid=36134&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D20542436%26dopt%3DAbstract Authors: Tidow H, Aperia A, Nissen P Na(+),K(+)-ATPase (NKA) has a fundamental role in ion transport across the plasma membrane of animal cells and uses approximately 50% of brain energy consumption. Recent work has uncovered additional roles for NKA in signal transduction. How might such different functions of the sodium-potassium pump be connected and regulated? We envision an integrated model of ion pumping and signaling, considering in particular the recently discovered regulation of the sodium-potassium pump by agrin, a protein that is cleaved specifically by neurotrypsin at the synapse. Based on the recently solved structure of NKA and sequence analysis, we propose a molecular model for the agrin-NKA interaction, in which agrin displaces the NKA beta-subunit and exploits the ouab... Trends in Biochemical Sciences journals http://www.medworm.com/rss/comments.php?id=3672803 Thu, 10 Jun 2010 23:00:00 +0100 3672803 http://www.medworm.com/index.php?rid=3672805&cid=s_36134_60_f&fid=36134&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D20541942%26dopt%3DAbstract Authors: Cerenius L, Kawabata SI, Lee BL, Nonaka M, Söderhäll K Bacteria and other potential pathogens are cleared rapidly from the body fluids of invertebrates by the immediate response of the innate immune system. Proteolytic cascades, following their initiation by pattern recognition proteins, control several such reactions, notably coagulation, melanisation, activation of the Toll receptor and complement-like reactions. However, there is considerable variation among invertebrates and these cascades, although widespread, are not present in all phyla. In recent years, significant progress has been made in identifying and characterizing these cascades in insects. Notably, recent work has identified several connections and shared principles among the different pathways, suggestin... Trends in Biochemical Sciences journals http://www.medworm.com/rss/comments.php?id=3672805 Wed, 09 Jun 2010 23:00:00 +0100 3672805 http://www.medworm.com/index.php?rid=3672804&cid=s_36134_60_f&fid=36134&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D20541943%26dopt%3DAbstract Authors: Csermely P, Palotai R, Nussinov R Single molecule and NMR measurements of protein dynamics increasingly uncover the complexity of binding scenarios. Here, we describe an extended conformational selection model that embraces a repertoire of selection and adjustment processes. Induced fit can be viewed as a subset of this repertoire, whose contribution is affected by the bond types stabilizing the interaction and the differences between the interacting partners. We argue that protein segments whose dynamics are distinct from the rest of the protein ('discrete breathers') can govern conformational transitions and allosteric propagation that accompany binding processes and, as such, might be more sensitive to mutational events. Additionally, we highlight the dynamic complexity of ... Trends in Biochemical Sciences journals http://www.medworm.com/rss/comments.php?id=3672804 Wed, 09 Jun 2010 23:00:00 +0100 3672804 http://www.medworm.com/index.php?rid=3672807&cid=s_36134_60_f&fid=36134&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D20541422%26dopt%3DAbstract Authors: Kumar P, Ziegler A, Grahn A, Hee CS, Ziegler A The ability to embed interactive three-dimensional (3D) models into electronic publications in portable document format (PDF) greatly enhances the accessibility of molecular structures. Here, we report advances in this procedure and discuss what is needed to develop this format into a truly useful tool for the structural biology community as well as for readers who are less well trained in molecular visualization. PMID: 20541422 [PubMed - as supplied by publisher] (Source: Trends in Biochemical Sciences) Trends in Biochemical Sciences journals http://www.medworm.com/rss/comments.php?id=3672807 Tue, 08 Jun 2010 23:00:00 +0100 3672807 http://www.medworm.com/index.php?rid=3672806&cid=s_36134_60_f&fid=36134&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D20541423%26dopt%3DAbstract Authors: Gallastegui N, Groll M The heart of the ubiquitin-mediated degradation pathway, the 26S proteasome, endoproteolytically cleaves most intracellular proteins, thereby maintaining biological homeostasis and regulating many crucial processes in the cell. This hydrolyzing machine comprises more than 30 different subunits, which perform different functions including the recognition, unfolding, translocating and cleavage of protein substrates. Thus, careful assemblage and regulation of the 26S proteasome is essential to ensure correct positioning and function of each subunit, thereby preserving the delicate cellular balance between protein synthesis and degradation. Here, we review the most current research on the 26S proteasome assembly pathway, and describe the mechanism used by th... Trends in Biochemical Sciences journals http://www.medworm.com/rss/comments.php?id=3672806 Tue, 08 Jun 2010 23:00:00 +0100 3672806 http://www.medworm.com/index.php?rid=3659611&cid=s_36134_60_f&fid=36134&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D20538466%26dopt%3DAbstract Authors: Palczewski K Oligomerization is a general characteristic of cell membrane receptors that is shared by G protein-coupled receptors (GPCRs) together with their G protein partners. Recent studies of these complexes, both in vivo and in purified reconstituted forms, unequivocally support this contention for GPCRs, perhaps with only rare exceptions. As evidence has evolved from experimental cell lines to more relevant in vivo studies and from indirect biophysical approaches to well defined isolated complexes of dimeric receptors alone and complexed with G proteins, there is an expectation that the structural basis of oligomerization and the functional consequences for membrane signaling will be elucidated. Oligomerization of cell membrane receptors is fully supported by both thermo... Trends in Biochemical Sciences journals http://www.medworm.com/rss/comments.php?id=3659611 Mon, 07 Jun 2010 23:00:00 +0100 3659611 http://www.medworm.com/index.php?rid=3659627&cid=s_36134_60_f&fid=36134&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D20537543%26dopt%3DAbstract Authors: Bialik S, Zalckvar E, Ber Y, Rubinstein AD, Kimchi A Systems biology, a combined computational and experimental approach to analyzing complex biological systems, has recently been applied to understanding the pathways that regulate programmed cell death. This approach has become especially crucial because recent advances have resulted in an expanded view of the network, to include not just a single death module (apoptosis) but multiple death programs, including programmed necrosis and autophagic cell death. Current research directions in the systems biology field range from quantitative analysis of subprocesses of individual death pathways to the study of interconnectivity among the various death modules of the larger network. These initial studies have provided great advances... Trends in Biochemical Sciences journals http://www.medworm.com/rss/comments.php?id=3659627 Thu, 27 May 2010 23:00:00 +0100 3659627 http://www.medworm.com/index.php?rid=3568595&cid=s_36134_60_f&fid=36134&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D20466550%26dopt%3DAbstract Authors: Slawson C, Copeland RJ, Hart GW O-linked beta-N-acetylglucosamine (O-GlcNAc) is a sugar attachment to serine or threonine hydroxyl moieties on nuclear and cytoplasmic proteins. In many ways, O-GlcNAcylation is similar to phosphorylation because both post-translational modifications cycle rapidly in response to internal or environmental cues. O-GlcNAcylated proteins are involved in transcription, translation, cytoskeletal assembly, signal transduction, and many other cellular functions. O-GlcNAc signaling is intertwined with cellular metabolism; indeed, the donor sugar for O-GlcNAcylation (UDP-GlcNAc) is synthesized from glucose, glutamine, and UTP via the hexosamine biosynthetic pathway. Emerging research indicates that O-GlcNAc signaling and its crosstalk with phosphorylation... Trends in Biochemical Sciences journals http://www.medworm.com/rss/comments.php?id=3568595 Mon, 10 May 2010 23:00:00 +0100 3568595 http://www.medworm.com/index.php?rid=3554622&cid=s_36134_60_f&fid=36134&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D20452774%26dopt%3DAbstract Authors: Sabio G, Davis RJ The cJun NH(2)-terminal kinase isoform JNK1 is implicated in the mechanism of obesity-induced insulin resistance. Feeding a high-fat diet causes activation of the JNK1 signaling pathway, insulin resistance, and obesity in mice. Germ-line ablation of Jnk1 prevents both diet-induced obesity and insulin resistance. Genetic analysis indicates that the effects of JNK1 on insulin resistance can be separated from effects of JNK1 on obesity. Emerging research indicates that JNK1 plays multiple roles in the regulation of insulin resistance, including altered gene expression, hormone/cytokine production, and lipid metabolism. Together, these studies establish JNK1 as a potential pharmacological target for the development of drugs that might be useful for the treatment ... Trends in Biochemical Sciences journals http://www.medworm.com/rss/comments.php?id=3554622 Thu, 06 May 2010 23:00:00 +0100 3554622 http://www.medworm.com/index.php?rid=3554623&cid=s_36134_60_f&fid=36134&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D20451393%26dopt%3DAbstract Authors: Stirnimann CU, Petsalaki E, Russell RB, Müller CW Recent findings indicate that WD40 domains play central roles in biological processes by acting as hubs in cellular networks; however, they have been studied less intensely than other common domains, such as the kinase, PDZ or SH3 domains. As suggested by various interactome studies, they are among the most promiscuous interactors. Structural studies suggest that this property stems from their ability, as scaffolds, to interact with diverse proteins, peptides or nucleic acids using multiple surfaces or modes of interaction. A general scaffolding role is supported by the fact that no WD40 domain has been found with intrinsic enzymatic activity despite often being part of large molecular machines. We discuss the WD40 domain di... Trends in Biochemical Sciences journals http://www.medworm.com/rss/comments.php?id=3554623 Tue, 04 May 2010 23:00:00 +0100 3554623 http://www.medworm.com/index.php?rid=3545792&cid=s_36134_60_f&fid=36134&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D20444609%26dopt%3DAbstract Authors: Das C, Tyler JK, Churchill ME Our genetic information is tightly packaged into a rather ingenious nucleoprotein complex called chromatin in a manner that enables it to be rapidly accessed during genomic processes. Formation of the nucleosome, which is the fundamental unit of chromatin, occurs via a stepwise process that is reversed to enable the disassembly of nucleosomes. Histone chaperone proteins have prominent roles in facilitating these processes as well as in replacing old histones with new canonical histones or histone variants during the process of histone exchange. Recent structural, biophysical and biochemical studies have begun to shed light on the molecular mechanisms whereby histone chaperones promote chromatin assembly, disassembly and histone exchange to facilit... Trends in Biochemical Sciences journals http://www.medworm.com/rss/comments.php?id=3545792 Sun, 02 May 2010 23:00:00 +0100 3545792 http://www.medworm.com/index.php?rid=3524695&cid=s_36134_60_f&fid=36134&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D20430626%26dopt%3DAbstract Authors: Hamanaka RB, Chandel NS Reactive oxygen species (ROS) have historically been viewed as toxic metabolic byproducts and causal agents in a myriad of human pathologies. More recent work, however, indicates that ROS are critical intermediates of cellular signaling pathways. Although it is clear that dedicated cellular ROS producers such as NADPH oxidases participate in signaling, evidence suggests that mitochondrial production of ROS is also a tightly controlled process, and plays a role in the maintenance of cellular oxidative homeostasis and propagation of cellular signaling pathways. Production of ROS at mitochondria thus integrates cellular energy state, metabolite concentrations, and other upstream signaling events and has important implications in cellular stress signaling, ... Trends in Biochemical Sciences journals http://www.medworm.com/rss/comments.php?id=3524695 Mon, 26 Apr 2010 23:00:00 +0100 3524695 http://www.medworm.com/index.php?rid=3480297&cid=s_36134_60_f&fid=36134&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D20395147%26dopt%3DAbstract Authors: Kawamata T, Tomari Y It is well established that 20- to 30-nt small RNAs, including small interfering RNAs, microRNAs and Piwi-interacting RNAs, play crucial roles in regulating gene expression and control a surprisingly diverse array of biological processes. These small RNAs cannot work alone: they must form effector ribonucleoprotein complexes - RNA-induced silencing complexes (RISCs) - to exert their function. Thus, RISC assembly is a key process in small RNA-mediated silencing. Recent biochemical analyses of RISC assembly, together with new structural studies of Argonaute, the core protein component of RISC, suggest a revised view of how mature RISC, which contains single-stranded guide RNA, is built from small RNAs that are born double-stranded. PMID: 20395147 [PubMed... Trends in Biochemical Sciences journals http://www.medworm.com/rss/comments.php?id=3480297 Mon, 12 Apr 2010 23:00:00 +0100 3480297 http://www.medworm.com/index.php?rid=3464426&cid=s_36134_60_f&fid=36134&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D20382026%26dopt%3DAbstract Authors: Kozakov D, Chuang GY, Beglov D, Vajda S Structures of the influenza A virus M2 proton channel in the open conformation have been determined by X-ray crystallography, and in the closed conformation by NMR. Whereas the X-ray structure shows a single inhibitor molecule in the middle of the channel, four inhibitor molecules bind the channel's outer surface in the NMR structure. In both structures, the strongest hot spots (i.e., regions that contribute substantially to the free energy of binding any potential ligand) lie inside the pore, and other hot spots are found at exterior locations. By considering all available models, we propose the primary drug binding site is inside the pore, but that exterior binding occurs under appropriate conditions. PMID: 20382026 [PubMed - as su... Trends in Biochemical Sciences journals http://www.medworm.com/rss/comments.php?id=3464426 Wed, 07 Apr 2010 23:00:00 +0100 3464426 http://www.medworm.com/index.php?rid=3464425&cid=s_36134_60_f&fid=36134&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D20382027%26dopt%3DAbstract Authors: Rutherford K, Daggett V Methyltransferases catalyze the methylation processes essential for protein/DNA repair, transcriptional regulation, and drug metabolism in vivo. More than 500 human methyltransferase polymorphisms have been identified, many of which are linked to disease. We mapped all available coding polymorphisms of seven methyltransferases onto their structures to address their structural significance, and identified a polymorphic hotspot approximately 20A from the active site in four of the proteins. Molecular dynamics simulations of these proteins reveal a common mechanism of destabilization: the mutations alter important side-chain contacts within the polymorphic site that are propagated through the protein, thereby distorting the active site. We propose that thi... Trends in Biochemical Sciences journals http://www.medworm.com/rss/comments.php?id=3464425 Wed, 07 Apr 2010 23:00:00 +0100 3464425 http://www.medworm.com/index.php?rid=3464424&cid=s_36134_60_f&fid=36134&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D20382028%26dopt%3DAbstract Authors: Hundley HA, Bass BL ADARs are a family of enzymes, present in all animals, that convert adenosine to inosine within double-stranded RNA (dsRNA). Inosine and adenosine have different base-pairing properties, and thus, editing alters RNA structure, coding potential and splicing patterns. The first ADAR substrates identified were edited in codons, and ADARs were presumed to function primarily in proteome diversification. Although this is an important function of ADARs, especially in the nervous system, editing in coding sequences is rare compared to editing in noncoding sequences. Introns and untranslated regions of mRNA are the primary noncoding targets, but editing also occurs in small RNAs, such as miRNAs. Although the role of editing in noncoding sequences remains unclear, on... Trends in Biochemical Sciences journals http://www.medworm.com/rss/comments.php?id=3464424 Wed, 07 Apr 2010 23:00:00 +0100 3464424 http://www.medworm.com/index.php?rid=3464427&cid=s_36134_60_f&fid=36134&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D20381358%26dopt%3DAbstract Authors: Yip SC, Saha S, Chernoff J PTP1B, a non-transmembrane protein tyrosine phosphatase that has long been studied as a negative regulator of insulin and leptin signaling, has received renewed attention as an unexpected positive factor in tumorigenesis. Here, we highlight how views of this enzyme have evolved from regarding it as a simple metabolic off-switch to a more complex view of PTP1B as an enzyme that can play both negative and positive roles in diverse signaling pathways. These dual characteristics make PTP1B a particularly attractive therapeutic target for diabetes, obesity, and perhaps breast cancer. PMID: 20381358 [PubMed - as supplied by publisher] (Source: Trends in Biochemical Sciences) Trends in Biochemical Sciences journals http://www.medworm.com/rss/comments.php?id=3464427 Tue, 06 Apr 2010 23:00:00 +0100 3464427 http://www.medworm.com/index.php?rid=3449426&cid=s_36134_60_f&fid=36134&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D20363631%26dopt%3DAbstract Authors: Bański P, Kodiha M, Stochaj U The nucleolus has emerged as a key player that regulates cell growth, survival and the recovery from stress. Progress in proteomics made it possible to sequence the nucleolar proteome under different physiological conditions. Together with other research, this work revealed the presence of multiple chaperones and co-chaperones in the nucleolus. Molecular chaperones are components of a larger network that promotes protein homeostasis, thereby providing continuous adaptation to a changing environment. Recent studies suggest that the cellular chaperone network is divided into individual branches which orchestrate specific functions. Input from separate branches is then combined to 'fine-tune' the cellular proteostasis network. Based on the late... Trends in Biochemical Sciences journals http://www.medworm.com/rss/comments.php?id=3449426 Thu, 01 Apr 2010 23:00:00 +0100 3449426 http://www.medworm.com/index.php?rid=3416741&cid=s_36134_60_f&fid=36134&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D20347313%26dopt%3DAbstract Authors: Massoumi R The tumor suppressor CYLD is a deubiquitylating enzyme that negatively regulates different signaling pathways by removing lysine 63-linked polyubiquitin chains from several specific substrates. In various tumor types, CYLD loss can lead to cell survival or cell proliferation. In addition to its loss due to mutations, CYLD expression can also be decreased through transcriptional and post-transcriptional regulatory mechanisms. Moreover, as epigenetic repression of CYLD can affect tumor progression in different cancer types, the activation of the CYLD promoter ensures the tight control of an inflammatory response. Recent work also shows that CYLD activity can be governed by different regulatory mechanisms including phosphorylation, thus providing another layer of contr... Trends in Biochemical Sciences journals http://www.medworm.com/rss/comments.php?id=3416741 Thu, 25 Mar 2010 00:00:00 +0100 3416741 http://www.medworm.com/index.php?rid=3416744&cid=s_36134_60_f&fid=36134&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D20346678%26dopt%3DAbstract Authors: Morey L, Helin K The polycomb group (PcG) proteins are essential for the normal development of multicellular organisms. They form multi-protein complexes that work as transcriptional repressors of several thousand genes controlling differentiation pathways during development. How the PcG proteins work as transcriptional repressors is incompletely understood, but involves post-translational modifications of histones by two major PcG protein complexes: polycomb repressive complex 1 and polycomb repressive complex 2. PMID: 20346678 [PubMed - as supplied by publisher] (Source: Trends in Biochemical Sciences) Trends in Biochemical Sciences journals http://www.medworm.com/rss/comments.php?id=3416744 Wed, 24 Mar 2010 00:00:00 +0100 3416744 http://www.medworm.com/index.php?rid=3416743&cid=s_36134_60_f&fid=36134&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D20346679%26dopt%3DAbstract Authors: Kraut-Cohen J, Gerst JE Translation-coupled protein translocation requires that mRNAs encoding secreted and membrane proteins (mSMPs) reach the ER membrane. The classical view is that the signal recognition particle (SRP) pathway delivers translating signal sequence-containing proteins to the SRP receptor present on the ER surface and engages the translocation machinery. However, recent studies demonstrate both SRP- and translation-independent mRNA recruitment to the ER, and that mRNAs encoding non-signal sequence-containing cytosolic proteins (mCPs) might be full-time residents of ER membranes. Furthermore, translation-independent cis-acting sequence elements present in both mCPs and mSMPs appear to govern the ability of mRNAs to associate with ER. Thus, a more complex pictur... Trends in Biochemical Sciences journals http://www.medworm.com/rss/comments.php?id=3416743 Wed, 24 Mar 2010 00:00:00 +0100 3416743 http://www.medworm.com/index.php?rid=3416742&cid=s_36134_60_f&fid=36134&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D20346680%26dopt%3DAbstract Authors: Moquin D, Chan FK Proper regulation of cell death is essential for metazoan development and functions. Unlike apoptosis, necrosis is a more inflammatory form of cell death that might contribute to antiviral immunity. Indeed, necrotic cell injury is distinguished from apoptosis by extensive organelle and cell swelling and plasma membrane rupture. Recent evidence indicates that an elaborate biochemical network emanating from receptors in the TNF superfamily can induce apoptosis as well as necrotic cell death. The induction of necrosis by TNF-like cytokines requires biochemical components that are distinct from those involved in apoptosis. Specifically, serine/threonine protein kinases in the receptor interacting protein (RIP) family are required for "programmed" necrotic cell in... Trends in Biochemical Sciences journals http://www.medworm.com/rss/comments.php?id=3416742 Wed, 24 Mar 2010 00:00:00 +0100 3416742 http://www.medworm.com/index.php?rid=3385872&cid=s_36134_60_f&fid=36134&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D20299225%26dopt%3DAbstract Authors: Taatjes DJ The Mediator complex interacts extensively with the RNA polymerase II enzyme and regulates its ability to express protein-coding genes. The mechanisms by which Mediator regulates gene expression remain poorly understood, in part because the structure of Mediator and even its composition can change, depending upon the promoter context. Combined with the sheer size of the human Mediator complex (26 subunits, 1.2 MDa), this structural adaptability bestows seemingly unlimited regulatory potential within the complex. Recent efforts to understand Mediator structure and function have identified expanded roles that include control of both pre- and post-initiation events; it is also evident that Mediator performs both general and gene-specific roles to regulate gene expressi... Trends in Biochemical Sciences journals http://www.medworm.com/rss/comments.php?id=3385872 Tue, 16 Mar 2010 00:00:00 +0100 3385872 http://www.medworm.com/index.php?rid=3385873&cid=s_36134_60_f&fid=36134&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D20236825%26dopt%3DAbstract Authors: Dezwaan DC, Freeman BC The telomere environment requires an efficient means to assemble and disassemble a multitude of structures to operate correctly and to help achieve cellular homeostasis. Telomeres are challenged by a common binding specificity displayed by many of the protein components for telomeric DNA, which could result in competitive DNA interactions, and by a cell cycle-restricted timing of events, which enforces a narrow working period in which to perform numerous tasks. In this review, we discuss how the HSP90 molecular chaperone network avoids these obstacles and facilitates an effective operation of the telomere system. PMID: 20236825 [PubMed - as supplied by publisher] (Source: Trends in Biochemical Sciences) Trends in Biochemical Sciences journals http://www.medworm.com/rss/comments.php?id=3385873 Mon, 15 Mar 2010 00:00:00 +0100 3385873 http://www.medworm.com/index.php?rid=3339934&cid=s_36134_60_f&fid=36134&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D20202851%26dopt%3DAbstract Authors: Beddoe T, Paton AW, Le Nours J, Rossjohn J, Paton JC AB(5) toxins are important virulence factors for several major bacterial pathogens, including Bordetella pertussis, Vibrio cholerae, Shigella dysenteriae and at least two distinct pathotypes of Escherichia coli. The AB(5) toxins are so named because they comprise a catalytic A-subunit, which is responsible for disruption of essential host functions, and a pentameric B-subunit that binds to specific glycan receptors on the target cell surface. The molecular mechanisms by which the AB(5) toxins cause disease have been largely unravelled, including recent insights into a novel AB(5) toxin family, subtilase cytotoxin (SubAB). Furthermore, AB(5) toxins have become a valuable tool for studying fundamental cellular functions, and a... Trends in Biochemical Sciences journals http://www.medworm.com/rss/comments.php?id=3339934 Tue, 02 Mar 2010 00:00:00 +0100 3339934 http://www.medworm.com/index.php?rid=3327991&cid=s_36134_60_f&fid=36134&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D20194025%26dopt%3DAbstract Authors: Svejstrup JQ Maintaining genome integrity is crucial for correctly regulated gene expression. Conversely, the process of transcription fundamentally impinges on genome stability, necessitating cellular mechanisms that lessen the genome destabilizing effect of reading genes. This review provides an overview of our present knowledge of how eukaryotic RNA polymerase II transcription affects, and is affected by, other DNA-related processes such as chromatin remodeling, DNA repair, recombination and replication. PMID: 20194025 [PubMed - as supplied by publisher] (Source: Trends in Biochemical Sciences) Trends in Biochemical Sciences journals http://www.medworm.com/rss/comments.php?id=3327991 Sat, 27 Feb 2010 00:00:00 +0100 3327991 http://www.medworm.com/index.php?rid=3327992&cid=s_36134_60_f&fid=36134&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D20189811%26dopt%3DAbstract Authors: Luhtala N, Parker R Ribonucleases of the T2 family are found in the genomes of protozoans, plants, bacteria, animals and viruses. A broad range of biological roles for these ribonucleases have been suggested, including scavenging of nucleic acids, degradation of self-RNA, serving as extra- or intracellular cytotoxins, and modulating host immune responses. Recently, RNaseT2 family members have been implicated in human pathologies such as cancer and parasitic diseases. Interestingly, certain functions of RNaseT2 family members are independent of their nuclease activity, suggesting that these proteins have additional functions. Moreover, humans lacking RNASET2 manifest a defect in neurological development, perhaps due to aberrant control of the immune system. We review the basic ... Trends in Biochemical Sciences journals http://www.medworm.com/rss/comments.php?id=3327992 Fri, 26 Feb 2010 00:00:00 +0100 3327992 http://www.medworm.com/index.php?rid=3327993&cid=s_36134_60_f&fid=36134&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D20188572%26dopt%3DAbstract Authors: von Lintig J, Kiser PD, Golczak M, Palczewski K Recently, much progress has been made in elucidating the chemistry and metabolism of retinoids and carotenoids, as well as the structures of processing proteins related to vision. Carotenoids and their retinoid metabolites are isoprenoids, so only a limited number of chemical transformations are possible, and just a few of these occur naturally. Although there is an intriguing evolutionary conservation of the key components involved in the production and recycling of chromophores, these genes have also adapted to the specific requirements of insect and vertebrate vision. These 'ancestral footprints' in animal genomes bear witness to the common origin of the chemistry of vision, and will further stimulate research across evolution... Trends in Biochemical Sciences journals http://www.medworm.com/rss/comments.php?id=3327993 Wed, 24 Feb 2010 00:00:00 +0100 3327993 http://www.medworm.com/index.php?rid=3318931&cid=s_36134_60_f&fid=36134&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D20181483%26dopt%3DAbstract Authors: Liu F, Walters KJ Ubiquitylation - the post-translational modification of proteins with ubiquitin - serves powerful regulatory roles in eukaryotes. It can label proteins for destruction or activate gene transcription. Despite its versatility, ubiquitin is used to signal for cellular events with exquisite specificity. To achieve both versatility and specificity, ubiquitin signaling pathways use multivalency, namely the coordinated use of multiple interaction surfaces. Multivalent interactions regulate each stage of ubiquitin signaling pathways, and appear within the ubiquitin signal, the ubiquitylated substrate, ubiquitin processing enzymes and ubiquitin recognition proteins. PMID: 20181483 [PubMed - as supplied by publisher] (Source: Trends in Biochemical Sciences) Trends in Biochemical Sciences journals http://www.medworm.com/rss/comments.php?id=3318931 Mon, 22 Feb 2010 00:00:00 +0100 3318931 http://www.medworm.com/index.php?rid=3302811&cid=s_36134_60_f&fid=36134&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D20176488%26dopt%3DAbstract Authors: Tora L, Marc Timmers HT Early work established the TATA box as the predominant DNA element of core promoters which directed accurate transcription initiation by RNA polymerase II. This element is recognized by TATA-binding protein (TBP), the central DNA-binding subunit of TFIID. In vitro binding and structural experiments indicate that TBP has a strong preference for TATA and induces severe DNA bending. Recent in vivo studies in Saccharomyces cerevisiae indicate that TBP turnover is higher at TATA-containing than at TATA-less promoters; this turnover seems to be regulated by NC2 and Mot1p. We propose that bending of TATA by TBP acts in synergy with NC2 and Mot1p to release TBP more rapidly from TATA promoters in vivo, thus providing a rationale for the predominance of TATA box... Trends in Biochemical Sciences journals http://www.medworm.com/rss/comments.php?id=3302811 Sat, 20 Feb 2010 00:00:00 +0100 3302811 http://www.medworm.com/index.php?rid=3302813&cid=s_36134_60_f&fid=36134&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D20172732%26dopt%3DAbstract This article focuses on the increasing importance of effective communication between scientists and their clinical colleagues. Some recent and innovative programs to facilitate these interactions are also discussed. PMID: 20172732 [PubMed - as supplied by publisher] (Source: Trends in Biochemical Sciences) Trends in Biochemical Sciences journals http://www.medworm.com/rss/comments.php?id=3302813 Fri, 19 Feb 2010 00:00:00 +0100 3302813 http://www.medworm.com/index.php?rid=3302812&cid=s_36134_60_f&fid=36134&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D20172733%26dopt%3DAbstract Authors: Wilson DM, Seidman MM DNA interstrand crosslinks (ICLs) can arise from reactions with endogenous chemicals, such as malondialdehyde - a lipid peroxidation product - or from exposure to various clinical anti-cancer drugs, most notably bifunctional alkylators and platinum compounds. Because they covalently link the two strands of DNA, ICLs completely block transcription and replication, and, as a result, are lethal to the cell. It is well established that proteins that function in nucleotide excision repair and homologous recombination are involved in ICL resolution. Recent work, coupled with a much earlier report, now suggest an emerging link between proteins of the base excision repair pathway and crosslink processing. PMID: 20172733 [PubMed - as supplied by publisher] (So... Trends in Biochemical Sciences journals http://www.medworm.com/rss/comments.php?id=3302812 Fri, 19 Feb 2010 00:00:00 +0100 3302812 http://www.medworm.com/index.php?rid=3291278&cid=s_36134_60_f&fid=36134&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D20163964%26dopt%3DAbstract Authors: Johansson E, Macneill SA Three multi-subunit DNA polymerase enzymes lie at the heart of the chromosome replication machinery in the eukaryotic cell nucleus. Through a combination of genetic, molecular biological and biochemical analysis, significant advances have been made in understanding the essential roles played by each of these enzymes at the replication fork. Until very recently, however, little information was available on their three-dimensional structures. Lately, a series of crystallographic and electron microscopic studies has been published, allowing the structures of the complexes and their constituent subunits to be visualised in detail for the first time. Taken together, these studies provide significant insights into the molecular makeup of the replication mach... Trends in Biochemical Sciences journals http://www.medworm.com/rss/comments.php?id=3291278 Mon, 15 Feb 2010 00:00:00 +0100 3291278 http://www.medworm.com/index.php?rid=3254899&cid=s_36134_60_f&fid=36134&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D20138767%26dopt%3DAbstract Authors: Hangen E, Blomgren K, Bénit P, Kroemer G, Modjtahedi N Apoptosis-inducing factor (AIF) was initially discovered as a caspase-independent death effector. AIF fulfills its lethal function after its release from mitochondria and its translocation to the nucleus of the dying cell. The contribution of AIF to programmed cell death is dependent upon the cell type and apoptotic insult. Recent in vivo data indicate that, in addition to its lethal activity, AIF plays a vital mitochondrial role in healthy cells. A segment of AIF which is dispensable for its apoptotic function carries an NADH-oxidase domain that regulates the respiratory chain complex I and is required for cell survival, proliferation and mitochondrial integrity. Mice that express reduced levels of AIF constitute a r... Trends in Biochemical Sciences journals http://www.medworm.com/rss/comments.php?id=3254899 Fri, 05 Feb 2010 00:00:00 +0100 3254899 http://www.medworm.com/index.php?rid=3254900&cid=s_36134_60_f&fid=36134&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D20137954%26dopt%3DAbstract Authors: Panse VG, Johnson AW In eukaryotic cells, ribosomes are pre-assembled in the nucleus and exported to the cytoplasm where they undergo final maturation. This involves the release of trans-acting shuttling factors, transport factors, incorporation of the remaining ribosomal proteins, and final rRNA processing steps. Recent work, particularly on the large (60S) ribosomal subunit, has confirmed that the 60S subunit is exported from the nucleus in a functionally inactive state. Its arrival in the cytoplasm triggers events that render it translationally competent. Here we focus on these cytoplasmic maturation events and speculate why eukaryotic cells have evolved such an elaborate maturation pathway. PMID: 20137954 [PubMed - as supplied by publisher] (Source: Trends in Biochemic... Trends in Biochemical Sciences journals http://www.medworm.com/rss/comments.php?id=3254900 Wed, 03 Feb 2010 00:00:00 +0100 3254900 http://www.medworm.com/index.php?rid=3236594&cid=s_36134_60_f&fid=36134&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D20116259%26dopt%3DAbstract Authors: Lundin VF, Leroux MR, Stirling PC Actins and tubulins are abundant cytoskeletal proteins that support diverse cellular processes. Owing to the unique properties of these filament-forming proteins, an intricate cellular machinery consisting minimally of the chaperonin CCT, prefoldin, phosducin-like proteins, and tubulin cofactors has evolved to facilitate their biogenesis. More recent evidence also suggests that regulated degradation pathways exist for actin (via TRIM32) and tubulin (via parkin or cofactor E-like). Collectively, these pathways maintain the quality control of cytoskeletal proteins ('proteostasis'), ensuring the appropriate function of microfilaments and microtubules. Here, we focus on the molecular mechanisms of the quality control of actin and tubulin, and disc... Trends in Biochemical Sciences journals http://www.medworm.com/rss/comments.php?id=3236594 Wed, 27 Jan 2010 00:00:00 +0100 3236594 http://www.medworm.com/index.php?rid=3218550&cid=s_36134_60_f&fid=36134&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D20106667%26dopt%3DAbstract Authors: Hottiger MO, Hassa PO, Lüscher B, Schüler H, Koch-Nolte F ADP-ribosylation is a post-translational modification of proteins catalyzed by ADP-ribosyltransferases. It comprises the transfer of the ADP-ribose moiety from NAD(+) to specific amino acid residues on substrate proteins or to ADP-ribose itself. Currently, 22 human genes encoding proteins that possess an ADP-ribosyltransferase catalytic domain are known. Recent structural and enzymological evidence of poly(ADP-ribose)polymerase (PARP) family members demonstrate that earlier proposed names and classifications of these proteins are no longer accurate. Here we summarize these new findings and propose a new consensus nomenclature for all ADP-ribosyltransferases (ARTs) based on the catalyzed reaction and on structu... Trends in Biochemical Sciences journals http://www.medworm.com/rss/comments.php?id=3218550 Mon, 25 Jan 2010 00:00:00 +0100 3218550 http://www.medworm.com/index.php?rid=3212675&cid=s_36134_60_f&fid=36134&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D20097077%26dopt%3DAbstract Authors: Lafontaine DL Ribosome synthesis is a major metabolic activity that involves hundreds of individual reactions, each of which is error-prone. Ribosomal insults occur in cis (alteration in rRNA sequences) and in trans (failure to bind to, or loss of, an assembly factor or ribosomal protein). In addition, specific growth conditions, such as starvation, require that excess ribosomes are turned over efficiently. Recent work indicates that cells evolved multiple strategies to recognize specifically, and target for clearance, ribosomes that are structurally and/or functionally deficient, as well as in excess. This surveillance is active at every step of the ribosome synthesis pathway and on mature ribosomes, involves nearly entirely different mechanisms for the small and large subuni... Trends in Biochemical Sciences journals http://www.medworm.com/rss/comments.php?id=3212675 Thu, 21 Jan 2010 00:00:00 +0100 3212675 http://www.medworm.com/index.php?rid=3212676&cid=s_36134_60_f&fid=36134&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D20096590%26dopt%3DAbstract Authors: Kadota Y, Shirasu K, Guerois R The NLR (nucleotide-binding domain and leucine-rich repeat containing) proteins provide pathogen-sensing systems that are conserved in both plants and animals. They can be activated directly or indirectly by pathogen-derived molecules through mechanisms that remain largely elusive. Studies in plants revealed that the molecular chaperone, HSP90, and its co-chaperones, SGT1 and RAR1, are major stabilizing factors for NLR proteins. More recent work indicates that SGT1 and HSP90 are also required for the function of NLR proteins in mammals, underscoring the evolutionary conservation of innate immune system regulatory mechanisms. Comparative analyses of plant and mammalian NLR proteins, together with recent insights provided by the structure of SGT1-H... Trends in Biochemical Sciences journals http://www.medworm.com/rss/comments.php?id=3212676 Wed, 20 Jan 2010 00:00:00 +0100 3212676 http://www.medworm.com/index.php?rid=3200950&cid=s_36134_60_f&fid=36134&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D20093032%26dopt%3DAbstract Authors: Shneider AM Often, new discoveries are not made at the moment when all of the necessary techniques and background knowledge become available. Instead, they are delayed as a result of mental inertia unrecognized by the scientist and/or the scientific community. In this paper, I introduce and classify various types of mental inertia that are common in science, using examples from the field of biology. PMID: 20093032 [PubMed - as supplied by publisher] (Source: Trends in Biochemical Sciences) Trends in Biochemical Sciences journals http://www.medworm.com/rss/comments.php?id=3200950 Tue, 19 Jan 2010 00:00:00 +0100 3200950 http://www.medworm.com/index.php?rid=3164211&cid=s_36134_60_f&fid=36134&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D20060301%26dopt%3DAbstract Authors: Grüning NM, Lehrach H, Ralser M The metabolic network has a modular architecture, is robust to perturbations, and responds to biological stimuli and environmental conditions. Through monitoring by metabolite responsive macromolecules, metabolic pathways interact with the transcriptome and proteome. Whereas pathway interconnecting cofactors and substrates report on the overall state of the network, specialised intermediates measure the activity of individual functional units. Transitions in the network affect many of these regulatory metabolites, facilitating the parallel regulation of the timing and control of diverse biological processes. The metabolic network controls its own balance, chromatin structure and the biosynthesis of molecular cofactors; moreover, metabolic s... Trends in Biochemical Sciences journals http://www.medworm.com/rss/comments.php?id=3164211 Wed, 06 Jan 2010 00:00:00 +0100 3164211 http://www.medworm.com/index.php?rid=3164210&cid=s_36134_60_f&fid=36134&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D20060302%26dopt%3DAbstract Authors: Ji HF, Zhang HY Structural information regarding normal prion protein (PrP(C)) and the scrapie isoform (PrP(Sc)) is of vital importance for elucidating the pathogenesis of prion diseases (PDs). Despite successful determination of the three-dimensional structures of PrP(C), the structural details of PrP(Sc) remain elusive. Nevertheless, accumulated evidence indicates that beta-sheets comprise the basic building blocks of PrP(Sc). Consensus has been reached about the beta-sheet constitution of the N-terminus of PrP, but the constitution of C-terminal beta-sheets is heavily debated. By evaluating the most recent observations regarding the dynamics and structures of PrP, we propose that helix 2 is more likely than helices 1 and 3 to participate in beta-sheet formation. This hypoth... Trends in Biochemical Sciences journals http://www.medworm.com/rss/comments.php?id=3164210 Wed, 06 Jan 2010 00:00:00 +0100 3164210 http://www.medworm.com/index.php?rid=3129930&cid=s_36134_60_f&fid=36134&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D20036556%26dopt%3DAbstract Authors: Moloney A, Sattelle DB, Lomas DA, Crowther DC The power of fruit fly genetics is being deployed against some of the most intractable and economically significant problems in modern medicine, the neurodegenerative diseases. Fly models of Alzheimer's disease can be exposed to the rich diversity of biological techniques that are available to the community and are providing new insights into disease mechanisms, and assisting in the identification of novel targets for therapy. Similar approaches might also help us to interpret the results of genome-wide association studies of human neurodegenerative diseases by allowing us to triage gene "hits" according to whether a candidate risk factor gene has a modifying effect on the disease phenotypes in fly model systems. PMID: 20036556... Trends in Biochemical Sciences journals http://www.medworm.com/rss/comments.php?id=3129930 Thu, 24 Dec 2009 00:00:00 +0100 3129930 http://www.medworm.com/index.php?rid=3105386&cid=s_36134_60_f&fid=36134&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D20006513%26dopt%3DAbstract Authors: Bolaños JP, Almeida A, Moncada S Following inhibition of mitochondrial respiration neurons die rapidly, whereas astrocytes utilize glycolytically-generated ATP to increase their mitochondrial membrane potential, thus becoming more resistant to pro-apoptotic stimuli. Neurons are unable to increase glycolysis due to the lack of activity of the glycolysis-promoting enzyme 6-phosphofructo-2-kinase/fructose 2,6-bisphosphatase, isoform 3 (PFKFB3). In neurons, PFKFB3 is degraded constantly via the E3 ubiquitin ligase anaphase-promoting complex/cyclosome (APC/C)- CDH1. Glucose metabolism in neurons is directed mainly to the pentose phosphate pathway, leading to regeneration of reduced glutathione. In addition to their relevance to brain physiology and pathophysiology, these obser... Trends in Biochemical Sciences journals http://www.medworm.com/rss/comments.php?id=3105386 Fri, 11 Dec 2009 00:00:00 +0100 3105386