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  • 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.

  • Phosphatidylserine Is the Signal for TAM Receptors and Their Ligands
    Trends Biochem. Sci. (IF 16.63) Pub Date : 2017-07-19
    Greg Lemke

    Nature repeatedly repurposes, in that molecules that serve as metabolites, energy depots, or polymer subunits are at the same time used to deliver signals within and between cells. The preeminent example of this repurposing is ATP, which functions as a building block for nucleic acids, an energy source for enzymatic reactions, a phosphate donor to regulate intracellular signaling, and a neurotransmitter to control the activity of neurons. A series of recent studies now consolidates the view that phosphatidylserine (PtdSer), a common phospholipid constituent of membrane bilayers, is similarly repurposed for use as a signal between cells and that the ligands and receptors of the Tyro3/Axl/Mer (TAM) family of receptor tyrosine kinases (RTKs) are prominent transducers of this signal.

  • A Bright Future for Serial Femtosecond Crystallography with XFELs
    Trends Biochem. Sci. (IF 16.63) Pub Date : 2017-07-18
    Linda C. Johansson, Benjamin Stauch, Andrii Ishchenko, Vadim Cherezov

    X-ray free electron lasers (XFELs) have the potential to revolutionize macromolecular structural biology due to the unique combination of spatial coherence, extreme peak brilliance, and short duration of X-ray pulses. A recently emerged serial femtosecond (fs) crystallography (SFX) approach using XFEL radiation overcomes some of the biggest hurdles of traditional crystallography related to radiation damage through the diffraction-before-destruction principle. Intense fs XFEL pulses enable high-resolution room-temperature structure determination of difficult-to-crystallize biological macromolecules, while simultaneously opening a new era of time-resolved structural studies. Here, we review the latest developments in instrumentation, sample delivery, data analysis, crystallization methods, and applications of SFX to important biological questions, and conclude with brief insights into the bright future of structural biology using XFELs.

  • Shaping and Reshaping Transcriptome Plasticity during Evolution
    Trends Biochem. Sci. (IF 16.63) Pub Date : 2017-07-14
    Shobbir Hussain

    Transcriptome plasticity, usually associated with alternative isoform generation, is recognised as a key mechanism driving proteomic diversity and biological complexity. Recent findings of Liscovitch-Brauer et al. and Ma et al. suggest that RNA base modifications are an additional central mode of transcriptome malleability that have the potential to determine evolutionary outcomes.

  • Biphasic Modeling of Mitochondrial Metabolism Dysregulation during Aging
    Trends Biochem. Sci. (IF 16.63) Pub Date : 2017-06-29
    Darren J. Baker, Shahaf Peleg

    Organismal aging is classically viewed as a gradual decline of cellular functions and a systemic deterioration of tissues that leads to an increased mortality rate in older individuals. According to the prevailing theory, aging is accompanied by a continuous and progressive decline in mitochondrial metabolic activity in cells. However, the most robust approaches to extending healthy lifespan are frequently linked with reduced energy intake or with lowering of mitochondrial activity. While these observations appear contradictory, recent work and technological advances demonstrate that metabolic deregulation during aging is potentially biphasic. In this Opinion we propose a novel framework where middle-age is accompanied by increased mitochondrial activity that subsequently declines at advanced ages.

  • Cytosolic Proteostasis Networks of the Mitochondrial Stress Response
    Trends Biochem. Sci. (IF 16.63) Pub Date : 2017-06-01
    Davide D’Amico, Vincenzo Sorrentino, Johan Auwerx

    Mitochondrial stress requires timely intervention to prevent mitochondrial and cellular dysfunction. Re-establishing the correct protein homeostasis is crucial for coping with mitochondrial stress and maintaining cellular homeostasis. The best-characterized adaptive pathways for mitochondrial stress involve a signal originating from stressed mitochondria that triggers a nuclear response. However, recent findings have shown that mitochondrial stress also affects a complex network of protein homeostasis pathways in the cytosol. We review how mitochondrial dysregulation affects cytosolic proteostasis by regulating the quantity and quality of protein synthesis, protein stability, and protein degradation, leading to an integrated regulation of cellular metabolism and proliferation. This mitochondria to cytosol network extends the current model of the mitochondrial stress response, with potential applications in the treatment of mitochondrial disease.

  • Bacterial Inclusion Bodies: Discovering Their Better Half
    Trends Biochem. Sci. (IF 16.63) Pub Date : 2017-02-27
    Ursula Rinas, Elena Garcia-Fruitós, José Luis Corchero, Esther Vázquez, Joaquin Seras-Franzoso, Antonio Villaverde

    Bacterial inclusion bodies (IBs) are functional, non-toxic amyloids occurring in recombinant bacteria showing analogies with secretory granules of the mammalian endocrine system. The scientific interest in these mesoscale protein aggregates has been historically masked by their status as a hurdle in recombinant protein production. However, progressive understanding of how the cell handles the quality of recombinant polypeptides and the main features of their intriguing molecular organization has stimulated the interest in inclusion bodies and spurred their use in diverse technological fields. The engineering and tailoring of IBs as functional protein particles for materials science and biomedicine is a good example of how formerly undesired bacterial byproducts can be rediscovered as promising functional materials for a broad spectrum of applications.

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.