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- Volume 88, 2019
Annual Review of Biochemistry - Volume 88, 2019
Volume 88, 2019
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Moving Through Barriers in Science and Life
Vol. 88 (2019), pp. 1–24More LessThis 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.
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Biophysical Techniques in Structural Biology
Vol. 88 (2019), pp. 25–33More LessOver 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.
In addition, this article acts as an introduction to four authoritative reviews in this volume. The first shows the ways that a multiplicity of biophysical methods can be combined with computational techniques to define the architectures of complex biological systems, such as those involving weak interactions within ensembles of molecular components. The second illustrates one aspect of this general approach by describing how recent advances in mass spectrometry, particularly in combination with other techniques, can generate fundamentally new insights into the properties of membrane proteins and their functional interactions with lipid molecules. The third reviewdemonstrates the increasing power of rapidly evolving diffraction techniques, employing the very short bursts of X-rays of extremely high intensity that are now accessible as a result of the construction of free-electron lasers, in particular to carry out time-resolved studies of biochemical reactions. The fourth describes in detail the application of such approaches to probe the mechanism of the light-induced changes associated with bacteriorhodopsin's ability to convert light energy into chemical energy.
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X-Ray Free-Electron Lasers for the Structure and Dynamics of Macromolecules
Vol. 88 (2019), pp. 35–58More LessX-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.
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Bacteriorhodopsin: Structural Insights Revealed Using X-Ray Lasers and Synchrotron Radiation
Vol. 88 (2019), pp. 59–83More LessDirectional 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.
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Membrane Protein–Lipid Interactions Probed Using Mass Spectrometry
Vol. 88 (2019), pp. 85–111More LessMembrane 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.
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Integrative Structure Modeling: Overview and Assessment
Vol. 88 (2019), pp. 113–135More LessIntegrative 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.
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Eukaryotic Base Excision Repair: New Approaches Shine Light on Mechanism
Vol. 88 (2019), pp. 137–162More LessGenomic 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.
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Redox Chemistry in the Genome: Emergence of the [4Fe4S] Cofactor in Repair and Replication
Vol. 88 (2019), pp. 163–190More LessMany 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.
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Evaluating and Enhancing Target Specificity of Gene-Editing Nucleases and Deaminases
Vol. 88 (2019), pp. 191–220More LessProgrammable 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.
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The BRCA Tumor Suppressor Network in Chromosome Damage Repair by Homologous Recombination
Vol. 88 (2019), pp. 221–245More LessMutations 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.
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Cancer Treatment in the Genomic Era
Vol. 88 (2019), pp. 247–280More LessThe 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.
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Eukaryotic Ribosome Assembly
Jochen Baßler, and Ed HurtVol. 88 (2019), pp. 281–306More LessRibosomes, 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.
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The Organizing Principles of Eukaryotic Ribosome Recruitment
Vol. 88 (2019), pp. 307–335More LessThe 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.
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Mechanisms of Cotranslational Maturation of Newly Synthesized Proteins
Vol. 88 (2019), pp. 337–364More LessThe 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.
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Lysine-Targeted Inhibitors and Chemoproteomic Probes
Vol. 88 (2019), pp. 365–381More LessCovalent 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.
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Horizontal Cell Biology: Monitoring Global Changes of Protein Interaction States with the Proteome-Wide Cellular Thermal Shift Assay (CETSA)
Vol. 88 (2019), pp. 383–408More LessThe 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.
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Soluble Methane Monooxygenase
Vol. 88 (2019), pp. 409–431More LessAerobic 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.
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Glycoengineering of Antibodies for Modulating Functions
Vol. 88 (2019), pp. 433–459More LessAntibodies 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.
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Lysosomal Glycosphingolipid Storage Diseases
Vol. 88 (2019), pp. 461–485More LessGlycosphingolipids 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).
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Exosomes
Vol. 88 (2019), pp. 487–514More LessExosomes 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.
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Previous Volumes
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Volume 92 (2023)
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Volume 91 (2022)
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Volume 90 (2021)
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Volume 89 (2020)
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Volume 88 (2019)
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Volume 87 (2018)
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Volume 86 (2017)
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Volume 85 (2016)
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Volume 84 (2015)
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Volume 83 (2014)
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Volume 82 (2013)
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Volume 81 (2012)
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Volume 80 (2011)
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Volume 79 (2010)
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Volume 78 (2009)
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Volume 77 (2008)
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Volume 76 (2007)
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Volume 75 (2006)
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Volume 74 (2005)
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Volume 73 (2004)
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Volume 72 (2003)
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Volume 71 (2002)
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Volume 70 (2001)
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Volume 69 (2000)
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Volume 68 (1999)
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Volume 67 (1998)
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Volume 66 (1997)
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Volume 65 (1996)
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Volume 64 (1995)
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Volume 63 (1994)
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Volume 62 (1993)
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Volume 61 (1992)
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Volume 60 (1991)
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Volume 59 (1990)
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Volume 58 (1989)
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Volume 57 (1988)
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Volume 56 (1987)
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Volume 55 (1986)
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Volume 54 (1985)
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Volume 53 (1984)
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Volume 52 (1983)
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Volume 51 (1982)
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Volume 50 (1981)
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Volume 49 (1980)
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Volume 48 (1979)
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Volume 47 (1978)
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Volume 46 (1977)
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Volume 45 (1976)
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Volume 44 (1975)
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Volume 43 (1974)
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Volume 42 (1973)
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Volume 41 (1972)
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Volume 40 (1971)
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Volume 39 (1970)
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Volume 38 (1969)
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Volume 37 (1968)
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Volume 36 (1967)
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Volume 35 (1966)
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Volume 34 (1965)
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Volume 33 (1964)
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Volume 32 (1963)
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Volume 31 (1962)
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Volume 30 (1961)
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Volume 29 (1960)
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Volume 28 (1959)
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Volume 27 (1958)
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Volume 26 (1957)
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Volume 25 (1956)
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Volume 24 (1955)
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Volume 23 (1954)
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Volume 22 (1953)
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Volume 21 (1952)
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Volume 20 (1951)
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Volume 19 (1950)
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Volume 18 (1949)
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Volume 17 (1948)
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Volume 16 (1947)
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Volume 15 (1946)
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Volume 14 (1945)
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Volume 13 (1944)
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Volume 12 (1943)
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Volume 11 (1942)
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Volume 10 (1941)
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Volume 9 (1940)
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Volume 8 (1939)
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Volume 7 (1938)
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Volume 6 (1937)
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Volume 5 (1936)
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Volume 4 (1935)
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Volume 3 (1934)
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Volume 2 (1933)
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Volume 1 (1932)
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Volume 0 (1932)