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  • Moving Through Barriers in Science and Life
    Annu. Rev. Biochem. (IF 26.922) Pub Date : 2019-06-20
    Judith P. Klinman

    This first serious attempt at an autobiographical accounting has forced me to sit still long enough to compile my thoughts about a long personal and scientific journey. I especially hope that my trajectory will be of interest and perhaps beneficial to much younger women who are just getting started in their careers. To paraphrase from Virginia Woolf's writings in A Room of One's Own at the beginning of the 20th century, “for most of history Anonymous was a Woman.” However, Ms. Woolf is also quoted as saying “nothing has really happened until it has been described,” a harbinger of the enormous historical changes that were about to be enacted and recorded by women in the sciences and other disciplines. The progress in my chosen field of study—the chemical basis of enzyme action—has also been remarkable, from the first description of an enzyme's 3D structure to a growing and deep understanding of the origins of enzyme catalysis.

    更新日期:2019-11-18
  • Biophysical Techniques in Structural Biology
    Annu. Rev. Biochem. (IF 26.922) Pub Date : 2019-06-20
    Christopher M. Dobson

    Over the past six decades, steadily increasing progress in the application of the principles and techniques of the physical sciences to the study of biological systems has led to remarkable insights into the molecular basis of life. Of particular significance has been the way in which the determination of the structures and dynamical properties of proteins and nucleic acids has so often led directly to a profound understanding of the nature and mechanism of their functional roles. The increasing number and power of experimental and theoretical techniques that can be applied successfully to living systems is now ushering in a new era of structural biology that is leading to fundamentally new information about the maintenance of health, the origins of disease, and the development of effective strategies for therapeutic intervention. This article provides a brief overview of some of the most powerful biophysical methods in use today, along with references that provide more detailed information about recent applications of each of them.

    更新日期:2019-11-18
  • X-Ray Free-Electron Lasers for the Structure and Dynamics of Macromolecules
    Annu. Rev. Biochem. (IF 26.922) Pub Date : 2019-06-20
    Henry N. Chapman

    X-ray free-electron lasers provide femtosecond-duration pulses of hard X-rays with a peak brightness approximately one billion times greater than is available at synchrotron radiation facilities. One motivation for the development of such X-ray sources was the proposal to obtain structures of macromolecules, macromolecular complexes, and virus particles, without the need for crystallization, through diffraction measurements of single noncrystalline objects. Initial explorations of this idea and of outrunning radiation damage with femtosecond pulses led to the development of serial crystallography and the ability to obtain high-resolution structures of small crystals without the need for cryogenic cooling. This technique allows the understanding of conformational dynamics and enzymatics and the resolution of intermediate states in reactions over timescales of 100 fs to minutes. The promise of more photons per atom recorded in a diffraction pattern than electrons per atom contributing to an electron micrograph may enable diffraction measurements of single molecules, although challenges remain.

    更新日期:2019-11-18
  • Bacteriorhodopsin: Structural Insights Revealed Using X-Ray Lasers and Synchrotron Radiation
    Annu. Rev. Biochem. (IF 26.922) Pub Date : 2019-06-20
    Cecilia Wickstrand, Przemyslaw Nogly, Eriko Nango, So Iwata, Jörg Standfuss, Richard Neutze

    Directional transport of protons across an energy transducing membrane—proton pumping—is ubiquitous in biology. Bacteriorhodopsin (bR) is a light-driven proton pump that is activated by a buried all-trans retinal chromophore being photoisomerized to a 13-cis conformation. The mechanism by which photoisomerization initiates directional proton transport against a proton concentration gradient has been studied by a myriad of biochemical, biophysical, and structural techniques. X-ray free electron lasers (XFELs) have created new opportunities to probe the structural dynamics of bR at room temperature on timescales from femtoseconds to milliseconds using time-resolved serial femtosecond crystallography (TR-SFX). Wereview these recent developments and highlight where XFEL studies reveal new details concerning the structural mechanism of retinal photoisomerization and proton pumping. We also discuss the extent to which these insights were anticipated by earlier intermediate trapping studies using synchrotron radiation. TR-SFX will open up the field for dynamical studies of other proteins that are not naturally light-sensitive.

    更新日期:2019-11-18
  • Membrane Protein–Lipid Interactions Probed Using Mass Spectrometry
    Annu. Rev. Biochem. (IF 26.922) Pub Date : 2019-06-20
    Jani Reddy Bolla, Mark T. Agasid, Shahid Mehmood, Carol V. Robinson

    Membrane proteins that exist in lipid bilayers are not isolated molecular entities. The lipid molecules that surround them play crucial roles in maintaining their full structural and functional integrity. Research directed at investigating these critical lipid–protein interactions is developing rapidly. Advancements in both instrumentation and software, as well as in key biophysical and biochemical techniques, are accelerating the field. In this review, we provide a brief outline of structural techniques used to probe protein–lipid interactions and focus on the molecular aspects of these interactions obtained from native mass spectrometry (native MS). We highlight examples in which lipids have been shown to modulate membrane protein structure and show how native MS has emerged as a complementary technique to X-ray crystallography and cryo–electron microscopy. We conclude with a short perspective on future developments that aim to better understand protein–lipid interactions in the native environment.

    更新日期:2019-11-18
  • Integrative Structure Modeling: Overview and Assessment
    Annu. Rev. Biochem. (IF 26.922) Pub Date : 2019-06-20
    Merav Braitbard, Dina Schneidman-Duhovny, Nir Kalisman

    Integrative structure modeling computationally combines data from multiple sources of information with the aim of obtaining structural insights that are not revealed by any single approach alone. In the first part of this review, we survey the commonly used sources of structural information and the computational aspects of model building. Throughout the past decade, integrative modeling was applied to various biological systems, with a focus on large protein complexes. Recent progress in the field of cryo–electron microscopy (cryo-EM) has resolved many of these complexes to near-atomic resolution. In the second part of this review, we compare a range of published integrative models with their higher-resolution counterparts with the aim of critically assessing their accuracy. This comparison gives a favorable view of integrative modeling and demonstrates its ability to yield accurate and informative results. We discuss possible roles of integrative modeling in the new era of cryo-EM and highlight future challenges and directions.

    更新日期:2019-11-18
  • Eukaryotic Base Excision Repair: New Approaches Shine Light on Mechanism
    Annu. Rev. Biochem. (IF 26.922) Pub Date : 2019-06-20
    William A. Beard, Julie K. Horton, Rajendra Prasad, Samuel H. Wilson

    Genomic DNA is susceptible to endogenous and environmental stresses that modify DNA structure and its coding potential. Correspondingly, cells have evolved intricate DNA repair systems to deter changes to their genetic material. Base excision DNA repair involves a number of enzymes and protein cofactors that hasten repair of damaged DNA bases. Recent advances have identified macromolecular complexes that assemble at the DNA lesion and mediate repair. The repair of base lesions generally requires five enzymatic activities: glycosylase, endonuclease, lyase, polymerase, and ligase. The protein cofactors and mechanisms for coordinating the sequential enzymatic steps of repair are being revealed through a range of experimental approaches. We discuss the enzymes and protein cofactors involved in eukaryotic base excision repair, emphasizing the challenge of integrating findings from multiple methodologies. The results provide an opportunity to assimilate biochemical findings with cell-based assays to uncover new insights into this deceptively complex repair pathway.

    更新日期:2019-11-18
  • Redox Chemistry in the Genome: Emergence of the [4Fe4S] Cofactor in Repair and Replication
    Annu. Rev. Biochem. (IF 26.922) Pub Date : 2019-06-20
    Jacqueline K. Barton, Rebekah M.B. Silva, Elizabeth O'Brien

    Many DNA-processing enzymes have been shown to contain a [4Fe4S] cluster, a common redox cofactor in biology. Using DNA electrochemistry, we find that binding of the DNA polyanion promotes a negative shift in [4Fe4S] cluster potential, which corresponds thermodynamically to a ∼500-fold increase in DNA-binding affinity for the oxidized [4Fe4S]3+ cluster versus the reduced [4Fe4S]2+ cluster. This redox switch can be activated from a distance using DNA charge transport (DNA CT) chemistry. DNA-processing proteins containing the [4Fe4S] cluster are enumerated, with possible roles for the redox switch highlighted. A model is described where repair proteins may signal one another using DNA-mediated charge transport as a first step in their search for lesions. The redox switch in eukaryotic DNA primases appears to regulate polymerase handoff, and in DNA polymerase δ, the redox switch provides a means to modulate replication in response to oxidative stress. We thus describe redox signaling interactions of DNA-processing [4Fe4S] enzymes, as well as the most interesting potential players to consider in delineating new DNA-mediated redox signaling networks.

    更新日期:2019-11-18
  • Evaluating and Enhancing Target Specificity of Gene-Editing Nucleases and Deaminases
    Annu. Rev. Biochem. (IF 26.922) Pub Date : 2019-06-20
    Daesik Kim, Kevin Luk, Scot A. Wolfe, Jin-Soo Kim

    Programmable nucleases and deaminases, which include zinc-finger nucleases, transcription activator-like effector nucleases, CRISPR RNA-guided nucleases, and RNA-guided base editors, are now widely employed for the targeted modification of genomes in cells and organisms. These gene-editing tools hold tremendous promise for therapeutic applications. Importantly, these nucleases and deaminases may display off-target activity through the recognition of near-cognate DNA sequences to their target sites, resulting in collateral damage to the genome in the form of local mutagenesis or genomic rearrangements. For therapeutic genome-editing applications with these classes of programmable enzymes, it is essential to measure and limit genome-wide off-target activity. Herein, we discuss the key determinants of off-target activity for these systems. We describe various cell-based and cell-free methods for identifying genome-wide off-target sites and diverse strategies that have been developed for reducing the off-target activity of programmable gene-editing enzymes.

    更新日期:2019-11-18
  • The BRCA Tumor Suppressor Network in Chromosome Damage Repair by Homologous Recombination
    Annu. Rev. Biochem. (IF 26.922) Pub Date : 2019-06-20
    Weixing Zhao, Claudia Wiese, Youngho Kwon, Robert Hromas, Patrick Sung

    Mutations in the BRCA1 and BRCA2 genes predispose afflicted individuals to breast, ovarian, and other cancers. The BRCA-encoded products form complexes with other tumor suppressor proteins and with the recombinase enzyme RAD51 to mediate chromosome damage repair by homologous recombination and also to protect stressed DNA replication forks against spurious nucleolytic attrition. Understanding how the BRCA tumor suppressor network executes its biological functions would provide the foundation for developing targeted cancer therapeutics, but progress in this area has been greatly hampered by the challenge of obtaining purified BRCA complexes for mechanistic studies. In this article, we review how recent effort begins to overcome this technical challenge, leading to functional and structural insights into the biochemical attributes of these complexes and the multifaceted roles that they fulfill in genome maintenance. We also highlight the major mechanistic questions that remain.

    更新日期:2019-11-18
  • Cancer Treatment in the Genomic Era
    Annu. Rev. Biochem. (IF 26.922) Pub Date : 2019-06-20
    Gary J. Doherty, Michele Petruzzelli, Emma Beddowes, Saif S. Ahmad, Carlos Caldas, Richard J. Gilbertson

    The complexity of human cancer underlies its devastating clinical consequences. Drugs designed to target the genetic alterations that drive cancer have improved the outcome for many patients, but not the majority of them. Here, we review the genomic landscape of cancer, how genomic data can provide much more than a sum of its parts, and the approaches developed to identify and validate genomic alterations with potential therapeutic value. We highlight notable successes and pitfalls in predicting the value of potential therapeutic targets and discuss the use of multi-omic data to better understand cancer dependencies and drug sensitivity. We discuss how integrated approaches to collecting, curating, and sharing these large data sets might improve the identification and prioritization of cancer vulnerabilities as well as patient stratification within clinical trials. Finally, we outline how future approaches might improve the efficiency and speed of translating genomic data into clinically effective therapies and how the use of unbiased genome-wide information can identify novel predictive biomarkers that can be either simple or complex.

    更新日期:2019-11-18
  • Eukaryotic Ribosome Assembly
    Annu. Rev. Biochem. (IF 26.922) Pub Date : 2019-06-20
    Jochen Baßler, Ed Hurt

    Ribosomes, which synthesize the proteins of a cell, comprise ribosomal RNA and ribosomal proteins, which coassemble hierarchically during a process termed ribosome biogenesis. Historically, biochemical and molecular biology approaches have revealed how preribosomal particles form and mature in consecutive steps, starting in the nucleolus and terminating after nuclear export into the cytoplasm. However, only recently, due to the revolution in cryo–electron microscopy, could pseudoatomic structures of different preribosomal particles be obtained. Together with in vitro maturation assays, these findings shed light on how nascent ribosomes progress stepwise along a dynamic biogenesis pathway. Preribosomes assemble gradually, chaperoned by a myriad of assembly factors and small nucleolar RNAs, before they reach maturity and enter translation. This information will lead to a better understanding of how ribosome synthesis is linked to other cellular pathways in humans and how it can cause diseases, including cancer, if disturbed.

    更新日期:2019-11-18
  • The Organizing Principles of Eukaryotic Ribosome Recruitment
    Annu. Rev. Biochem. (IF 26.922) Pub Date : 2019-06-20
    Jerry Pelletier, Nahum Sonenberg

    The stage at which ribosomes are recruited to messenger RNAs (mRNAs) is an elaborate and highly regulated phase of protein synthesis. Upon completion of this step, a ribosome is positioned at an appropriate initiation codon and primed to synthesize the encoded polypeptide product. In most circumstances, this step commits the ribosome to translate the mRNA. We summarize the knowledge regarding the initiation factors implicated in this activity as well as review different mechanisms by which this process is conducted.

    更新日期:2019-11-18
  • Mechanisms of Cotranslational Maturation of Newly Synthesized Proteins
    Annu. Rev. Biochem. (IF 26.922) Pub Date : 2019-06-20
    Günter Kramer, Ayala Shiber, Bernd Bukau

    The timely production of functional proteins is of critical importance for the biological activity of cells. To reach the functional state, newly synthesized polypeptides have to become enzymatically processed, folded, and assembled into oligomeric complexes and, for noncytosolic proteins, translocated across membranes. Key activities of these processes occur cotranslationally, assisted by a network of machineries that transiently engage nascent polypeptides at distinct phases of translation. The sequence of events is tuned by intrinsic features of the nascent polypeptides and timely association of factors with the translating ribosome. Considering the dynamics of translation, the heterogeneity of cellular proteins, and the diversity of interaction partners, it is a major cellular achievement that these processes are temporally and spatially so precisely coordinated, minimizing the generation of damaged proteins. This review summarizes the current progress we have made toward a comprehensive understanding of the cotranslational interactions of nascent chains, which pave the way to their functional state.

    更新日期:2019-11-18
  • Lysine-Targeted Inhibitors and Chemoproteomic Probes
    Annu. Rev. Biochem. (IF 26.922) Pub Date : 2019-06-20
    Adolfo Cuesta, Jack Taunton

    Covalent inhibitors are widely used in drug discovery and chemical biology. Although covalent inhibitors are frequently designed to react with noncatalytic cysteines, many ligand binding sites lack an accessible cysteine. Here, we review recent advances in the chemical biology of lysine-targeted covalent inhibitors and chemoproteomic probes. By analyzing crystal structures of proteins bound to common metabolites and enzyme cofactors, we identify a large set of mostly unexplored lysines that are potentially targetable with covalent inhibitors. In addition, we describe mass spectrometry–based approaches for determining proteome-wide lysine ligandability and lysine-reactive chemoproteomic probes for assessing drug–target engagement. Finally, we discuss the design of amine-reactive inhibitors that form reversible covalent bonds with their protein targets.

    更新日期:2019-11-18
  • Horizontal Cell Biology: Monitoring Global Changes of Protein Interaction States with the Proteome-Wide Cellular Thermal Shift Assay (CETSA)
    Annu. Rev. Biochem. (IF 26.922) Pub Date : 2019-06-20
    Lingyun Dai, Nayana Prabhu, Liang Ying Yu, Smaranda Bacanu, Anderson Daniel Ramos, Pär Nordlund

    The cellular thermal shift assay (CETSA) is a biophysical technique allowing direct studies of ligand binding to proteins in cells and tissues. The proteome-wide implementation of CETSA with mass spectrometry detection (MS-CETSA) has now been successfully applied to discover targets for orphan clinical drugs and hits from phenotypic screens, to identify off-targets, and to explain poly-pharmacology and drug toxicity. Highly sensitive multidimensional MS-CETSA implementations can now also access binding of physiological ligands to proteins, such as metabolites, nucleic acids, and other proteins. MS-CETSA can thereby provide comprehensive information on modulations of protein interaction states in cellular processes, including downstream effects of drugs and transitions between different physiological cell states. Such horizontal information on ligandmodulation in cells is largely orthogonal to vertical information on the levels of different proteins and therefore opens novel opportunities to understand operational aspects of cellular proteomes.

    更新日期:2019-11-18
  • Soluble Methane Monooxygenase
    Annu. Rev. Biochem. (IF 26.922) Pub Date : 2019-06-20
    Rahul Banerjee, Jason C. Jones, John D. Lipscomb

    Aerobic life is possible because the molecular structure of oxygen (O2) makes direct reaction with most organic materials at ambient temperatures an exceptionally slow process. Of course, these reactions are inherently very favorable, and they occur rapidly with the release of a great deal of energy at high temperature. Nature has been able to tap this sequestered reservoir of energy with great spatial and temporal selectivity at ambient temperatures through the evolution of oxidase and oxygenase enzymes. One mechanism used by these enzymes for O2 activation has been studied in detail for the soluble form of the enzyme methane monooxygenase. These studies have revealed the step-by-step process of O2 activation and insertion into the ultimately stable C–H bond of methane. Additionally, an elegant regulatory mechanism has been defined that enlists size selection and quantum tunneling to allow methane oxidation to occur specifically in the presence of more easily oxidized substrates.

    更新日期:2019-11-18
  • Glycoengineering of Antibodies for Modulating Functions
    Annu. Rev. Biochem. (IF 26.922) Pub Date : 2019-06-20
    Lai-Xi Wang, Xin Tong, Chao Li, John P. Giddens, Tiezheng Li

    Antibodies are immunoglobulins that play essential roles in immune systems. All antibodies are glycoproteins that carry at least one or more conserved N-linked oligosaccharides (N-glycans) at the Fc domain. Many studies have demonstrated that both the presence and fine structures of the attached glycans can exert a profound impact on the biological functions and therapeutic efficacy of antibodies. However, antibodies usually exist as mixtures of heterogeneous glycoforms that are difficult to separate in pure glycoforms. Recent progress in glycoengineering has provided useful methods that enable production of glycan-defined and site-selectively modified antibodies for functional studies and for improved therapeutic efficacy. This review highlights major approaches in glycoengineering of antibodies with a focus on recent advances in three areas: glycoengineering through glycan biosynthetic pathway manipulation, glycoengineering through in vitro chemoenzymatic glycan remodeling, and glycoengineering of antibodies for site-specific antibody–drug conjugation.

    更新日期:2019-11-18
  • Lysosomal Glycosphingolipid Storage Diseases
    Annu. Rev. Biochem. (IF 26.922) Pub Date : 2019-06-20
    Bernadette Breiden, Konrad Sandhoff

    Glycosphingolipids are cell-type-specific components of the outer leaflet of mammalian plasma membranes. Gangliosides, sialic acid–containing glycosphingolipids, are especially enriched on neuronal surfaces. As amphi-philic molecules, they comprise a hydrophilic oligosaccharide chain attached to a hydrophobic membrane anchor, ceramide. Whereas glycosphingolipid formation is catalyzed by membrane-bound enzymes along the secretory pathway, degradation takes place at the surface of intralysosomal vesicles of late endosomes and lysosomes catalyzed in a stepwise fashion by soluble hydrolases and assisted by small lipid-binding glycoproteins. Inherited defects of lysosomal hydrolases or lipid-binding proteins cause the accumulation of undegradable material in lysosomal storage diseases (GM1 and GM2 gangliosidosis; Fabry, Gaucher, and Krabbe diseases; and metachromatic leukodystrophy). The catabolic processes are strongly modified by the lipid composition of the substrate-carrying membranes, and the pathological accumulation of primary storage compounds can trigger an accumulation of secondary storage compounds (e.g., small glycosphingolipids and cholesterol in Niemann-Pick disease).

    更新日期:2019-11-18
  • Exosomes
    Annu. Rev. Biochem. (IF 26.922) Pub Date : 2019-06-20
    D. Michiel Pegtel, Stephen J. Gould

    Exosomes are small, single-membrane, secreted organelles of ∼30 to ∼200 nm in diameter that have the same topology as the cell and are enriched in selected proteins, lipids, nucleic acids, and glycoconjugates. Exosomes contain an array of membrane-associated, high-order oligomeric protein complexes, display pronounced molecular heterogeneity, and are created by budding at both plasma and endosome membranes. Exosome biogenesis is a mechanism of protein quality control, and once released, exosomes have activities as diverse as remodeling the extracellular matrix and transmitting signals and molecules to other cells. This pathway of intercellular vesicle traffic plays important roles in many aspects of human health and disease, including development, immunity, tissue homeostasis, cancer, and neurodegenerative diseases. In addition, viruses co-opt exosome biogenesis pathways both for assembling infectious particles and for establishing host permissiveness. On the basis of these and other properties, exosomes are being developed as therapeutic agents in multiple disease models.

    更新日期:2019-11-18
  • Structure and Mechanisms of F-Type ATP Synthases
    Annu. Rev. Biochem. (IF 26.922) Pub Date : 2019-06-20
    Werner Kühlbrandt

    F1Fo ATP synthases produce most of the ATP in the cell. F-type ATP synthases have been investigated for more than 50 years, but a full understanding of their molecular mechanisms has become possible only with the recent structures of complete, functionally competent complexes determined by electron cryo-microscopy (cryo-EM). High-resolution cryo-EM structures offer a wealth of unexpected new insights. The catalytic F1 head rotates with the central γ-subunit for the first part of each ATP-generating power stroke. Joint rotation is enabled by subunit δ/OSCP acting as a flexible hinge between F1 and the peripheral stalk. Subunit a conducts protons to and from the c-ring rotor through two conserved aqueous channels. The channels are separated by ∼6 Å in the hydrophobic core of Fo, resulting in a strong local field that generates torque to drive rotary catalysis in F1. The structure of the chloroplast F1Fo complex explains how ATPase activity is turned off at night by a redox switch. Structures of mitochondrial ATP synthase dimers indicate how they shape the inner membrane cristae. The new cryo-EM structures complete our picture of the ATP synthases and reveal the unique mechanism by which they transform an electrochemical membrane potential into biologically useful chemical energy.

    更新日期:2019-11-18
  • ECF-Type ATP-Binding Cassette Transporters
    Annu. Rev. Biochem. (IF 26.922) Pub Date : 2019-06-20
    S. Rempel, W.K. Stanek, D.J. Slotboom

    Energy-coupling factor (ECF)–type ATP-binding cassette (ABC) transporters catalyze membrane transport of micronutrients in prokaryotes. Crystal structures and biochemical characterization have revealed that ECF transporters are mechanistically distinct from other ABC transport systems. Notably, ECF transporters make use of small integral membrane subunits (S-components) that are predicted to topple over in the membrane when carrying the bound substrate from the extracellular side of the bilayer to the cytosol. Here, we review the phylogenetic diversity of ECF transporters as well as recent structural and biochemical advancements that have led to the postulation of conceptually different mechanistic models. These models can be described as power stroke and thermal ratchet. Structural data indicate that the lipid composition and bilayer structure are likely to have great impact on the transport function. We argue that study of ECF transporters could lead to generic insight into membrane protein structure, dynamics, and interaction.

    更新日期:2019-11-18
  • The Hippo Pathway: Biology and Pathophysiology
    Annu. Rev. Biochem. (IF 26.922) Pub Date : 2019-06-20
    Shenghong Ma, Zhipeng Meng, Rui Chen, Kun-Liang Guan

    The Hippo pathway was initially discovered in Drosophila melanogaster as a key regulator of tissue growth. It is an evolutionarily conserved signaling cascade regulating numerous biological processes, including cell growth and fate decision, organ size control, and regeneration. The core of the Hippo pathway in mammals consists of a kinase cascade, MST1/2 and LATS1/2, as well as downstream effectors, transcriptional coactivators YAP and TAZ. These core components of the Hippo pathway control transcriptional programs involved in cell proliferation, survival, mobility, stemness, and differentiation. The Hippo pathway is tightly regulated by both intrinsic and extrinsic signals, such as mechanical force, cell–cell contact, polarity, energy status, stress, and many diffusible hormonal factors, the majority of which act through G protein–coupled receptors. Here, we review the current understanding of molecular mechanisms by which signals regulate the Hippo pathway with an emphasis on mechanotransduction and the effects of this pathway on basic biology and human diseases.

    更新日期:2019-11-18
  • Small-Molecule-Based Fluorescent Sensors for Selective Detection of Reactive Oxygen Species in Biological Systems
    Annu. Rev. Biochem. (IF 26.922) Pub Date : 2019-06-20
    Xiaoyu Bai, Kenneth King-Hei Ng, Jun Jacob Hu, Sen Ye, Dan Yang

    Reactive oxygen species (ROS) encompass a collection of intricately linked chemical entities characterized by individually distinct physicochemical properties and biological reactivities. Although excessive ROS generation is well known to underpin disease development, it has become increasingly evident that ROS also play central roles in redox regulation and normal physiology. A major challenge in uncovering the relevant biological mechanisms and deconvoluting the apparently paradoxical roles of distinct ROS in human health and disease lies in the selective and sensitive detection of these transient species in the complex biological milieu. Small-molecule-based fluorescent sensors enable molecular imaging of ROS with great spatial and temporal resolution and have thus been appreciated as excellent tools for aiding discoveries in modern redox biology. We review a selection of state-of-the-art sensors with demonstrated utility in biological systems. By providing a systematic overview based on underlying chemical sensing mechanisms, we wish to highlight the strengths and weaknesses in prior sensor works and propose some guiding principles for the development of future probes.

    更新日期:2019-11-18
  • Single-Molecule Kinetics in Living Cells
    Annu. Rev. Biochem. (IF 26.922) Pub Date : 2019-06-20
    Johan Elf, Irmeli Barkefors

    In the past decades, advances in microscopy have made it possible to study the dynamics of individual biomolecules in vitro and resolve intramolecular kinetics that would otherwise be hidden in ensemble averages. More recently, single-molecule methods have been used to image, localize, and track individually labeled macromolecules in the cytoplasm of living cells, allowing investigations of intermolecular kinetics under physiologically relevant conditions. In this review, we illuminate the particular advantages of single-molecule techniques when studying kinetics in living cells and discuss solutions to specific challenges associated with these methods.

    更新日期:2019-11-18
  • Molecular Mechanism of Cytokinesis
    Annu. Rev. Biochem. (IF 26.922) Pub Date : 2019-06-20
    Thomas D. Pollard, Ben O'Shaughnessy

    Division of amoebas, fungi, and animal cells into two daughter cells at the end of the cell cycle depends on a common set of ancient proteins, principally actin filaments and myosin-II motors. Anillin, formins, IQGAPs, and many other proteins regulate the assembly of the actin filaments into a contractile ring positioned between the daughter nuclei by different mechanisms in fungi and animal cells. Interactions of myosin-II with actin filaments produce force to assemble and then constrict the contractile ring to form a cleavage furrow. Contractile rings disassemble as they constrict. In some cases, knowledge about the numbers of participating proteins and their biochemical mechanisms has made it possible to formulate molecularly explicit mathematical models that reproduce the observed physical events during cytokinesis by computer simulations.

    更新日期:2019-11-18
  • Mechanism and Regulation of Centriole and Cilium Biogenesis
    Annu. Rev. Biochem. (IF 26.922) Pub Date : 2019-06-20
    David K. Breslow, Andrew J. Holland

    The centriole is an ancient microtubule-based organelle with a conserved nine-fold symmetry. Centrioles form the core of centrosomes, which organize the interphase microtubule cytoskeleton of most animal cells and form the poles of the mitotic spindle. Centrioles can also be modified to form basal bodies, which template the formation of cilia and play central roles in cellular signaling, fluid movement, and locomotion. In this review, we discuss developments in our understanding of the biogenesis of centrioles and cilia and the regulatory controls that govern their structure and number. We also discuss how defects in these processes contribute to a spectrum of human diseases and how new technologies have expanded our understanding of centriole and cilium biology, revealing exciting avenues for future exploration.

    更新日期:2019-11-18
  • The Structure of the Nuclear Pore Complex (An Update)
    Annu. Rev. Biochem. (IF 26.922) Pub Date : 2019-06-20
    Daniel H. Lin, André Hoelz

    The nuclear pore complex (NPC) serves as the sole bidirectional gateway of macromolecules in and out of the nucleus. Owing to its size and complexity (∼1,000 protein subunits, ∼110 MDa in humans), the NPC has remained one of the foremost challenges for structure determination. Structural studies have now provided atomic-resolution crystal structures of most nucleoporins. The acquisition of these structures, combined with biochemical reconstitution experiments, cross-linking mass spectrometry, and cryo–electron tomography, has facilitated the determination of the near-atomic overall architecture of the symmetric core of the human, fungal, and algal NPCs. Here, we discuss the insights gained from these new advances and outstanding issues regarding NPC structure and function. The powerful combination of bottom-up and top-down approaches toward determining the structure of the NPC offers a paradigm for uncovering the architectures of other complex biological machines to near-atomic resolution.

    更新日期:2019-11-18
  • Propagation of Protein Aggregation in Neurodegenerative Diseases
    Annu. Rev. Biochem. (IF 26.922) Pub Date : 2019-06-20
    Jaime Vaquer-Alicea, Marc I. Diamond

    Most common neurodegenerative diseases feature deposition of protein amyloids and degeneration of brain networks. Amyloids are ordered protein assemblies that can act as templates for their own replication through monomer addition. Evidence suggests that this characteristic may underlie the progression of pathology in neurodegenerative diseases. Many different amyloid proteins, including Aβ, tau, and α-synuclein, exhibit properties similar to those of infectious prion protein in experimental systems: discrete and self-replicating amyloid structures, transcellular propagation of aggregation, and transmissible neuropathology. This review discusses the contribution of prion phenomena and transcellular propagation to the progression of pathology in common neurodegenerative diseases such as Alzheimer's and Parkinson's. It reviews fundamental events such as cell entry, amplification, and transcellular movement. It also discusses amyloid strains, which produce distinct patterns of neuropathology and spread through the nervous system. These concepts may impact the development of new diagnostic and therapeutic strategies.

    更新日期:2019-11-18
  • Botulinum and Tetanus Neurotoxins
    Annu. Rev. Biochem. (IF 26.922) Pub Date : 2019-06-20
    Min Dong, Geoffrey Masuyer, Pål Stenmark

    Botulinum neurotoxins (BoNTs) and tetanus neurotoxin (TeNT) are the most potent toxins known and cause botulism and tetanus, respectively. BoNTs are also widely utilized as therapeutic toxins. They contain three functional domains responsible for receptor-binding, membrane translocation, and proteolytic cleavage of host proteins required for synaptic vesicle exocytosis. These toxins also have distinct features: BoNTs exist within a progenitor toxin complex (PTC), which protects the toxin and facilitates its absorption in the gastrointestinal tract, whereas TeNT is uniquely transported retrogradely within motor neurons. Our increasing knowledge of these toxins has allowed the development of engineered toxins for medical uses. The discovery of new BoNTs and BoNT-like proteins provides additional tools to understand the evolution of the toxins and to engineer toxin-based therapeutics. This review summarizes the progress on our understanding of BoNTs and TeNT, focusing on the PTC, receptor recognition, new BoNT-like toxins, and therapeutic toxin engineering.

    更新日期:2019-11-18
  • Inactivation and detoxication of pressor amines.
    Annu. Rev. Biochem. (IF 26.922) Pub Date : 1946-01-01
    W H HARTUNG

    更新日期:2019-11-01
  • The viruses.
    Annu. Rev. Biochem. (IF 26.922) Pub Date : 1946-01-01
    N W PIRIE

    更新日期:2019-11-01
  • Organic insecticides.
    Annu. Rev. Biochem. (IF 26.922) Pub Date : 1946-01-01
    W M HOSKINS,R CRAIG

    更新日期:2019-11-01
  • Immunochemistry.
    Annu. Rev. Biochem. (IF 26.922) Pub Date : 1946-01-01
    E A KABAT

    更新日期:2019-11-01
  • Bacterial metabolism.
    Annu. Rev. Biochem. (IF 26.922) Pub Date : 1946-01-01
    H A BARKER,M DOUDOROFF

    更新日期:2019-11-01
  • The biochemistry of yeast.
    Annu. Rev. Biochem. (IF 26.922) Pub Date : 1946-01-01
    C NEUBERG

    更新日期:2019-11-01
  • The respiration of plants.
    Annu. Rev. Biochem. (IF 26.922) Pub Date : 1946-01-01
    W O JAMES

    更新日期:2019-11-01
  • Photosynthesis.
    Annu. Rev. Biochem. (IF 26.922) Pub Date : 1946-01-01
    C S FRENCH

    更新日期:2019-11-01
  • Growth factors for micro-organisms.
    Annu. Rev. Biochem. (IF 26.922) Pub Date : 1946-01-01
    E E SNELL

    更新日期:2019-11-01
  • The biochemistry of teeth.
    Annu. Rev. Biochem. (IF 26.922) Pub Date : 1946-01-01
    H M LEICESTER

    更新日期:2019-11-01
  • The chemistry of the hormones.
    Annu. Rev. Biochem. (IF 26.922) Pub Date : 1946-01-01
    H SELYE,H JENSEN

    更新日期:2019-11-01
  • The vitamins.
    Annu. Rev. Biochem. (IF 26.922) Pub Date : 1946-01-01
    R A DUTCHER,N B GUERRANT

    更新日期:2019-11-01
  • The metabolism of proteins and amino acids.
    Annu. Rev. Biochem. (IF 26.922) Pub Date : 1946-01-01
    D RITTENBERG,D SHEMIN

    更新日期:2019-11-01
  • Fat metabolism.
    Annu. Rev. Biochem. (IF 26.922) Pub Date : 1946-01-01
    W C STADIE

    更新日期:2019-11-01
  • Carbohydrate metabolism.
    Annu. Rev. Biochem. (IF 26.922) Pub Date : 1946-01-01
    C F CORI,G T CORI

    更新日期:2019-11-01
  • The chemistry of the steroids.
    Annu. Rev. Biochem. (IF 26.922) Pub Date : 1946-01-01
    T REICHSTEIN,H REICH

    更新日期:2019-11-01
  • The chemistry of the proteins and amino acids.
    Annu. Rev. Biochem. (IF 26.922) Pub Date : 1946-01-01
    T L McMEEKIN,R C WARNER

    更新日期:2019-11-01
  • The chemistry of the lipids.
    Annu. Rev. Biochem. (IF 26.922) Pub Date : 1946-01-01
    J B BROWN

    更新日期:2019-11-01
  • Plant carbohydrates.
    Annu. Rev. Biochem. (IF 26.922) Pub Date : 1946-01-01
    S PEAT

    更新日期:2019-11-01
  • Non-oxidative enzymes.
    Annu. Rev. Biochem. (IF 26.922) Pub Date : 1946-01-01
    A M WYNNE

    更新日期:2019-11-01
  • Biological oxidations and reductions.
    Annu. Rev. Biochem. (IF 26.922) Pub Date : 1946-01-01
    K A C ELLIOTT

    更新日期:2019-11-01
  • The chemistry of the steroids.
    Annu. Rev. Biochem. (IF 26.922) Pub Date : 1947-01-01
    L H SARETT,E S WALLIS

    更新日期:2019-11-01
  • 更新日期:2019-11-01
  • Bacterial metabolism.
    Annu. Rev. Biochem. (IF 26.922) Pub Date : 1947-01-01
    D D WOODS

    更新日期:2019-11-01
  • Antimalarial drugs.
    Annu. Rev. Biochem. (IF 26.922) Pub Date : 1947-01-01
    K C BLANCHARD

    更新日期:2019-11-01
  • Growth substances in higher plants.
    Annu. Rev. Biochem. (IF 26.922) Pub Date : 1947-01-01
    F SKOOG

    更新日期:2019-11-01
  • Marine bacteriology.
    Annu. Rev. Biochem. (IF 26.922) Pub Date : 1947-01-01
    C E ZOBELL

    更新日期:2019-11-01
  • Mineral nutrition of plants.
    Annu. Rev. Biochem. (IF 26.922) Pub Date : 1947-01-01
    H LUNDEGARDH

    更新日期:2019-11-01
  • The nitrogenous constituents of plants.
    Annu. Rev. Biochem. (IF 26.922) Pub Date : 1947-01-01
    F C STEWARD,H E STREET

    更新日期:2019-11-01
  • Carotenoid and indolic biochromes of animals.
    Annu. Rev. Biochem. (IF 26.922) Pub Date : 1947-01-01
    D L FOX

    更新日期:2019-11-01
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