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  • A Lethal Channel between the ATP Synthase Monomers
    Trends Biochem. Sci. (IF 16.63) Pub Date : 2018-03-16
    Salvatore Nesci

    The molecular structure of the transmembrane domain of ATP synthases is responsible for the inner mitochondrial membrane bending. According to the hypothesized mechanism, ATP synthase dissociation from dimers to monomers, triggered by Ca2+ binding to F1, allows the mitochondrial permeability transition pore formation at the interface between the detached monomers.

  • Evolving Linear Chromosomes and Telomeres: A C-Strand-Centric View
    Trends Biochem. Sci. (IF 16.63) Pub Date : 2018-03-14
    Neal F. Lue

    Recent studies have resulted in deeper understanding of a variety of telomere maintenance mechanisms as well as plausible models of telomere evolution. Often overlooked in the discussion of telomere regulation and evolution is the synthesis of the DNA strand that bears the 5′-end (i.e., the C-strand). Herein, I describe a scenario for telomere evolution that more explicitly accounts for the evolution of the C-strand synthesis machinery. In this model, CTC1-STN1-TEN1 (CST), the G-strand-binding complex that regulates primase-Pol α-mediated C-strand synthesis, emerges as a pivotal player and evolutionary link. Itself arising from RPA, CST not only coordinates telomere synthesis, but also gives rise to the POT1-TPP1 complex, which became part of shelterin and regulates telomerase in G-strand elongation.

  • Affimer Proteins: Theranostics of the Future?
    Trends Biochem. Sci. (IF 16.63) Pub Date : 2018-03-14
    Stuart Kyle

    Affimer proteins can bind to a wide variety of target molecules. They can complement and represent a promising alternative to conventional antibodies as they can target molecules with high affinity, specificity, and stability. In addition, they can be selected and expressed in bacterial and mammalian systems. Affimer protein technology shows promise as a tool in the biologist’s arsenal of the future in imaging, diagnostic, and therapeutic applications.

  • Homing in: Mechanisms of Substrate Targeting by Protein Kinases
    Trends Biochem. Sci. (IF 16.63) Pub Date : 2018-03-12
    Chad J. Miller, Benjamin E. Turk

    Protein phosphorylation is the most common reversible post-translational modification in eukaryotes. Humans have over 500 protein kinases, of which more than a dozen are established targets for anticancer drugs. All kinases share a structurally similar catalytic domain, yet each one is uniquely positioned within signaling networks controlling essentially all aspects of cell behavior. Kinases are distinguished from one another based on their modes of regulation and their substrate repertoires. Coupling specific inputs to the proper signaling outputs requires that kinases phosphorylate a limited number of sites to the exclusion of hundreds of thousands of off-target phosphorylation sites. Here, we review recent progress in understanding mechanisms of kinase substrate specificity and how they function to shape cellular signaling networks.

  • The Cytokinin-Activating LOG-Family Proteins Are Not Lysine Decarboxylases
    Trends Biochem. Sci. (IF 16.63) Pub Date : 2018-03-07
    Muhammad Naseem, Elena Bencurova, Thomas Dandekar

    A conserved PGGxGTxxE motif misleads the cytokinin (CK) converting LONELY GUY enzymes to be wrongly annotated as lysine decarboxylases (LDCs). However, so far PGGxGTxxE motif-containing LDCs do not show any LDC activity. Instead, they show phosphoribohydrolase activity by converting inactive CK nucleotides into active free-base forms to invoke CK responses.

  • Fine-Tuning Limited Proteolysis: A Major Role for Regulated Site-Specific O-Glycosylation
    Trends Biochem. Sci. (IF 16.63) Pub Date : 2018-03-02
    Christoffer K. Goth, Sergey Y. Vakhrushev, Hiren J. Joshi, Henrik Clausen, Katrine T. Schjoldager

    Limited proteolytic processing is an essential and ubiquitous post-translational modification (PTM) affecting secreted proteins; failure to regulate the process is often associated with disease. Glycosylation is also a ubiquitous protein PTM and site-specific O-glycosylation in close proximity to sites of proteolysis can regulate and direct the activity of proprotein convertases, a disintegrin and metalloproteinases (ADAMs), and metalloproteinases affecting the activation or inactivation of many classes of proteins, including G-protein-coupled receptors (GPCRs). Here, we summarize the emerging data that suggest O-glycosylation to be a key regulator of limited proteolysis, and highlight the potential for crosstalk between multiple PTMs.

  • Native RNA-Sequencing Throws its Hat into the Transcriptomics Ring
    Trends Biochem. Sci. (IF 16.63) Pub Date : 2018-03-01
    Shobbir Hussain

    De novo sequence-level surveys of transcriptomes have previously relied on sequencing via a DNA intermediate. While such methods can yield massive data sets, various problems mean that these do not always accurately reflect the true innate composition of transcriptomes. Enter Garalde et al., who present for the first time highly parallel native RNA-Sequencing (RNA-seq), with potentially disruptive future-implications for the transcriptomics field.

  • Protein Disaggregation in Multicellular Organisms
    Trends Biochem. Sci. (IF 16.63) Pub Date : 2018-02-28
    Nadinath B. Nillegoda, Anne S. Wentink, Bernd Bukau

    Protein aggregates are formed in cells with profoundly perturbed proteostasis, where the generation of misfolded proteins exceeds the cellular refolding and degradative capacity. They are a hallmark of protein conformational disorders and aged and/or environmentally stressed cells. Protein aggregation is a reversible process in vivo, which counteracts proteotoxicities derived from aggregate persistence, but the chaperone machineries involved in protein disaggregation in Metazoa were uncovered only recently. Here we highlight recent advances in the mechanistic understanding of the major protein disaggregation machinery mediated by the Hsp70 chaperone system and discuss emerging alternative disaggregation activities in multicellular organisms.

  • SREBPs in Lipid Metabolism, Insulin Signaling, and Beyond
    Trends Biochem. Sci. (IF 16.63) Pub Date : 2018-02-27
    Russell A. DeBose-Boyd, Jin Ye

    Sterol regulatory element-binding proteins (SREBPs) are a family of membrane-bound transcription factors that activate genes encoding enzymes required for synthesis of cholesterol and unsaturated fatty acids. SREBPs are controlled by multiple mechanisms at the level of mRNA synthesis, proteolytic activation, and transcriptional activity. In this review, we summarize the recent findings that contribute to the current understanding of the regulation of SREBPs and their physiologic roles in maintenance of lipid homeostasis, insulin signaling, innate immunity, and cancer development.

  • Unravelling the Mechanisms of RNA Helicase Regulation
    Trends Biochem. Sci. (IF 16.63) Pub Date : 2018-02-24
    Katherine E. Sloan, Markus T. Bohnsack

    RNA helicases are critical regulators at the nexus of multiple pathways of RNA metabolism, and in the complex cellular environment, tight spatial and temporal regulation of their activity is essential. Dedicated protein cofactors play key roles in recruiting helicases to specific substrates and modulating their catalytic activity. Alongside individual RNA helicase cofactors, networks of cofactors containing evolutionarily conserved domains such as the G-patch and MIF4G domains highlight the potential for cross-regulation of different aspects of gene expression. Structural analyses of RNA helicase–cofactor complexes now provide insight into the diverse mechanisms by which cofactors can elicit specific and coordinated regulation of RNA helicase action. Furthermore, post-translational modifications (PTMs) and long non-coding RNA (lncRNA) regulators have recently emerged as novel modes of RNA helicase regulation.

  • Guiding Mitotic Progression by Crosstalk between Post-translational Modifications
    Trends Biochem. Sci. (IF 16.63) Pub Date : 2018-02-24
    Sabine A.G. Cuijpers, Alfred C.O. Vertegaal

    Cell division is tightly regulated to disentangle copied chromosomes in an orderly manner and prevent loss of genome integrity. During mitosis, transcriptional activity is limited and post-translational modifications (PTMs) are responsible for functional protein regulation. Essential mitotic regulators, including polo-like kinase 1 (PLK1) and cyclin-dependent kinases (CDK), as well as the anaphase-promoting complex/cyclosome (APC/C), are members of the enzymatic machinery responsible for protein modification. Interestingly, communication between PTMs ensures the essential tight and timely control during all consecutive phases of mitosis. Here, we present an overview of current concepts and understanding of crosstalk between PTMs regulating mitotic progression.

  • Reactive Acyl-CoA Species Modify Proteins and Induce Carbon Stress
    Trends Biochem. Sci. (IF 16.63) Pub Date : 2018-02-22
    Alec G. Trub, Matthew D. Hirschey

    In recent years, our understanding of the scope and diversity of protein post-translational modifications (PTMs) has rapidly expanded. In particular, mitochondrial proteins are decorated with an array of acyl groups that can occur non-enzymatically. Interestingly, these modifying chemical moieties are often associated with intermediary metabolites from core metabolic pathways. In this Review, we describe biochemical reactions and biological mechanisms that activate carbon metabolites for protein PTM. We explore the emerging links between the intrinsic reactivity of metabolites, non-enzymatic protein acylation, and possible signaling roles for this system. Finally, we propose a model of ‘carbon stress’, similar to oxidative stress, as an effective way to conceptualize the relationship between widespread protein acylation, nutrient sensing, and metabolic homeostasis.

  • Metabolic Kinases Moonlighting as Protein Kinases
    Trends Biochem. Sci. (IF 16.63) Pub Date : 2018-02-17
    Zhimin Lu, Tony Hunter

    Protein kinases regulate every aspect of cellular activity, whereas metabolic enzymes are responsible for energy production and catabolic and anabolic processes. Emerging evidence demonstrates that some metabolic enzymes, such as pyruvate kinase M2 (PKM2), phosphoglycerate kinase 1 (PGK1), ketohexokinase (KHK) isoform A (KHK-A), hexokinase (HK), and nucleoside diphosphate kinase 1 and 2 (NME1/2), that phosphorylate soluble metabolites can also function as protein kinases and phosphorylate a variety of protein substrates to regulate the Warburg effect, gene expression, cell cycle progression and proliferation, apoptosis, autophagy, exosome secretion, T cell activation, iron transport, ion channel opening, and many other fundamental cellular functions. The elevated protein kinase functions of these moonlighting metabolic enzymes in tumor development make them promising therapeutic targets for cancer.

  • Getting Momentum: From Biocatalysis to Advanced Synthetic Biology
    Trends Biochem. Sci. (IF 16.63) Pub Date : 2018-02-06
    Christoffel P.S. Badenhorst, Uwe T. Bornscheuer

    Applied biocatalysis is driven by environmental and economic incentives for using enzymes in the synthesis of various pharmaceutical and industrially important chemicals. Protein engineering is used to tailor the properties of enzymes to catalyze desired chemical transformations, and some engineered enzymes now outperform the best chemocatalytic alternatives by orders of magnitude. Unfortunately, custom engineering of a robust biocatalyst is still a time-consuming process, but an understanding of how enzyme function depends on amino acid sequence will speed up the process. This review demonstrates how recent advances in ultrahigh-throughput screening, mutational scanning, DNA synthesis, metagenomics, and machine learning will soon make it possible to model, predict, and manipulate the relationship between protein sequence and function, accelerating the tailor design of novel biocatalysts.

  • Clustering of Rac1: Selective Lipid Sorting Drives Signaling
    Trends Biochem. Sci. (IF 16.63) Pub Date : 2017-11-30
    Kelsey N. Maxwell, Yong Zhou, John F. Hancock

    The ability of lipid-anchored small GTPases to form nanometer-scale lipid domains on the cell plasma membrane (PM) is precipitating exciting new insights into membrane-anchored protein regulation. A recent article by Remorino et al. demonstrates that Rac1, similar to Ras, forms nanoclusters on the PM. The implications of these findings are discussed herein.

  • Methylation of Elongation Factor 1A: Where, Who, and Why?
    Trends Biochem. Sci. (IF 16.63) Pub Date : 2018-02-01
    Joshua J. Hamey, Marc R. Wilkins

    Eukaryotic elongation factor 1A (eEF1A) is an essential and highly conserved protein involved in diverse cellular processes, including translation, cytoskeleton organisation, nuclear export, and proteasomal degradation. Recently, nine novel and site-specific methyltransferases were discovered that target eEF1A, five in yeast and four in human, making it the eukaryotic protein with the highest number of independent methyltransferases. Some of these methyltransferases show striking evolutionary conservation. Yet, they come from diverse methyltransferase families, indicating they confer competitive advantage through independent origins. As might be expected, the first functional studies of specific methylation sites found them to have distinct effects, notably on eEF1A-related processes of translation and tRNA aminoacylation. Further functional studies of sites will likely reveal other unique roles for this interesting modification.

  • Protein Tertiary Structure by Crosslinking/Mass Spectrometry
    Trends Biochem. Sci. (IF 16.63) Pub Date : 2018-01-31
    Michael Schneider, Adam Belsom, Juri Rappsilber

    Observing the structures of proteins within the cell and tracking structural changes under different cellular conditions are the ultimate challenges for structural biology. This, however, requires an experimental technique that can generate sufficient data for structure determination and is applicable in the native environment of proteins. Crosslinking/mass spectrometry (CLMS) and protein structure determination have recently advanced to meet these requirements and crosslinking-driven de novo structure determination in native environments is now possible. In this opinion article, we highlight recent successes in the field of CLMS with protein structure modeling and challenges it still holds.

  • Mind the Organelle Gap – Peroxisome Contact Sites in Disease
    Trends Biochem. Sci. (IF 16.63) Pub Date : 2018-01-31
    Inês Gomes Castro, Maya Schuldiner, Einat Zalckvar

    The eukaryotic cell is organized as a complex grid system where membrane-bound cellular compartments, organelles, must be localized to the right place at the right time. One way to facilitate correct organelle localization and organelle cooperation is through membrane contact sites, areas of close proximity between two organelles that are bridged by protein/lipid complexes. It is now clear that all organelles physically contact each other. The main focus of this review is contact sites of peroxisomes, central metabolic hubs whose defects lead to a variety of diseases. New peroxisome contacts, their tethering complexes and functions have been recently discovered. However, if and how peroxisome contacts contribute to the development of peroxisome-related diseases is still a mystery.

  • RNA Selection by PIWI Proteins
    Trends Biochem. Sci. (IF 16.63) Pub Date : 2018-01-24
    Alexey L. Arkov

    Gene regulation by PIWI–piRNA complexes is determined by the selection of cognate target RNAs by PIWI–piRNA. What are the mechanisms for this selection? There is a rigorous multistep control in identifying target RNAs by PIWI–piRNA structures, and RNA helicases play a potentially crucial role in this process.

  • Oxa1 Superfamily: New Members Found in the ER
    Trends Biochem. Sci. (IF 16.63) Pub Date : 2018-01-12
    Yuanyuan Chen, Ross E. Dalbey

    Oxa1/Alb3/YidC family members promote the insertion of proteins into the mitochondrial inner membrane, the chloroplast thylakoid membrane, and the bacterial plasma membrane. Remarkably, two recent studies identify new Oxa1 homologs that reside in the endoplasmic reticulum (ER) and function in ER membrane protein biogenesis.

  • Replication-Coupled Nucleosome Assembly in the Passage of Epigenetic Information and Cell Identity
    Trends Biochem. Sci. (IF 16.63) Pub Date : 2017-12-29
    Albert Serra-Cardona, Zhiguo Zhang

    During S phase, replicated DNA must be assembled into nucleosomes using both newly synthesized and parental histones in a process that is tightly coupled to DNA replication. This DNA replication-coupled process is regulated by multitude of histone chaperones as well as by histone-modifying enzymes. In recent years novel insights into nucleosome assembly of new H3–H4 tetramers have been gained through studies on the classical histone chaperone CAF-1 and the identification of novel factors involved in this process. Moreover, in vitro reconstitution of chromatin replication has shed light on nucleosome assembly of parental H3–H4, a process that remains elusive. Finally, recent studies have revealed that the replication-coupled nucleosome assembly is important for the determination and maintenance of cell fate in multicellular organisms.

  • Resolving the Gordian Knot: Srs2 Strips Intermediates Formed during Homologous Recombination
    Trends Biochem. Sci. (IF 16.63) Pub Date : 2017-12-28
    Harshad Ghodke, Jacob S. Lewis, Antoine M. van Oijen

    Cells use a suite of specialized enzymes to repair chromosomal double-strand breaks (DSBs). Two recent studies describe how single-molecule fluorescence imaging techniques are used in the direct visualization of some of the key molecular steps involved. De Tullio et al. and Kaniecki et al. watch individual Srs2 helicase molecules disrupt repair intermediates formed by RPA, Rad51, and Rad52 on DNA during homologous recombination.

  • Paraspeckles: Where Long Noncoding RNA Meets Phase Separation
    Trends Biochem. Sci. (IF 16.63) Pub Date : 2017-12-27
    Archa H. Fox, Shinichi Nakagawa, Tetsuro Hirose, Charles S. Bond

    Long noncoding RNA (lncRNA) molecules are some of the newest and least understood players in gene regulation. Hence, we need good model systems with well-defined RNA and protein components. One such system is paraspeckles – protein-rich nuclear organelles built around a specific lncRNA scaffold. New discoveries show how paraspeckles are formed through multiple RNA–protein and protein–protein interactions, some of which involve extensive polymerization, and others with multivalent interactions driving phase separation. Once formed, paraspeckles influence gene regulation through sequestration of component proteins and RNAs, with subsequent depletion in other compartments. Here we focus on the dual aspects of paraspeckle structure and function, revealing an emerging role for these dynamic bodies in a multitude of cellular settings.

  • MK2–TNF–Signaling Comes Full Circle
    Trends Biochem. Sci. (IF 16.63) Pub Date : 2017-12-21
    Manoj B. Menon, Matthias Gaestel

    MK2 (p38MAPK-activated protein kinase 2) is essential for tumor necrosis factor (TNF) biosynthesis, mainly operating by post-transcriptional regulation. Deletion of the gene encoding MK2 strongly reduced serum TNF and protected against endotoxic shock, demonstrating the positive role of p38MAPK/MK2 in TNF signaling at the level of ligand expression. Recent evidence indicates that MK2 directly phosphorylates the TNF receptor interactor RIPK1 and suppresses its activity, thereby limiting TNF-mediated apoptosis and necroptosis – pointing to a more complex, double-edged role of MK2 in TNF signaling. In addition, novel MK2 substrates have emerged in the DNA damage response, autophagy, and obesity, making MK2 a multifunctional kinase at the crossroads of stress response and cell death. We therefore propose a more general role of p38MAPK/MK2 signaling in the timely coordinated onset and resolution of inflammation and beyond.

  • TCR Signaling: Mechanisms of Initiation and Propagation
    Trends Biochem. Sci. (IF 16.63) Pub Date : 2017-12-18
    Adam H. Courtney, Wan-Lin Lo, Arthur Weiss

    The mechanisms by which a T cell detects antigen using its T cell antigen receptor (TCR) are crucial to our understanding of immunity and the harnessing of T cells therapeutically. A hallmark of the T cell response is the ability of T cells to quantitatively respond to antigenic ligands derived from pathogens while remaining inert to similar ligands derived from host tissues. Recent studies have revealed exciting properties of the TCR and the behaviors of its signaling effectors that are used to detect and discriminate between antigens. Here we highlight these recent findings, focusing on the proximal TCR signaling molecules Zap70, Lck, and LAT, to provide mechanistic models and insights into the exquisite sensitivity and specificity of the TCR.

  • Organization and Function of Non-dynamic Biomolecular Condensates
    Trends Biochem. Sci. (IF 16.63) Pub Date : 2017-12-16
    Jeffrey B. Woodruff, Anthony A. Hyman, Elvan Boke

    Cells compartmentalize biochemical reactions using organelles. Organelles can be either membrane-bound compartments or supramolecular assemblies of protein and ribonucleic acid known as ‘biomolecular condensates’. Biomolecular condensates, such as nucleoli and germ granules, have been described as liquid like, as they have the ability to fuse, flow, and undergo fission. Recent experiments have revealed that some liquid-like condensates can mature over time to form stable gels. In other cases, biomolecular condensates solidify into amyloid-like fibers. Here we discuss the assembly, organization, and physiological roles of these more stable condensates in cells, focusing on Balbiani bodies, centrosomes, nuclear pores, and amyloid bodies. We discuss how the material properties of these condensates can be explained by the principles of liquid–liquid phase separation and maturation.

  • Hippo Signaling in the Immune System
    Trends Biochem. Sci. (IF 16.63) Pub Date : 2017-12-14
    Yuchao Zhang, Haitao Zhang, Bin Zhao

    Hippo signaling has a pivotal role in organ size control, tissue regeneration, and cancer. Recent studies have demonstrated critical functions of Hippo signaling in cancer immunity, innate immune responses against pathogens, and autoimmune diseases, refreshing our understanding of the implications of this pathway in the context of disease and therapy design.

  • Cullin 3-Based Ubiquitin Ligases as Master Regulators of Mammalian Cell Differentiation
    Trends Biochem. Sci. (IF 16.63) Pub Date : 2017-12-14
    Wolfgang Dubiel, Dawadschargal Dubiel, Dieter A. Wolf, Michael Naumann

    Specificity of the ubiquitin proteasome system is controlled by ubiquitin E3 ligases, including their major representatives, the multisubunit cullin-RING ubiquitin (Ub) ligases (CRLs). More than 200 different CRLs are divided into seven families according to their cullin scaffolding proteins (CUL1–7) around which they are assembled. Research over two decades has revealed that different CRL families are specialized to fulfill specific cellular functions. Whereas many CUL1-based CRLs (CRL1s) ubiquitylate cell cycle regulators, CRL4 complexes often associate with chromatin to control DNA metabolism. Based on studies about differentiation programs of mesenchymal stem cells (MSCs), including myogenesis, neurogenesis, chondrogenesis, osteogenesis and adipogenesis, we propose here that CRL3 complexes evolved to fulfill a pivotal role in mammalian cell differentiation.

  • N-term 2017: Proteostasis via the N-terminus
    Trends Biochem. Sci. (IF 16.63) Pub Date : 2017-12-09
    Nico Dissmeyer, Emmanuelle Graciet, Michael J. Holdsworth, Daniel J. Gibbs

    N-term 2017 was the first international meeting to bring together researchers from diverse disciplines with a shared interest in protein N-terminal modifications and the N-end rule pathway of ubiquitin-mediated proteolysis, providing a platform for interdisciplinary cross-kingdom discussions and collaborations, as well as strengthening the visibility of this growing scientific community.

  • The PAQosome, an R2TP-Based Chaperone for Quaternary Structure Formation
    Trends Biochem. Sci. (IF 16.63) Pub Date : 2017-12-05
    Walid A. Houry, Edouard Bertrand, Benoit Coulombe

    The Rvb1–Rvb2–Tah1–Pih1/prefoldin-like (R2TP/PFDL) complex is a unique chaperone that provides a platform for the assembly and maturation of many key multiprotein complexes in mammalian cells. Here, we propose to rename R2TP/PFDL as PAQosome (particle for arrangement of quaternary structure) to more accurately represent its unique function.

  • Paving TRAIL’s Path with Ubiquitin
    Trends Biochem. Sci. (IF 16.63) Pub Date : 2017-11-28
    Elodie Lafont, Torsten Hartwig, Henning Walczak

    Despite its name, signalling induced by the tumour necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) is versatile. Besides eliciting cell death by both apoptosis and necroptosis, TRAIL can also induce migration, proliferation, and cytokine production in cancerous and non-cancerous cells. Unravelling the mechanisms regulating the intricate balance between these different outputs could therefore facilitate our understanding of the role of TRAIL in tissue homeostasis, immunity, and cancer. Ubiquitination and its reversal, deubiquitination, are crucial modulators of immune receptor signalling. This review discusses recent progress on the orchestration of TRAIL signalling outcomes by ubiquitination of various components of the signalling complexes, our understanding of the molecular switches that decide between cell death and gene activation, and what remains to be discovered.

  • Stereochemical Divergence of Polyprenol Phosphate Glycosyltransferases
    Trends Biochem. Sci. (IF 16.63) Pub Date : 2017-11-25
    Jerry Eichler, Barbara Imperiali

    In the three domains of life, lipid-linked glycans contribute to various cellular processes ranging from protein glycosylation to glycosylphosphatidylinositol anchor biosynthesis to peptidoglycan assembly. In generating many of these glycoconjugates, phosphorylated polyprenol-based lipids are charged with single sugars by polyprenol phosphate glycosyltransferases. The resultant substrates serve as glycosyltransferase donors, complementing the more common nucleoside diphosphate sugars. It had been accepted that these polyprenol phosphate glycosyltransferases acted similarly, given their considerable sequence homology. Recent findings, however, suggest that matters may not be so simple. In this Opinion we propose that the stereochemistry of sugar addition by polyprenol phosphate glycosyltransferases is not conserved across evolution, even though the GT-A fold that characterizes such enzymes is omnipresent.

  • Immune Responses – Transcriptional and Post-Transcriptional Networks Pass the Baton
    Trends Biochem. Sci. (IF 16.63) Pub Date : 2017-11-24
    Johannes Lichti, Christian Gallus, Elke Glasmacher

    Diverse gene regulatory mechanisms impact on immune homeostasis, and a new model now emerges as fundamental in light of recent genome-wide studies. In this picture, transcriptional networks drive functional changes during immune activation, whereas autoregulatory feedback loops of post-transcriptional programs ensure the original cell lineage identity and subsequent immune resolution.

  • Spatiotemporal Control of Acetyl-CoA Metabolism in Chromatin Regulation
    Trends Biochem. Sci. (IF 16.63) Pub Date : 2017-11-23
    Sharanya Sivanand, Isabella Viney, Kathryn E. Wellen

    The epigenome is sensitive to the availability of metabolites that serve as substrates of chromatin-modifying enzymes. Links between acetyl-CoA metabolism, histone acetylation, and gene regulation have been documented, although how specificity in gene regulation is achieved by a metabolite has been challenging to answer. Recent studies suggest that acetyl-CoA metabolism is tightly regulated both spatially and temporally to elicit responses to nutrient availability and signaling cues. Here we discuss evidence that acetyl-CoA production is differentially regulated in the nucleus and cytosol of mammalian cells. Recent findings indicate that acetyl-CoA availability for site-specific histone acetylation is influenced through post-translational modification of acetyl-CoA-producing enzymes, as well as through dynamic regulation of the nuclear localization and chromatin recruitment of these enzymes.

  • Opposing Functions of Heparanase-1 and Heparanase-2 in Cancer Progression
    Trends Biochem. Sci. (IF 16.63) Pub Date : 2017-11-20
    Israel Vlodavsky, Miriam Gross-Cohen, Marina Weissmann, Neta Ilan, Ralph D. Sanderson

    Heparanase, the sole heparan sulfate (HS)-degrading endoglycosidase, regulates multiple biological activities that enhance tumor growth, metastasis, angiogenesis, and inflammation. Heparanase accomplishes this by degrading HS and thereby regulating the bioavailability of heparin-binding proteins; priming the tumor microenvironment; mediating tumor–host crosstalk; and inducing gene transcription, signaling pathways, exosome formation, and autophagy that together promote tumor cell performance and chemoresistance. By contrast, heparanase-2, a close homolog of heparanase, lacks enzymatic activity, inhibits heparanase activity, and regulates selected genes that promote normal differentiation, endoplasmic reticulum stress, tumor fibrosis, and apoptosis, together resulting in tumor suppression. The emerging premise is that heparanase is a master regulator of the aggressive phenotype of cancer, while heparanase-2 functions as a tumor suppressor.

  • How Are Proteins Reduced in the Endoplasmic Reticulum?
    Trends Biochem. Sci. (IF 16.63) Pub Date : 2017-11-15
    Lars Ellgaard, Carolyn S. Sevier, Neil J. Bulleid

    The reversal of thiol oxidation in proteins within the endoplasmic reticulum (ER) is crucial for protein folding, degradation, chaperone function, and the ER stress response. Our understanding of this process is generally poor but progress has been made. Enzymes performing the initial reduction of client proteins, as well as the ultimate electron donor in the pathway, have been identified. Most recently, a role for the cytosol in ER protein reduction has been revealed. Nevertheless, how reducing equivalents are transferred from the cytosol to the ER lumen remains an open question. We review here why proteins are reduced in the ER, discuss recent data on catalysis of steps in the pathway, and consider the implications for redox homeostasis within the early secretory pathway.

  • Extending the Structural View of Class B GPCRs
    Trends Biochem. Sci. (IF 16.63) Pub Date : 2017-11-11
    Chris de Graaf, Gaojie Song, Can Cao, Qiang Zhao, Ming-Wei Wang, Beili Wu, Raymond C. Stevens

    The secretin-like class B family of G protein-coupled receptors (GPCRs) are key players in hormonal homeostasis. Recent structures of various receptors in complex with a variety of orthosteric and allosteric ligands provide fundamental new insights into the function and mechanism of class B GPCRs, including: (i) ligand-induced changes in the relative orientation of the extracellular and transmembrane receptor domains; (ii) intramolecular interaction networks that stabilize conformational changes to accommodate intracellular G protein binding; and (iii) allosteric modulation of receptor activation. This review provides a comprehensive analysis of the structural, biochemical, and pharmacological data on class B GPCRs for understanding ligand–receptor interaction and modulation mechanisms and assessing the potential implications for drug discovery for the secretin-like GPCR family.

  • Hidden Secrets of Sigma54 Promoters Revealed
    Trends Biochem. Sci. (IF 16.63) Pub Date : 2017-11-07
    Nan Hao, Keith E. Shearwin

    Bacterial sigma54 (σ54) promoters are the DNA-binding motif for σ54-containing RNA polymerase (RNAP) holoenzymes. A recent study using a combination of synthetic oligonucleotide library screening, biochemical characterization, and bioinformatics has uncovered a new and unexpected role for σ54 promoters, encoding a form of bacterial ‘insulator sequence’ to dampen unwanted translation.

  • Histone Marks in the ‘Driver’s Seat’: Functional Roles in Steering the Transcription Cycle
    Trends Biochem. Sci. (IF 16.63) Pub Date : 2017-11-06
    Leah A. Gates, Charles E. Foulds, Bert W. O’Malley

    Particular chromatin modifications are associated with different states of gene transcription, yet our understanding of which modifications are causal ‘drivers’ in promoting transcription is incomplete. Here, we discuss new developments describing the ordered, mechanistic role of select histone marks occurring during distinct steps in the RNA polymerase II (Pol II) transcription cycle. In particular, we highlight the interplay between histone marks in specifying the ‘next step’ of transcription. While many studies have described correlative relationships between histone marks and their occupancy at distinct gene regions, we focus on studies that elucidate clear functional consequences of specific histone marks during different stages of transcription. These recent discoveries have refined our current mechanistic understanding of how histone marks promote Pol II transcriptional progression.

  • Cracking the Chaperone Code: Cellular Roles for Hsp70 Phosphorylation
    Trends Biochem. Sci. (IF 16.63) Pub Date : 2017-11-05
    Nitika, Andrew W. Truman

    Heat shock protein 70 (Hsp70) is a molecular chaperone required for protein folding, cell viability, and cancer cell proliferation. Recent studies suggest that Hsp70 phosphorylation regulates important cellular processes, such as cell cycle progression, apoptosis, protein degradation, and resistance to anticancer therapeutics.

  • The Unsolved Problem of How Cells Sense Micron-Scale Curvature
    Trends Biochem. Sci. (IF 16.63) Pub Date : 2017-10-28
    Kevin S. Cannon, Benjamin L. Woods, Amy S. Gladfelter

    Membrane curvature is a fundamental feature of cells and their organelles. Much of what we know about how cells sense curved surfaces comes from studies examining nanometer-sized molecules on nanometer-scale curvatures. We are only just beginning to understand how cells recognize curved topologies at the micron scale. In this review, we provide the reader with an overview of our current understanding of how cells sense and respond to micron-scale membrane curvature.

  • Outer Membrane Protein OmpB Methylation May Mediate Bacterial Virulence
    Trends Biochem. Sci. (IF 16.63) Pub Date : 2017-10-13
    David C.H. Yang, Amila H. Abeykoon, Bok-Eum Choi, Wei-Mei Ching, P. Boon Chock

    Methylation of outer membrane proteins (OMPs) has been implicated in bacterial virulence. Lysine methylation in rickettsial OmpB is correlated with rickettsial virulence, and N- and O-methylations are also observed in virulence-relevant OMPs from several pathogenic bacteria that cause typhus, leptospirosis, tuberculosis, and anaplasmosis. We summarize recent findings on the structure of methylated OmpB, biochemical characterization, and crystal structures of OmpB methyltransferases. Native rickettsial OmpB purified from highly virulent strains contains multiple clusters of trimethyllysine, in contrast with mostly monomethyllysine, and no trimethyllysine is found in an avirulent strain. Crystal structure of the methyltransferases reveals mechanistic insights for catalysis, and a working model is discussed for this unusual post-translational modification.

  • Visualizing Nuclear RNA Editing
    Trends Biochem. Sci. (IF 16.63) Pub Date : 2017-09-28
    Hodaya Hochberg, Yaron Shav-Tal

    RNA editing results in the site-specific conversion of adenosine to inosine in mRNAs. Genomics has revealed millions of editing sites in metazoans, but examining the spatial aspects of editing in cells has been challenging. A new method, inosineFISH (inoFISH), provides the ability to detect edited and unedited mRNAs within intact cells.

  • Sharing the SAGA
    Trends Biochem. Sci. (IF 16.63) Pub Date : 2017-09-27
    Dominique Helmlinger, László Tora

    Transcription initiation is a major regulatory step in eukaryotic gene expression. Co-activators establish transcriptionally competent promoter architectures and chromatin signatures to allow the formation of the pre-initiation complex (PIC), comprising RNA polymerase II (Pol II) and general transcription factors (GTFs). Many GTFs and co-activators are multisubunit complexes, in which individual components are organized into functional modules carrying specific activities. Recent advances in affinity purification and mass spectrometry analyses have revealed that these complexes often share functional modules, rather than containing unique components. This observation appears remarkably prevalent for chromatin-modifying and remodeling complexes. Here, we use the modular organization of the evolutionary conserved Spt-Ada-Gcn5 acetyltransferase (SAGA) complex as a paradigm to illustrate how co-activators share and combine a relatively limited set of functional tools.

  • Regulation of the Hippo Pathway Transcription Factor TEAD
    Trends Biochem. Sci. (IF 16.63) Pub Date : 2017-09-27
    Kimberly C. Lin, Hyun Woo Park, Kun-Liang Guan

    The TEAD transcription factor family is best known for transcriptional output of the Hippo signaling pathway and has been implicated in processes such as development, cell growth and proliferation, tissue homeostasis, and regeneration. Our understanding of the functional importance of TEADs has increased dramatically since its initial discovery three decades ago. The majority of our knowledge of TEADs is in the context of Hippo signaling as nuclear DNA-binding proteins passively activated by Yes-associated protein (YAP) and transcriptional activator with PDZ-binding domain (TAZ), transcription coactivators downstream of the Hippo pathway. However, recent studies suggest that TEAD itself is actively regulated. Here, we highlight evidence demonstrating Hippo-independent regulation of TEADs and the potential impacts these studies may have on new cancer therapeutics.

  • The Ubiquitin Code in the Ubiquitin-Proteasome System and Autophagy
    Trends Biochem. Sci. (IF 16.63) Pub Date : 2017-09-22
    Yong Tae Kwon, Aaron Ciechanover

    The conjugation of the 76 amino acid protein ubiquitin to other proteins can alter the metabolic stability or non-proteolytic functions of the substrate. Once attached to a substrate (monoubiquitination), ubiquitin can itself be ubiquitinated on any of its seven lysine (Lys) residues or its N-terminal methionine (Met1). A single ubiquitin polymer may contain mixed linkages and/or two or more branches. In addition, ubiquitin can be conjugated with ubiquitin-like modifiers such as SUMO or small molecules such as phosphate. The diverse ways to assemble ubiquitin chains provide countless means to modulate biological processes. We overview here the complexity of the ubiquitin code, with an emphasis on the emerging role of linkage-specific degradation signals (degrons) in the ubiquitin-proteasome system (UPS) and the autophagy-lysosome system (hereafter autophagy).

  • Biochemistry of Mitochondrial Coenzyme Q Biosynthesis
    Trends Biochem. Sci. (IF 16.63) Pub Date : 2017-09-17
    Jonathan A. Stefely, David J. Pagliarini

    Coenzyme Q (CoQ, ubiquinone) is a redox-active lipid produced across all domains of life that functions in electron transport and oxidative phosphorylation and whose deficiency causes human diseases. Yet, CoQ biosynthesis has not been fully defined in any organism. Several proteins with unclear molecular functions facilitate CoQ biosynthesis through unknown means, and multiple steps in the pathway are catalyzed by currently unidentified enzymes. Here we highlight recent progress toward filling these knowledge gaps through both traditional biochemistry and cutting-edge ‘omics’ approaches. To help fill the remaining gaps, we present questions framed by the recently discovered CoQ biosynthetic complex and by putative biophysical barriers. Mapping CoQ biosynthesis, metabolism, and transport pathways has great potential to enhance treatment of numerous human diseases.

  • Biochemical Mechanisms of Pathogen Restriction by Intestinal Bacteria
    Trends Biochem. Sci. (IF 16.63) Pub Date : 2017-09-17
    Kavita J. Rangan, Howard C. Hang

    The intestine is a highly complex ecosystem where many bacterial species interact with each other and host cells to influence animal physiology and susceptibility to pathogens. Genomic methods have provided a broad framework for understanding how alterations in microbial communities are associated with host physiology and infection, but the biochemical mechanisms of specific intestinal bacterial species are only emerging. In this review, we focus on recent studies that have characterized the biochemical mechanisms by which intestinal bacteria interact with other bacteria and host pathways to restrict pathogen infection. Understanding the biochemical mechanisms of intestinal microbiota function should provide new opportunities for therapeutic development towards a variety of infectious diseases.

  • How Do Enzymes ‘Meet’ Nanoparticles and Nanomaterials?
    Trends Biochem. Sci. (IF 16.63) Pub Date : 2017-09-13
    Ming Chen, Guangming Zeng, Piao Xu, Cui Lai, Lin Tang

    Enzymes are fundamental biological catalysts responsible for biological regulation and metabolism. The opportunity for enzymes to ‘meet’ nanoparticles and nanomaterials is rapidly increasing due to growing demands for applications in nanomaterial design, environmental monitoring, biochemical engineering, and biomedicine. Therefore, understanding the nature of nanomaterial–enzyme interactions is becoming important. Since 2014, enzymes have been used to modify, degrade, or make nanoparticles/nanomaterials, while numerous nanoparticles/nanomaterials have been used as materials for enzymatic immobilization and biosensors and as enzyme mimicry. Among the various nanoparticles and nanomaterials, metal nanoparticles and carbon nanomaterials have received extensive attention due to their fascinating properties. This review provides an overview about how enzymes meet nanoparticles and nanomaterials.

  • How Fast Is Protein–Ligand Association?
    Trends Biochem. Sci. (IF 16.63) Pub Date : 2017-09-13
    Stefano Gianni, Per Jemth

    There is increasing interest in studying protein interactions and their role in cell biology using kinetics. However, there is confusion about the proper terminology in terms of the distinction between rates and rate constants. We recommend a more stringent use of the words speed, fast, slow, rate, and rate constant.

  • Emerging Structural Understanding of Amyloid Fibrils by Solid-State NMR
    Trends Biochem. Sci. (IF 16.63) Pub Date : 2017-09-12
    Beat H. Meier, Roland Riek, Anja Böckmann

    Amyloid structures at atomic resolution have remained elusive mainly because of their extensive polymorphism and because their polymeric properties have hampered structural studies by classical approaches. Progress in sample preparation, as well as solid-state NMR methods, recently enabled the determination of high-resolution 3D structures of fibrils such as the amyloid-β fibril, which is involved in Alzheimer’s disease. Notably, the simultaneous but independent structure determination of Aβ1-42, a peptide that forms fibrillar deposits in the brain of Alzheimer patients, by two independent laboratories, which yielded virtually identical results, has highlighted how structures can be obtained that allow further functional investigation.

  • Stress-Activated Chaperones: A First Line of Defense
    Trends Biochem. Sci. (IF 16.63) Pub Date : 2017-09-08
    Wilhelm Voth, Ursula Jakob

    Proteins are constantly challenged by environmental stress conditions that threaten their structure and function. Especially problematic are oxidative, acid, and severe heat stress which induce very rapid and widespread protein unfolding and generate conditions that make canonical chaperones and/or transcriptional responses inadequate to protect the proteome. We review here recent advances in identifying and characterizing stress-activated chaperones which are inactive under non-stress conditions but become potent chaperones under specific protein-unfolding stress conditions. We discuss the post-translational mechanisms by which these chaperones sense stress, and consider the role that intrinsic disorder plays in their regulation and function. We examine their physiological roles under both non-stress and stress conditions, their integration into the cellular proteostasis network, and their potential as novel therapeutic targets.

  • Emerging Insights into the Roles of the Paf1 Complex in Gene Regulation
    Trends Biochem. Sci. (IF 16.63) Pub Date : 2017-09-01
    S. Branden Van Oss, Christine E. Cucinotta, Karen M. Arndt

    The conserved, multifunctional Polymerase-Associated Factor 1 complex (Paf1C) regulates all stages of the RNA polymerase (Pol) II transcription cycle. In this review, we examine a diverse set of recent studies from various organisms that build on foundational studies in budding yeast. These studies identify new roles for Paf1C in the control of gene expression and the regulation of chromatin structure. In exploring these advances, we find that various functions of Paf1C, such as the regulation of promoter-proximal pausing and development in higher eukaryotes, are complex and context dependent. As more becomes known about the role of Paf1C in human disease, interest in the molecular mechanisms underpinning Paf1C function will continue to increase.

  • There Is an Inclusion for That: Material Properties of Protein Granules Provide a Platform for Building Diverse Cellular Functions
    Trends Biochem. Sci. (IF 16.63) Pub Date : 2017-08-29
    Daniel Kaganovich

    Proteins perform a staggering variety of functions in the cell. Traditionally, protein function was thought to be hard-wired into the folded structure and conformational dynamics of each protein molecule. Recent work describes a new mode of protein functionality driven by the collective behavior of many different proteins; most of which lack a defined structure. These proteins form clusters or granules in which unstructured polypeptides interact transiently. Nonspecific multivalent interactions drive the formation of phase-separated structures resembling aggregates. This type of functional aggregate granule can be thought of as a single supermolecular functional entity that derives function from its unique material properties. In this review we examine the emerging idea of protein granules as a new functional and structural unit of cellular organization.

  • In the Hunger Games, the Winner Takes Everything
    Trends Biochem. Sci. (IF 16.63) Pub Date : 2017-08-28
    Franziska Püschel, Cristina Muñoz-Pinedo

    Entosis is an atypical form of cell death that occurs when a cell engulfs and kills another cell. A recent article by Overholtzer and colleagues indicates that glucose deprivation promotes entosis. AMP-activated protein kinase (AMPK) activation in the loser cells triggers their engulfment and elimination by winner cells, which endure starvation.

  • Good Ol’ Fat: Links between Lipid Signaling and Longevity
    Trends Biochem. Sci. (IF 16.63) Pub Date : 2017-08-09
    Victor Bustos, Linda Partridge

    Aging is the single greatest risk factor for the development of disease. Understanding the biological molecules and mechanisms that modulate aging is therefore critical for the development of health-maximizing interventions for older people. The effect of fats on longevity has traditionally been disregarded as purely detrimental. However, new studies are starting to uncover the possible beneficial effects of lipids working as signaling molecules on health and longevity. These studies highlight the complex links between aging and lipid signaling. In this review we summarize accumulating evidence that points to changes in lipid metabolism, and in particular lipid signaling, as an underlying mechanism for healthy aging.

  • The Ribosome Holds the RNA Polymerase on Track in Bacteria
    Trends Biochem. Sci. (IF 16.63) Pub Date : 2017-08-08
    Bruno P. Klaholz

    The central dogma of molecular biology comprises two fundamental mechanistic steps of gene expression (transcription and translation), which, in bacteria, are coupled. A recent study provides structural insights into a supercomplex between the RNA polymerase and the ribosome, thus highlighting the synergy between two key macromolecular machineries in the cell.

  • How Hsp90 and Cdc37 Lubricate Kinase Molecular Switches
    Trends Biochem. Sci. (IF 16.63) Pub Date : 2017-08-04
    Kliment A. Verba, David A. Agard

    The Hsp90/Cdc37 chaperone system interacts with and supports 60% of the human kinome. Not only are Hsp90 and Cdc37 generally required for initial folding, but many kinases rely on the Hsp90/Cdc37 throughout their lifetimes. A large fraction of these ‘client’ kinases are key oncoproteins, and their interactions with the Hsp90/Cdc37 machinery are crucial for both their normal and malignant activity. Recently, advances in single-particle cryo-electron microscopy (cryoEM) and biochemical strategies have provided the first key molecular insights into kinase–chaperone interactions. The surprising results suggest a re-evaluation of the role of chaperones in the kinase lifecycle, and suggest that such interactions potentially allow kinases to more rapidly respond to key signals while simultaneously protecting unstable kinases from degradation and suppressing unwanted basal activity.

  • d-Tyrosyl-tRNA Deacylase: A New Function
    Trends Biochem. Sci. (IF 16.63) Pub Date : 2017-07-29
    Richard Calendar

    d-Aminoacyl-tRNA deacylase (DTD) hydrolyzes d-amino acids mistakenly attached to tRNAs and, thus, has been implicated in perpetuating protein homochirality. Fifty years after the discovery of DTD, it has now been shown that its function extends beyond ‘chiral proofreading’ because it also eliminates glycine that has been erroneously coupled to tRNAAla.

  • A Process of Resection-Dependent Nonhomologous End Joining Involving the Goddess Artemis
    Trends Biochem. Sci. (IF 16.63) Pub Date : 2017-07-21
    Markus Löbrich, Penny Jeggo

    DNA double-strand breaks (DSBs) are a hazardous form of damage that can potentially cause cell death or genomic rearrangements. In mammalian G1- and G2-phase cells, DSBs are repaired with two-component kinetics. In both phases, a fast process uses canonical nonhomologous end joining (c-NHEJ) to repair the majority of DSBs. In G2, slow repair occurs by homologous recombination. The slow repair process in G1 also involves c-NHEJ proteins but additionally requires the nuclease Artemis and DNA end resection. Here, we consider the nature of slow DSB repair in G1 and evaluate factors determining whether DSBs are repaired with fast or slow kinetics. We consider limitations in our current knowledge and present a speculative model for Artemis-dependent c-NHEJ and the environment underlying its usage.

Some contents have been Reproduced with permission of the American Chemical Society.
Some contents have been Reproduced by permission of The Royal Society of Chemistry.
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