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  • N-Terminal Proteoforms in Human Disease
    Trends Biochem. Sci. (IF 16.889) Pub Date : 2020-01-27
    Annelies Bogaert; Esperanza Fernandez; Kris Gevaert

    The collection of chemically different protein variants, or proteoforms, by far exceeds the number of protein-coding genes in the human genome. Major contributors are alternative splicing and protein modifications. In this review, we focus on those proteoforms that differ at their N termini with a molecular link to disease. We describe the main underlying mechanisms that give rise to such N-terminal proteoforms, these being splicing, initiation of protein translation, and protein modifications. Given their role in several human diseases, it is becoming increasingly clear that several of these N-terminal proteoforms may have potential as therapeutic interventions and/or for diagnosing and prognosing their associated disease.

  • How Cells Respond to DNA Breaks in Mitosis
    Trends Biochem. Sci. (IF 16.889) Pub Date : 2020-01-27
    Andrew N. Blackford; Manuel Stucki

    DNA double-strand breaks (DSBs) are highly toxic lesions that can lead to chromosomal instability if they are not repaired correctly. DSBs are especially dangerous in mitosis when cells go through the complex process of equal chromosome segregation into daughter cells. When cells encounter DSBs in interphase, they are able to arrest the cell cycle until the breaks are repaired before entering mitosis. However, when DSBs occur during mitosis, cells no longer arrest but prioritize completion of cell division over repair of DNA damage. This review focuses on recent progress in our understanding of the mechanisms that allow mitotic cells to postpone DSB repair without accumulating massive chromosomal instability. Additionally, we review possible physiological consequences of failed DSB responses in mitosis.

  • FANally…A Structure Emerges of the Fanconi Anemia Core Complex
    Trends Biochem. Sci. (IF 16.889) Pub Date : 2020-01-24
    Jacob D. Aguirre; Nicolas H. Thomä

    The Fanconi anemia (FA) core complex is the ~0.9-mDa ubiquitin ligase most frequently mutated in patients with FA. New cryo-electron microscopy (cryo-EM) data from Shakeel et al. reveals a surprisingly complex ubiquitin ligase architecture, providing unprecedented insight into this critical hub at the interface of DNA crosslink detection and repair.

  • Stable Isotopes for Tracing Mammalian-Cell Metabolism In Vivo
    Trends Biochem. Sci. (IF 16.889) Pub Date : 2020-01-17
    Juan Fernández-García; Patricia Altea-Manzano; Erica Pranzini; Sarah-Maria Fendt

    Metabolism is at the cornerstone of all cellular functions and mounting evidence of its deregulation in different diseases emphasizes the importance of a comprehensive understanding of metabolic regulation at the whole-organism level. Stable-isotope measurements are a powerful tool for probing cellular metabolism and, as a result, are increasingly used to study metabolism in in vivo settings. The additional complexity of in vivo metabolic measurements requires paying special attention to experimental design and data interpretation. Here, we review recent work where in vivo stable-isotope measurements have been used to address relevant biological questions within an in vivo context, summarize different experimental and data interpretation approaches and their limitations, and discuss future opportunities in the field.

  • Histone Lactylation: A New Role for Glucose Metabolism
    Trends Biochem. Sci. (IF 16.889) Pub Date : 2019-12-31
    Maria V. Liberti; Jason W. Locasale

    Lactate is an end product of glucose metabolism, which serves metabolic and nonmetabolic functions. A new study by Zhang et al. establishes a novel function for lactate whereby it is utilized in a new histone modification, histone lysine lactylation, to regulate gene expression in macrophages.

  • Reshaping Chromatin Architecture around DNA Breaks
    Trends Biochem. Sci. (IF 16.889) Pub Date : 2019-12-24
    Pierre Caron; Sophie E. Polo

    DNA double-strand breaks (DSBs) elicit major chromatin changes. Using super-resolution microscopy in human cells, Ochs et al. unveil that the DSB response protein 53BP1 and its effector RIF1 organize DSB-flanking chromatin into circular micro-domains. These structures control the spatial distribution of DSB repair factors safeguarding genome integrity.

  • Strategies for Engineering and Rewiring Kinase Regulation
    Trends Biochem. Sci. (IF 16.889) Pub Date : 2019-12-20
    James W. McCormick; David Pincus; Orna Resnekov; Kimberly A. Reynolds

    Eukaryotic protein kinases (EPKs) catalyze the transfer of a phosphate group onto another protein in response to appropriate regulatory cues. In doing so, they provide a primary means for cellular information transfer. Consequently, EPKs play crucial roles in cell differentiation and cell-cycle progression, and kinase dysregulation is associated with numerous disease phenotypes including cancer. Nonnative cues for synthetically regulating kinases are thus much sought after, both for dissecting cell signaling pathways and for pharmaceutical development. In recent years advances in protein engineering and sequence analysis have led to new approaches for manipulating kinase activity, localization, and in some instances specificity. These tools have revealed fundamental principles of intracellular signaling and suggest paths forward for the design of therapeutic allosteric kinase regulators.

  • Linker Domains: Why ABC Transporters ‘Live in Fragments no Longer’
    Trends Biochem. Sci. (IF 16.889) Pub Date : 2019-12-12
    Robert C. Ford; Dominic Marshall-Sabey; John Schuetz

    ATP-binding cassette (ABC) transporters are membrane proteins present in all kingdoms of life. We have considered the disordered region that connects the N- and C-terminal halves in many eukaryotic ABC transporters, allowing all four consensus functional domains to be linked. The recent availability of structures of ABC transporters containing linker regions has allowed us to identify the start and end points of the connectors as well as hinting at their localisation. We address questions such as: Where did the linker regions come from? Why do some ABC transporters have connectors and others not? What are the rules and roles of the linker regions? What are the consequences of mutations in these connector regions for disease in humans?

  • Computational Dissection of Membrane Transport at a Microscopic Level
    Trends Biochem. Sci. (IF 16.889) Pub Date : 2019-12-05
    Tao Jiang, Po-Chao Wen, Noah Trebesch, Zhiyu Zhao, Shashank Pant, Karan Kapoor, Mrinal Shekhar, Emad Tajkhorshid

    Membrane transporters are key gatekeeper proteins at cellular membranes that closely control the traffic of materials. Their function relies on structural rearrangements of varying degrees that facilitate substrate translocation across the membrane. Characterizing these functionally important molecular events at a microscopic level is key to our understanding of membrane transport, yet challenging to achieve experimentally. Recent advances in simulation technology and computing power have rendered molecular dynamics (MD) simulation a powerful biophysical tool to investigate a wide range of dynamical events spanning multiple spatial and temporal scales. Here, we review recent studies of diverse membrane transporters using computational methods, with an emphasis on highlighting the technical challenges, key lessons learned, and new opportunities to illuminate transporter structure and function.

  • The Cytoskeleton as Regulator of Cell Signaling Pathways
    Trends Biochem. Sci. (IF 16.889) Pub Date : 2019-12-05
    Ossama Moujaber, Ursula Stochaj

    During interphase, filamentous actin, microtubules, and intermediate filaments regulate cell shape, motility, transport, and interactions with the environment. These activities rely on signaling events that control cytoskeleton properties. Recent studies uncovered mechanisms that go far beyond this one-directional flow of information. Thus, the three branches of the cytoskeleton impinge on signaling pathways to determine their activities. We propose that this regulatory role of the cytoskeleton provides sophisticated mechanisms to control the spatiotemporal output and the intensity of signaling events. Specific examples emphasize these emerging contributions of the cytoskeleton to cell physiology. In our opinion, further exploration of these pathways will uncover new concepts of cellular communication that originate from the cytoskeleton.

  • Molecular Mobility-Mediated Regulation of E-Cadherin Adhesion
    Trends Biochem. Sci. (IF 16.889) Pub Date : 2019-12-04
    Kabir H. Biswas

    Cells in epithelial tissues utilize homotypic E-cadherin interaction-mediated adhesions to both physically adhere to each other and sense the physical properties of their microenvironment, such as the presence of other cells in close vicinity or an alteration in the mechanical tension of the tissue. These position E-cadherin centrally in organogenesis and other processes, and its function is therefore tightly regulated through a variety of means including endocytosis and gene expression. How does membrane molecular mobility of E-cadherin, and thus membrane physical properties and associated actin cytoskeleton, impinges on the assembly of adhesive clusters and signaling is discussed.

  • The SLC25 Mitochondrial Carrier Family: Structure and Mechanism
    Trends Biochem. Sci. (IF 16.889) Pub Date : 2019-11-29
    Jonathan J. Ruprecht, Edmund R.S. Kunji

    Members of the mitochondrial carrier family (SLC25) provide the transport steps for amino acids, carboxylic acids, fatty acids, cofactors, inorganic ions, and nucleotides across the mitochondrial inner membrane and are crucial for many cellular processes. Here, we use new insights into the transport mechanism of the mitochondrial ADP/ATP carrier to examine the structure and function of other mitochondrial carriers. They all have a single substrate-binding site and two gates, which are present on either side of the membrane and involve salt-bridge networks. Transport is likely to occur by a common mechanism, in which the coordinated movement of six structural elements leads to the alternating opening and closing of the matrix or cytoplasmic side of the carriers.

  • Striking Diversity of Mitochondria-Specific Translation Processes across Eukaryotes
    Trends Biochem. Sci. (IF 16.889) Pub Date : 2019-11-25
    Florent Waltz, Philippe Giegé

    Mitochondria are essential organelles that act as energy conversion powerhouses and metabolic hubs. Their gene expression machineries combine traits inherited from prokaryote ancestors and specific features acquired during eukaryote evolution. Mitochondrial research has wide implications ranging from human health to agronomy. We highlight recent advances in mitochondrial translation. Functional, biochemical, and structural data have revealed an unexpected diversity of mitochondrial translation systems, particularly of their key players, the mitochondrial ribosomes (mitoribosomes). Ribosome assembly and translation mechanisms, such as initiation, are discussed and put in perspective with the prevalence of eukaryote-specific families of mitochondrial translation factors such as pentatricopeptide repeat (PPR) proteins.

  • The Brain Epigenome Goes Drunk: Alcohol Consumption Alters Histone Acetylation and Transcriptome
    Trends Biochem. Sci. (IF 16.889) Pub Date : 2019-11-22
    Irene de Diego, Annika Müller-Eigner, Shahaf Peleg

    Recent studies demonstrated that alcohol consumption can induce epigenetic changes in the brain, although the exact mechanism underlying such changes remained unclear. Now, a report by Mews et al. shows a direct link between alcohol consumption and histone acetylation changes in the brain, which are mediated by the neuronal acetyl-CoA synthase, ACSS2.

  • New Structures Reveal Interaction Dynamics in Respiratory Supercomplexes
    Trends Biochem. Sci. (IF 16.889) Pub Date : 2019-11-19
    Peter Brzezinski

    Mitochondrial energy conversion involves a chain of membrane-bound proteins that are wired to conduct an electron current, which drives transmembrane proton translocation. These enzymes associate to form supercomplexes, but the functional relevance of the higher-order structures is unknown. A recent study by Letts et al. presents structures of a supercomplex, which suggest how the interaction choreography may control overall functionality.

  • Expansion and Cell-Cycle Arrest: Common Denominators of Cellular Senescence
    Trends Biochem. Sci. (IF 16.889) Pub Date : 2019-07-22
    Mikolaj Ogrodnik, Hanna Salmonowicz, Diana Jurk, João F. Passos

    Cellular senescence is a major driver of age-related diseases, and senotherapies are being tested in clinical trials. Despite its popularity, cellular senescence is weakly defined and is frequently referred to as irreversible cell-cycle arrest. In this article we hypothesize that cellular senescence is a phenotype that results from the coordination of two processes: cell expansion and cell-cycle arrest. We provide evidence for the compatibility of the proposed model with recent findings showing senescence in postmitotic tissues, wound healing, obesity, and development. We believe our model also explains why some characteristics of senescence can be found in non-senescent cells. Finally, we propose new avenues for research from our model.

  • Conservation and Variability of the AUG Initiation Codon Context in Eukaryotes
    Trends Biochem. Sci. (IF 16.889) Pub Date : 2019-07-25
    Greco Hernández, Vincent G. Osnaya, Xochitl Pérez-Martínez

    Selection of the translation initiation site (TIS) is a crucial step during translation. In the 1980s Marylin Kozak performed key studies on vertebrate mRNAs to characterize the optimal TIS consensus sequence, the Kozak motif. Within this motif, conservation of nucleotides in crucial positions, namely a purine at −3 and a G at +4 (where the A of the AUG is numbered +1), is essential for TIS recognition. Ever since its characterization the Kozak motif has been regarded as the optimal sequence to initiate translation in all eukaryotes. We revisit here published in silico data on TIS consensus sequences, as well as experimental studies from diverse eukaryotic lineages, and propose that, while the −3A/G position is universally conserved, the remaining variability of the consensus sequences enables their classification as optimal, strong, and moderate TIS sequences.

  • Engineering Metalloprotein Functions in Designed and Native Scaffolds
    Trends Biochem. Sci. (IF 16.889) Pub Date : 2019-07-13
    Flavia Nastri, Daniele D’Alonzo, Linda Leone, Gerardo Zambrano, Vincenzo Pavone, Angela Lombardi

    Metalloproteins are crucial for life. The mutual relationship between metal ions and proteins makes metalloproteins able to accomplish key processes in biological systems, often very difficult to reproduce with inorganic coordination compounds under mild conditions. Taking inspiration from nature, many efforts have been devoted to developing artificial molecules as metalloprotein mimics. We have witnessed an explosion of protein design strategies leading to designed metalloproteins, ranging from stable structures to functional molecules. This review illustrates the most recent results for inserting metalloprotein functions in designed and engineered protein scaffolds. The selected examples highlight the potential of different approaches for the construction of artificial molecules capable of simulating and even overcoming the features of natural metalloproteins.

  • Nutrient Zinc at the Host–Pathogen Interface
    Trends Biochem. Sci. (IF 16.889) Pub Date : 2019-07-17
    Zachery R. Lonergan, Eric P. Skaar

    Zinc is an essential cofactor required for life and, as such, mechanisms exist for its homeostatic maintenance in biological systems. Despite the evolutionary distance between vertebrates and microbial life, there are parallel mechanisms to balance the essentiality of zinc with its inherent toxicity. Vertebrates regulate zinc homeostasis through a complex network of metal transporters and buffering systems that respond to changes in nutritional zinc availability or inflammation. Fine-tuning of this network becomes crucial during infections, where host nutritional immunity attempts to limit zinc availability to pathogens. However, accumulating evidence demonstrates that pathogens have evolved mechanisms to subvert host-mediated zinc withholding, and these metal homeostasis systems are important for survival within the host. We discuss here the mechanisms of vertebrate and bacterial zinc homeostasis and mobilization, as well as recent developments in our understanding of microbial zinc acquisition.

  • Do All Roads Lead to Rome in G-Protein Activation?
    Trends Biochem. Sci. (IF 16.889) Pub Date : 2019-11-18
    Pradipta Ghosh, Mikel Garcia-Marcos

    High-resolution structural studies on G-protein-coupled receptors (GPCRs) have flourished recently, providing long-sought insights into the dynamic process of guanine nucleotide-binding protein (G-protein) activation. In parallel, analogous studies are starting to shed light on how the same G-proteins are activated by non-GPCR proteins. Can we learn about common themes and variations in G-protein activation from them?

  • Dynamic Interplay between miRNAs and the Extracellular Matrix Influences the Tumor Microenvironment
    Trends Biochem. Sci. (IF 16.889) Pub Date : 2019-07-06
    Zoi Piperigkou, Nikos K. Karamanos

    Expression of miRNAs is critical for the regulation of several cell functions including proliferation, migration, differentiation, and survival, as well as extracellular matrix (ECM) remodeling. The dynamic interplay between miRNAs, ECM macromolecules, and the tumor microenvironment plays critical roles in many aspects of human diseases such as metabolic disorders and cancers. Circulating and secreted miRNAs, via membrane vesicles, affect cell–cell communication and cellular metabolic pathways, underscoring their significance in tumor progression. The primary goal of this article is to highlight the importance of epigenetic regulatory factors, focusing on miRNA-mediated ECM reorganization and their functional relationships, and how matrix-mediated miRNAs affect tumor progression.

  • Functional Diversification of ER Stress Responses in Arabidopsis
    Trends Biochem. Sci. (IF 16.889) Pub Date : 2019-11-18
    Noelia Pastor-Cantizano, Dae Kwan Ko, Evan Angelos, Yunting Pu, Federica Brandizzi

    The endoplasmic reticulum (ER) is responsible for the synthesis of one-third of the cellular proteome and is constantly challenged by physiological and environmental situations that can perturb its homeostasis and lead to the accumulation of misfolded secretory proteins, a condition referred to as ER stress. In response, the ER evokes a set of intracellular signaling processes, collectively known as the unfolded protein response (UPR), which are designed to restore biosynthetic capacity of the ER. As single-cell organisms evolved into multicellular life, the UPR complexity has increased to suit their growth and development. In this review, we discuss recent advances in the understanding of the UPR, emphasizing conserved UPR elements between plants and metazoans and highlighting unique plant-specific features.

  • Switching Condensates: The CTD Code Goes Liquid
    Trends Biochem. Sci. (IF 16.889) Pub Date : 2019-11-13
    Bede Portz, James Shorter

    Condensates containing RNA polymerase II (Pol II) materialize at sites of active transcription. Young and coworkers now establish that C-terminal domain phosphorylation regulates Pol II partitioning into distinct condensates connected with transcription initiation or splicing. This advance hints that distinct condensates with specialized functional compositions might choreograph distinct stages of transcription.

  • Netrin Synergizes Signaling and Adhesion through DCC
    Trends Biochem. Sci. (IF 16.889) Pub Date : 2019-11-05
    Rob Meijers, Robert G. Smock, Yan Zhang, Jia-Huai Wang

    Netrin is a prototypical axon guidance cue. Structural studies have revealed how netrin interacts with the deleted in colorectal cancer (DCC) receptor, other receptors, and co-factors for signaling. Recently, genetic studies suggested that netrin is involved in neuronal haptotaxis, which requires a reversible adhesion process. Structural data indicate that netrin can also mediate trans-adhesion between apposing cells decorated with its receptors on the condition that the auxiliary guidance cue draxin is present. Here, we propose that netrin is involved in conditional adhesion, a reversible and localized process that can contribute to cell adhesion and migration. We suggest that netrin-mediated adhesion and signaling are linked, and that local environmental factors in the ventricular zone, the floor plate, or other tissues coordinate its function.

  • Running the Light: Nucleotide Metabolism Drives Bypass of Senescence in Cancer
    Trends Biochem. Sci. (IF 16.889) Pub Date : 2019-11-04
    Christopher J. Halbrook, Daniel R. Wahl, Costas A. Lyssiotis

    Senescence is engaged in response to oncogenes to suppress proliferation. Cancers rewire metabolism to facilitate proliferation; however, it is not well appreciated how this enables senescence bypass. Recent work by Buj et al. demonstrates that loss of the tumor suppressor p16 engages a mTORC1-dependent increase in nucleotide pools to override senescence.

  • Renaissance of Allostery to Disrupt Protein Kinase Interactions
    Trends Biochem. Sci. (IF 16.889) Pub Date : 2019-11-02
    Alejandro E. Leroux, Ricardo M. Biondi

    Protein–protein interactions often regulate the activity of protein kinases by allosterically modulating the conformation of the ATP-binding site. Bidirectional allostery implies that reverse modulation (i.e., from the ATP-binding site to the interaction and regulatory sites) must also be possible. Here, we review both the allosteric regulation of protein kinases and recent work describing how compounds binding at the ATP-binding site can promote or inhibit protein kinase interactions at regulatory sites via the reverse mechanism. Notably, the pharmaceutical industry has been developing compounds that bind to the ATP-binding site of protein kinases and potently disrupt protein–protein interactions between target protein kinases and their regulatory interacting partners. Learning to modulate allosteric processes will facilitate the development of protein–protein interaction modulators.

  • Bacterial RNA Degradosomes: Molecular Machines under Tight Control
    Trends Biochem. Sci. (IF 16.889) Pub Date : 2019-11-01
    Alejandro Tejada-Arranz, Valérie de Crécy-Lagard, Hilde de Reuse

    Bacterial RNA degradosomes are multienzyme molecular machines that act as hubs for post-transcriptional regulation of gene expression. The ribonuclease activities of these complexes require tight regulation, as they are usually essential for cell survival while potentially destructive. Recent studies have unveiled a wide variety of regulatory mechanisms including autoregulation, post-translational modifications, and protein compartmentalization. Recently, the subcellular organization of bacterial RNA degradosomes was found to present similarities with eukaryotic messenger ribonucleoprotein (mRNP) granules, membraneless compartments that are also involved in mRNA and protein storage and/or mRNA degradation. In this review, we present the current knowledge on the composition and targets of RNA degradosomes, the most recent developments regarding the regulation of these machineries, and their similarities with the eukaryotic mRNP granules.

  • Evasins: Tick Salivary Proteins that Inhibit Mammalian Chemokines
    Trends Biochem. Sci. (IF 16.889) Pub Date : 2019-11-01
    Ram Prasad Bhusal, James R.O. Eaton, Sayeeda T. Chowdhury, Christine A. Power, Amanda E.I. Proudfoot, Martin J. Stone, Shoumo Bhattacharya

    Ticks are hematophagous arachnids that parasitize mammals and other hosts, feeding on their blood. Ticks secrete numerous salivary factors that enhance host blood flow or suppress the host inflammatory response. The recruitment of leukocytes, a hallmark of inflammation, is regulated by chemokines, which activate chemokine receptors on the leukocytes. Ticks target this process by secreting glycoproteins called Evasins, which bind to chemokines and prevent leukocyte recruitment. This review describes the recent discovery of numerous Evasins produced by ticks, their classification into two structural and functional classes, and the efficacy of Evasins in animal models of inflammatory diseases. The review also proposes a standard nomenclature system for Evasins and discusses the potential of repurposing or engineering Evasins as therapeutic anti-inflammatory agents.

  • Strategies for Development of a Next-Generation Protein Sequencing Platform
    Trends Biochem. Sci. (IF 16.889) Pub Date : 2019-10-30
    Nicholas Callahan, Jennifer Tullman, Zvi Kelman, John Marino

    Proteomic analysis can be a critical bottleneck in cellular characterization. The current paradigm relies primarily on mass spectrometry of peptides and affinity reagents (i.e., antibodies), both of which require a priori knowledge of the sample. An unbiased protein sequencing method, with a dynamic range that covers the full range of protein concentrations in proteomes, would revolutionize the field of proteomics, allowing a more facile characterization of novel gene products and subcellular complexes. To this end, several new platforms based on single-molecule protein-sequencing approaches have been proposed. This review summarizes four of these approaches, highlighting advantages, limitations, and challenges for each method towards advancing as a core technology for next-generation protein sequencing.

  • Protein quality control: U-box-containing E3 ubiquitin ligases join the fold.
    Trends Biochem. Sci. (IF 16.889) Pub Date : 2002-07-13
    Douglas M Cyr,Jörg Höhfeld,Cam Patterson

    Molecular chaperones act with folding co-chaperones to suppress protein aggregation and refold stress damaged proteins. However, it is not clear how slowly folding or misfolded polypeptides are targeted for proteasomal degradation. Generally, selection of proteins for degradation is mediated by E3 ubiquitin ligases of the mechanistically distinct HECT and RING domain sub-types. Recent studies suggest that the U-box protein family represents a third class of E3 enzymes. CHIP, a U-box-containing protein, is a degradatory co-chaperone of heat-shock protein 70 (Hsp70) and Hsp90 that facilitates the polyubiquitination of chaperone substrates. These data indicate a model for protein quality control in which the interaction of Hsp70 and Hsp90 with co-chaperones that have either folding or degradatory activity helps to determine the fate of non-native cellular proteins.

  • Glutamine repeats and neurodegenerative diseases: molecular aspects.
    Trends Biochem. Sci. (IF 16.889) Pub Date : 1999-03-31
    M F Perutz

    Eight severe inherited neurodegenerative diseases are caused by expansion of glutamine repeats in the affected proteins. In every case, proteins with repeats of fewer than 38 glutamine residues are harmless, but those with repeats of more than 41 glutamine residues form toxic neuronal nuclear aggregates in the affected neurons. Similarly, proteins that have repeats of fewer than 37 glutamine residues are soluble in vitro, whereas proteins with repeats of more than 40 glutamine residues precipitate as insoluble fibres, apparently because of a structural transition associated with the increased length.

  • Contact Mapping to Unravel Chromosome Folding.
    Trends Biochem. Sci. (IF 16.889) Pub Date : 2019-11-05
    Tiffany Ge,Celeste D Rosencrance,Kyle P Eagen

  • Deciphering Gene Regulation Using Massively Parallel Reporter Assays.
    Trends Biochem. Sci. (IF 16.889) Pub Date : null
    Max Trauernicht,Miguel Martinez-Ara,Bas van Steensel

  • 更新日期:2019-11-01
  • Fatty Acid Oxidation in Cell Fate Determination.
    Trends Biochem. Sci. (IF 16.889) Pub Date : 2018-05-08
    Jianhua Xiong

    Mitochondrial fatty acid β-oxidation (FAO) is a major catabolic process that degrades long-chain fatty acids. Recent reports reveal a broad role for FAO in cell fate control in endothelial cells, immune cells, and cancer cells. Concurrently, unique molecular pathways influenced by FAO have been identified that alter cell fate decisions.

  • Synthesis at the Speed of Codons.
    Trends Biochem. Sci. (IF 16.889) Pub Date : 2015-11-04
    Kristin S Koutmou,Aditya Radhakrishnan,Rachel Green

    The possibility that different mRNA sequences encoding identical peptides are translated dissimilarly has long been of great interest. Recent work by Yu and co-workers provides striking evidence that mRNA sequences influence the rate of protein synthesis, and lends support to the emerging idea that mRNA sequence informs protein folding.

  • DNA-Protein Crosslink Proteolysis Repair.
    Trends Biochem. Sci. (IF 16.889) Pub Date : 2017-04-19
    Bruno Vaz,Marta Popovic,Kristijan Ramadan

    Proteins that are covalently bound to DNA constitute a specific type of DNA lesion known as DNA-protein crosslinks (DPCs). DPCs represent physical obstacles to the progression of DNA replication. If not repaired, DPCs cause stalling of DNA replication forks that consequently leads to DNA double-strand breaks, the most cytotoxic DNA lesion. Although DPCs are common DNA lesions, the mechanism of DPC repair was unclear until now. Recent work unveiled that DPC repair is orchestrated by proteolysis performed by two distinct metalloproteases, SPARTAN in metazoans and Wss1 in yeast. This review summarizes recent discoveries on two proteases in DNA replication-coupled DPC repair and establishes DPC proteolysis repair as a separate DNA repair pathway for genome stability and protection from accelerated aging and cancer.

  • Caspases and caspase inhibitors.
    Trends Biochem. Sci. (IF 16.889) Pub Date : 1997-11-14
    P Villa,S H Kaufmann,W C Earnshaw

    Five years ago, little was known about mechanisms of apoptotic execution. Now, one class of cell-death gene, the cysteine and aspartases (caspases) has come under intensive study. This review discusses the two classes of caspases, the reasons why humans may have so many caspase genes, the growing list of caspase substrates, and viral and pharmacological caspase inhibitors.

  • A relationship betweena DNA-repair/recombination nuclease family and archaeal helicases.
    Trends Biochem. Sci. (IF 16.889) Pub Date : 1999-04-27
    J Sgouros,Pierre-Henri L Gaillard,R D Wood

  • Emerging Role of Electron Microscopy in Drug Discovery.
    Trends Biochem. Sci. (IF 16.889) Pub Date : 2019-08-15
    Rachel M Johnson,Anna J Higgins,Stephen P Muench

  • 更新日期:2019-11-01
  • POTRA: a conserved domain in the FtsQ family and a class of beta-barrel outer membrane proteins.
    Trends Biochem. Sci. (IF 16.889) Pub Date : 2003-10-16
    Luis Sánchez-Pulido,Damien Devos,Stéphanie Genevrois,Miguel Vicente,Alfonso Valencia

    POTRA (for polypeptide-transport-associated domain) is a novel domain identified in proteins of the ShlB, Toc75, D15 and FtsQ/DivIB families. In most cases, the POTRA domain is associated with a beta-barrel outer membrane domain and its function has been experimentally related to polypeptide transport in Toc75 (Tic-Toc protein import system in chloroplast) and ShlB families. In addition to potential key roles in protein transport across the outer membrane and in bacterial septation, the POTRA domain has attractive features for vaccine development in diseases such as cholera, meningitis, gonorrhoea and syphilis.

  • Integrin structure: heady advances in ligand binding, but activation still makes the knees wobble.
    Trends Biochem. Sci. (IF 16.889) Pub Date : 2003-06-27
    Martin J Humphries,Paul A McEwan,Stephanie J Barton,Patrick A Buckley,Jordi Bella,A Paul Mould

    Integrins are one of the major families of cell-adhesion receptors. In the past year, the first structure of an integrin has been published, ligand-binding pockets have been defined, and mechanisms of receptor priming and activation elucidated. Like all major advances, however, these studies have raised more questions than they have answered about issues such as the mechanisms underlying ligand-binding specificity and long-range conformational regulation.

  • Amidase domains from bacterial and phage autolysins define a family of gamma-D,L-glutamate-specific amidohydrolases.
    Trends Biochem. Sci. (IF 16.889) Pub Date : 2003-05-27
    Daniel J Rigden,Mark J Jedrzejas,Michael Y Galperin

    Several phage-encoded peptidoglycan hydrolases have been found to share a conserved amidase domain with a variety of bacterial autolysins (N-acetylmuramoyl-L-alanine amidases), bacterial and eukaryotic glutathionylspermidine amidases, gamma-D-glutamyl-L-diamino acid endopeptidase and NLP/P60 family proteins. All these proteins contain conserved cysteine and histidine residues and hydrolyze gamma-glutamyl-containing substrates. These cysteine residues have been shown to be essential for activity of several of these amidases and their thiol groups apparently function as the nucleophiles in the catalytic mechanisms of all enzymes containing this domain. The CHAP (cysteine, histidine-dependent amidohydrolases/peptidases) superfamily includes a variety of previously uncharacterized proteins, including the tail assembly protein K of phage lambda. Some members of this superfamily are important surface antigens in pathogenic bacteria and might represent drug and/or vaccine targets.

  • Historical review: viruses, crystals and geodesic domes.
    Trends Biochem. Sci. (IF 16.889) Pub Date : 2003-02-11
    Gregory J Morgan

    In the mid 1950s, Francis Crick and James Watson attempted to explain the structure of spherical viruses. They hypothesized that spherical viruses consist of 60 identical equivalently situated subunits. Such an arrangement has icosahedral symmetry. Subsequent biophysical and electron micrographic data suggested that many viruses had >60 subunits. Drawing inspiration from architecture, Donald Caspar and Aaron Klug discovered a solution to the problem - they proposed that spherical viruses were structured like miniature geodesic domes.

  • Lectin control of protein folding and sorting in the secretory pathway.
    Trends Biochem. Sci. (IF 16.889) Pub Date : 2003-01-09
    Joseph D Schrag,Daniela O Procopio,Miroslaw Cygler,David Y Thomas,John J M Bergeron

    Glycan moieties are essential for folding, sorting and targeting of glycoproteins through the secretory pathway to various cellular compartments. The molecular mechanisms that underlie these processes, however, are only now coming to light. Recent crystallographic and NMR studies of proteins located in the endoplasmic reticulum (ER), Golgi complex and ER-Golgi intermediate compartment have illuminated their roles in glycoprotein folding and secretion. Calnexin and calreticulin, both ER-resident proteins, have lectin domains that are crucial for their function as chaperones. The crystal structure of the carbohydrate-recognition domain of ER-Golgi intermediate compartment (ERGIC)-53 complements the biochemical and functional characterization of the protein, confirming that a lectin domain is essential for the role of this protein in sorting and transfer of glycoproteins from the ER to the Golgi complex. The lectin domains of calnexin and ERGIC-53 are structurally similar, although there is little primary sequence similarity. By contrast, sequence similarity between ERGIC-53 and vesicular integral membrane protein (VIP36), a Golgi-resident protein, leaves little doubt that a similar lectin domain is central to the transport and/or sorting functions of VIP36. The theme emerging from these studies is that carbohydrate recognition and modification are central to mediation of glycoprotein folding and secretion.

  • Linking chromatin function with metabolic networks: Sir2 family of NAD(+)-dependent deacetylases.
    Trends Biochem. Sci. (IF 16.889) Pub Date : 2003-01-09
    John M Denu

    Chromatin remodeling enzymes rely on coenzymes derived from metabolic pathways, suggesting a tight synchronization among apparently diverse cellular processes. A unique example of this link is the recently described NAD(+)-dependent protein and/or histone deacetylases. The founding member of this family - yeast silent information regulator 2 (ySir2) - is involved in gene silencing, chromosomal stability and ageing. Sir2-like enzymes catalyze a reaction in which the cleavage of NAD(+)and histone and/or protein deacetylation are coupled to the formation of O-acetyl-ADP-ribose, a novel metabolite. The dependence of the reaction on both NAD(+) and the generation of this potential second messenger offers new clues to understanding the function and regulation of nuclear, cytoplasmic and mitochondrial Sir2-like enzymes.

  • Structure, mechanism and regulation of peroxiredoxins.
    Trends Biochem. Sci. (IF 16.889) Pub Date : 2003-01-09
    Zachary A Wood,Ewald Schröder,J Robin Harris,Leslie B Poole

    Peroxiredoxins (Prxs) are a ubiquitous family of antioxidant enzymes that also control cytokine-induced peroxide levels which mediate signal transduction in mammalian cells. Prxs can be regulated by changes to phosphorylation, redox and possibly oligomerization states. Prxs are divided into three classes: typical 2-Cys Prxs; atypical 2-Cys Prxs; and 1-Cys Prxs. All Prxs share the same basic catalytic mechanism, in which an active-site cysteine (the peroxidatic cysteine) is oxidized to a sulfenic acid by the peroxide substrate. The recycling of the sulfenic acid back to a thiol is what distinguishes the three enzyme classes. Using crystal structures, a detailed catalytic cycle has been derived for typical 2-Cys Prxs, including a model for the redox-regulated oligomeric state proposed to control enzyme activity.

  • Transferring substrates to the 26S proteasome.
    Trends Biochem. Sci. (IF 16.889) Pub Date : 2003-01-09
    Rasmus Hartmann-Petersen,Michael Seeger,Colin Gordon

    Ubiquitin-dependent protein degradation is not only involved in the recycling of amino acids from damaged or misfolded proteins but also represents an essential and deftly controlled mechanism for modulating the levels of key regulatory proteins. Chains of ubiquitin conjugated to a substrate protein specifically target it for degradation by the 26S proteasome, a huge multi-subunit protein complex found in all eukaryotic cells. Recent reports have clarified some of the molecular mechanisms involved in the transfer of ubiquitinated substrates from the ubiquitination machinery to the proteasome. This novel substrate transportation step in the ubiquitin-proteasome pathway seems to occur either directly or indirectly via certain substrate-recruiting proteins and appears to involve chaperones.

  • Is there a unifying mechanism for protein folding?
    Trends Biochem. Sci. (IF 16.889) Pub Date : 2003-01-09
    Valerie Daggett,Alan R Fersht

    Proteins appear to fold by diverse pathways, but variations of a simple mechanism - nucleation-condensation - describe the overall features of folding of most domains. In general, secondary structure is inherently unstable and its stability is enhanced by tertiary interactions. Consequently, an extensive interplay of secondary and tertiary interactions determines the transition-state for folding, which is structurally similar to the native state, being formed in a general collapse (condensation) around a diffuse nucleus. As the propensity for stable secondary structure increases, folding becomes more hierarchical and eventually follows a framework mechanism where the transition state is assembled from pre-formed secondary structural elements.

  • Activation of G-protein Galpha subunits by receptors through Galpha-Gbeta and Galpha-Ggamma interactions.
    Trends Biochem. Sci. (IF 16.889) Pub Date : 2003-01-09
    Jacqueline Cherfils,Marc Chabre

    Activation of the Galpha subunit of heterotrimeric GTP-binding proteins by transmembrane receptors requires the propagation of structural signals from the receptor-binding site to the nucleotide-binding site at the opposite side of the protein. In a previous model, it was suggested that the Gbeta-Ggamma dimer is tilted away from Galpha by a lever-arm motion of the Galpha N-terminal helix. Here, we propose that the motion occurs in the opposite direction, close-packing the Galpha-Gbeta interface and creating a novel interface between the helical domain of Galpha and the N terminus of Ggamma, which determines the specificity of activation.

  • A conserved domain in prokaryotic bifunctional FAD synthetases can potentially catalyze nucleotide transfer.
    Trends Biochem. Sci. (IF 16.889) Pub Date : 2003-01-09
    Ananth Krupa,Kumaraswamy Sandhya,Narayanaswamy Srinivasan,Sobhanaditya Jonnalagadda

    Biosynthesis of flavin adenine dinucleotides in most prokaryotes is catalyzed by a family of bifunctional flavin adenine dinucleotide (FAD) synthetases. These enzymes carry out the dual functions of phosphorylation of flavin mononucleotide (FMN) and its subsequent adenylylation to generate FAD. Using various sequence analysis methods, a new domain has been identified in the N-terminal region that is well conserved in all the bacterial FAD synthetases. We also identify remote similarity of this domain to the nucleotidyl transferases and, hence, this domain is suggested to be invloved in the adenylylation reaction of FAD synthetases.

  • Cellular genomics: which genes are transcribed, when and where?
    Trends Biochem. Sci. (IF 16.889) Pub Date : 2003-01-09
    Ana Pombo

    Gene expression involves a cascade of events, from transcription factor transactivation and RNA polymerase binding to RNA processing and maturation. mRNA profiling has yielded a vast amount of information about the total RNA content in different tissues physiological states. However, it has been unclear how the variable amounts of mRNA might correlate with transcriptional events. Recent advances in single-cell imaging offer a platform for 'cellular genomics', the high throughput analysis of transcriptional activity in single cells.

  • AlkB mystery solved: oxidative demethylation of N1-methyladenine and N3-methylcytosine adducts by a direct reversal mechanism.
    Trends Biochem. Sci. (IF 16.889) Pub Date : 2003-01-09
    Thomas J Begley,Leona D Samson

    All organisms have multiple DNA repair pathways to protect against alkylation-induced mutation and cell death. For nearly two decades, we have known that the Escherichia coli alkB gene product protects against cell killing by S(N)2-alkylating agents, probably through DNA repair. Despite numerous attempts, a specific DNA repair activity could not be assigned to AlkB. Now, a breakthrough in biology and biochemistry, coupled with the discovery of an in silico protein structure, has uncovered a novel direct reversal DNA repair mechanism that is catalyzed by AlkB, namely the oxidative demethylation of N1-methyladenine or N3-methylcytosine DNA lesions. This reaction occurs on both single- and double-stranded DNA, and requires AlkB-bound non-heme Fe(2+), O(2) and alpha-ketogluterate to oxidize the offending methyl group. This is followed by the release of succinate, CO(2) and formaldehyde, and the restoration of undamaged A or C in DNA.

  • Biochemistry, the early years at Liverpool.
    Trends Biochem. Sci. (IF 16.889) Pub Date : 2002-12-07
    Emma Wilson

  • The third dimension for protein interactions and complexes.
    Trends Biochem. Sci. (IF 16.889) Pub Date : 2002-12-07
    Patrick Aloy,Robert B Russell

  • The chaperonin folding machine.
    Trends Biochem. Sci. (IF 16.889) Pub Date : 2002-12-07
    Helen R Saibil,Neil A Ranson

  • Multisite phosphorylation provides sophisticated regulation of transcription factors.
    Trends Biochem. Sci. (IF 16.889) Pub Date : 2002-12-07
    Carina I Holmberg,Stefanie E F Tran,John E Eriksson,Lea Sistonen

    Reversible phosphorylation is a prevalent mechanism by which the activity of eukaryotic transcription factors is regulated rapidly in response to changes in the cellular environment. Accumulated evidence has expanded the concept of phosphorylation to a process that provides dynamic and precise tuning of the transactivating potential of a factor, rather than being a static on/off switch. In the case of transcription factors such as heat shock factor 1 (HSF1), p53 and nuclear factor of activated T cells (NFAT), multisite phosphorylation enables several effects to operate within a single factor, thereby functioning as a key to signal integration. Studies on these transcription factors illustrate recent progress in solving the dynamic nature of transcriptional regulation by multisite phosphorylation.

  • p53 latency--out of the blind alley.
    Trends Biochem. Sci. (IF 16.889) Pub Date : 2002-12-07
    Tatiana Yakovleva,Aladdin Pramanik,Lars Terenius,Tomas J Ekström,Georgy Bakalkin

  • TSE agent strains and PrP: reconciling structure and function.
    Trends Biochem. Sci. (IF 16.889) Pub Date : 2002-12-07
    Robert A Somerville

    The molecular structures of the infectious agents that cause transmissible spongiform encephalopathy (TSE) diseases are still not known despite the current wide acceptance of the prion hypothesis as the basis for their resolution. Here, data supporting and challenging the prion hypothesis in relation to both the biochemical and biological properties of TSE infectious agents are discussed. The need for the independent transmission of TSE agent-specific genetic information is described and the requirements for the molecule to carry this information are proposed. Such a molecule is likely to be a small nucleic acid encoding information to determine the diversity of the pathogenesis of TSE agents.

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