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The Nicotinic Acetylcholine Receptor and its Pentameric Homologs: Toward an Allosteric Mechanism of Signal Transduction at the Atomic Level Annu. Rev. Biochem. (IF 16.6) Pub Date : 2024-02-12 Marco Cecchini, Pierre-Jean Corringer, Jean-Pierre Changeux
The nicotinic acetylcholine receptor has served, since its biochemical identification in the 1970s, as a model of an allosteric ligand-gated ion channel mediating signal transition at the synapse. In recent years, the application of X-ray crystallography and high-resolution cryo–electron microscopy, together with molecular dynamic simulations of nicotinic receptors and homologs, have opened a new era
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Signaling from RAS to RAF: The Molecules and Their Mechanisms Annu. Rev. Biochem. (IF 16.6) Pub Date : 2024-02-05 Hyesung Jeon, Emre Tkacik, Michael J. Eck
RAF family protein kinases are a key node in the RAS/RAF/MAP kinase pathway, the signaling cascade that controls cellular proliferation, differentiation, and survival in response to engagement of growth factor receptors on the cell surface. Over the past few years, structural and biochemical studies have provided new understanding of RAF autoregulation, RAF activation by RAS and the SHOC2 phosphatase
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A Life of Translocations Annu. Rev. Biochem. (IF 16.6) Pub Date : 2023-11-29 Tom A. Rapoport
Writing a career retrospective for this prestigious series is a huge challenge. Is my story really of that much interest? One thing that is different about my life in science is the heavy influence of the turmoil of the past century. Born in the US, raised in East Germany, and returning to the US relatively late in life, I experienced research under both suboptimal and privileged conditions. My scientific
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Lipid Quality Control and Ferroptosis: From Concept to Mechanism Annu. Rev. Biochem. (IF 16.6) Pub Date : 2023-11-14 Zhipeng Li, Mike Lange, Scott J. Dixon, James A. Olzmann
Cellular quality control systems sense and mediate homeostatic responses to prevent the buildup of aberrant macromolecules, which arise from errors during biosynthesis, damage by environmental insults, or imbalances in enzymatic and metabolic activity. Lipids are structurally diverse macromolecules that have many important cellular functions, ranging from structural roles in membranes to functions
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The Inseparable Relationship Between Cholesterol and Hedgehog Signaling Annu. Rev. Biochem. (IF 16.6) Pub Date : 2023-06-20 Christian Siebold, Rajat Rohatgi
Ligands of the Hedgehog (HH) pathway are paracrine signaling molecules that coordinate tissue development in metazoans. A remarkable feature of HH signaling is the repeated use of cholesterol in steps spanning ligand biogenesis, secretion, dispersal, and reception on target cells. A cholesterol molecule covalently attached to HH ligands is used as a molecular baton by transfer proteins to guide their
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Looping the Genome with SMC Complexes Annu. Rev. Biochem. (IF 16.6) Pub Date : 2023-05-03 Eugene Kim, Roman Barth, Cees Dekker
SMC (structural maintenance of chromosomes) protein complexes are an evolutionarily conserved family of motor proteins that hold sister chromatids together and fold genomes throughout the cell cycle by DNA loop extrusion. These complexes play a key role in a variety of functions in the packaging and regulation of chromosomes, and they have been intensely studied in recent years. Despite their importance
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Rubisco Function, Evolution, and Engineering Annu. Rev. Biochem. (IF 16.6) Pub Date : 2023-04-26 Noam Prywes, Naiya R. Phillips, Owen T. Tuck, Luis E. Valentin-Alvarado, David F. Savage
Carbon fixation is the process by which CO2 is converted from a gas into biomass. The Calvin–Benson–Bassham cycle (CBB) is the dominant carbon-consuming pathway on Earth, driving >99.5% of the ∼120 billion tons of carbon that are converted to sugar by plants, algae, and cyanobacteria. The carboxylase enzyme in the CBB, ribulose-1,5-bisphosphate carboxylase/oxygenase (rubisco), fixes one CO2 molecule
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The Proteins of mRNA Modification: Writers, Readers, and Erasers Annu. Rev. Biochem. (IF 16.6) Pub Date : 2023-04-17 Mathieu N. Flamand, Matthew Tegowski, Kate D. Meyer
Over the past decade, mRNA modifications have emerged as important regulators of gene expression control in cells. Fueled in large part by the development of tools for detecting RNA modifications transcriptome wide, researchers have uncovered a diverse epitranscriptome that serves as an additional layer of gene regulation beyond simple RNA sequence. Here, we review the proteins that write, read, and
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Thiolase: A Versatile Biocatalyst Employing Coenzyme A–Thioester Chemistry for Making and Breaking C–C Bonds Annu. Rev. Biochem. (IF 16.6) Pub Date : 2023-04-17 Rajesh K. Harijan, Subhadra Dalwani, Tiila-Riikka Kiema, Rajaram Venkatesan, Rik K. Wierenga
Thiolases are CoA-dependent enzymes that catalyze the thiolytic cleavage of 3-ketoacyl-CoA, as well as its reverse reaction, which is the thioester-dependent Claisen condensation reaction. Thiolases are dimers or tetramers (dimers of dimers). All thiolases have two reactive cysteines: ( a) a nucleophilic cysteine, which forms a covalent intermediate, and ( b) an acid/base cysteine. The best characterized
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Transcription-Coupled Nucleotide Excision Repair and the Transcriptional Response to UV-Induced DNA Damage Annu. Rev. Biochem. (IF 16.6) Pub Date : 2023-04-11 Nicolás Nieto Moreno, Anouk M. Olthof, Jesper Q. Svejstrup
Ultraviolet (UV) irradiation and other genotoxic stresses induce bulky DNA lesions, which threaten genome stability and cell viability. Cells have evolved two main repair pathways to remove such lesions: global genome nucleotide excision repair (GG-NER) and transcription-coupled nucleotide excision repair (TC-NER). The modes by which these subpathways recognize DNA lesions are distinct, but they converge
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The Design and Application of DNA-Editing Enzymes as Base Editors Annu. Rev. Biochem. (IF 16.6) Pub Date : 2023-04-05 Kartik L. Rallapalli, Alexis C. Komor
DNA-editing enzymes perform chemical reactions on DNA nucleobases. These reactions can change the genetic identity of the modified base or modulate gene expression. Interest in DNA-editing enzymes has burgeoned in recent years due to the advent of clustered regularly interspaced short palindromic repeat-associated (CRISPR-Cas) systems, which can be used to direct their DNA-editing activity to specific
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Mechanism of Radical Initiation in the Radical SAM Enzyme Superfamily Annu. Rev. Biochem. (IF 16.6) Pub Date : 2023-04-05 Brian M. Hoffman, William E. Broderick, Joan B. Broderick
Radical S-adenosylmethionine (SAM) enzymes use a site-differentiated [4Fe-4S] cluster and SAM to initiate radical reactions through liberation of the 5′-deoxyadenosyl (5′-dAdo•) radical. They form the largest enzyme superfamily, with more than 700,000 unique sequences currently, and their numbers continue to grow as a result of ongoing bioinformatics efforts. The range of extremely diverse, highly
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Polyamines in Parkinson's Disease: Balancing Between Neurotoxicity and Neuroprotection Annu. Rev. Biochem. (IF 16.6) Pub Date : 2023-04-05 Stephanie Vrijsen, Marine Houdou, Ana Cascalho, Jan Eggermont, Peter Vangheluwe
The polyamines putrescine, spermidine, and spermine are abundant polycations of vital importance in mammalian cells. Their cellular levels are tightly regulated by degradation and synthesis, as well as by uptake and export. Here, we discuss the delicate balance between the neuroprotective and neurotoxic effects of polyamines in the context of Parkinson's disease (PD). Polyamine levels decline with
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mRNA Regulation by RNA Modifications Annu. Rev. Biochem. (IF 16.6) Pub Date : 2023-04-05 Wendy V. Gilbert, Sigrid Nachtergaele
Chemical modifications on mRNA represent a critical layer of gene expression regulation. Research in this area has continued to accelerate over the last decade, as more modifications are being characterized with increasing depth and breadth. mRNA modifications have been demonstrated to influence nearly every step from the early phases of transcript synthesis in the nucleus through to their decay in
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Molecular Mechanisms of Transcription-Coupled Repair Annu. Rev. Biochem. (IF 16.6) Pub Date : 2023-03-31 Christopher P. Selby, Laura A. Lindsey-Boltz, Wentao Li, Aziz Sancar
Transcription-coupled repair (TCR), discovered as preferential nucleotide excision repair of UV-induced cyclobutane pyrimidine dimers located in transcribed mammalian genes compared to those in nontranscribed regions of the genome, is defined as faster repair of the transcribed strand versus the nontranscribed strand in transcribed genes. The phenomenon, universal in model organisms including Escherichia
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The Activation Mechanism of the Insulin Receptor: A Structural Perspective Annu. Rev. Biochem. (IF 16.6) Pub Date : 2023-03-31 Eunhee Choi, Xiao-Chen Bai
The insulin receptor (IR) is a type II receptor tyrosine kinase that plays essential roles in metabolism, growth, and proliferation. Dysregulation of IR signaling is linked to many human diseases, such as diabetes and cancers. The resolution revolution in cryo–electron microscopy has led to the determination of several structures of IR with different numbers of bound insulin molecules in recent years
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Structural Biochemistry of Muscle Contraction Annu. Rev. Biochem. (IF 16.6) Pub Date : 2023-03-31 Zhexin Wang, Stefan Raunser
Muscles are essential for movement and heart function. Contraction and relaxation of muscles rely on the sliding of two types of filaments—the thin filament and the thick myosin filament. The thin filament is composed mainly of filamentous actin (F-actin), tropomyosin, and troponin. Additionally, several other proteins are involved in the contraction mechanism, and their malfunction can lead to diverse
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Mitochondrial DNA Release in Innate Immune Signaling Annu. Rev. Biochem. (IF 16.6) Pub Date : 2023-03-31 Laura E. Newman, Gerald S. Shadel
According to the endosymbiotic theory, most of the DNA of the original bacterial endosymbiont has been lost or transferred to the nucleus, leaving a much smaller (∼16 kb in mammals), circular molecule that is the present-day mitochondrial DNA (mtDNA). The ability of mtDNA to escape mitochondria and integrate into the nuclear genome was discovered in budding yeast, along with genes that regulate this
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3′-End Processing of Eukaryotic mRNA: Machinery, Regulation, and Impact on Gene Expression Annu. Rev. Biochem. (IF 16.6) Pub Date : 2023-03-31 Vytautė Boreikaitė, Lori A. Passmore
Formation of the 3′ end of a eukaryotic mRNA is a key step in the production of a mature transcript. This process is mediated by a number of protein factors that cleave the pre-mRNA, add a poly(A) tail, and regulate transcription by protein dephosphorylation. Cleavage and polyadenylation specificity factor (CPSF) in humans, or cleavage and polyadenylation factor (CPF) in yeast, coordinates these enzymatic
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DNA Fragility and Repair: Some Personal Recollections Annu. Rev. Biochem. (IF 16.6) Pub Date : 2023-03-31 Tomas Robert Lindahl
In this autobiographical article, I reflect on my Swedish background. Then I discuss endogenous DNA alterations and the base excision repair pathway and alternative repair strategies for some unusual DNA lesions. Endogenous DNA damage, such as loss of purine bases and cytosine deamination, is proposed as a major source of cancer-causing mutations.
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Translation and mRNA Stability Control Annu. Rev. Biochem. (IF 16.6) Pub Date : 2023-03-31 Qiushuang Wu, Ariel A. Bazzini
Messenger RNA (mRNA) stability and translational efficiency are two crucial aspects of the post-transcriptional process that profoundly impact protein production in a cell. While it is widely known that ribosomes produce proteins, studies during the past decade have surprisingly revealed that ribosomes also control mRNA stability in a codon-dependent manner, a process referred to as codon optimality
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In Vitro Genetic Code Reprogramming for the Expansion of Usable Noncanonical Amino Acids Annu. Rev. Biochem. (IF 16.6) Pub Date : 2022-06-22 Takayuki Katoh, Hiroaki Suga
Genetic code reprogramming has enabled us to ribosomally incorporate various nonproteinogenic amino acids (npAAs) into peptides in vitro. The repertoire of usable npAAs has been expanded to include not only l-α-amino acids with noncanonical sidechains but also those with noncanonical backbones. Despite successful single incorporation of npAAs, multiple and consecutive incorporations often suffer from
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The Life of SARS-CoV-2 Inside Cells: Replication–Transcription Complex Assembly and Function Annu. Rev. Biochem. (IF 16.6) Pub Date : 2022-06-22 Zhiyong Lou, Zihe Rao
The persistence of the coronavirus disease 2019 (COVID-19) pandemic has resulted in increasingly disruptive impacts, and it has become the most devastating challenge to global health in a century. The rapid emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants challenges the currently available therapeutics for clinical application. Nonstructural proteins (also known as
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Structural Mimicry in Microbial and Antimicrobial Amyloids Annu. Rev. Biochem. (IF 16.6) Pub Date : 2022-06-22 Nimrod Golan, Yizhaq Engelberg, Meytal Landau
The remarkable variety of microbial species of human pathogens and microbiomes generates significant quantities of secreted amyloids, which are structured protein fibrils that serve diverse functions related to virulence and interactions with the host. Human amyloids are associated largely with fatal neurodegenerative and systemic aggregation diseases, and current research has put forward the hypothesis
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Kinetic Proofreading Annu. Rev. Biochem. (IF 16.6) Pub Date : 2022-04-01 Hinrich Boeger
Biochemistry and molecular biology rely on the recognition of structural complementarity between molecules. Molecular interactions must be both quickly reversible, i.e., tenuous, and specific. How the cell reconciles these conflicting demands is the subject of this article. The problem and its theoretical solution are discussed within the wider theoretical context of the thermodynamics of stochastic
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Validating Small Molecule Chemical Probes for Biological Discovery Annu. Rev. Biochem. (IF 16.6) Pub Date : 2022-04-01 Victoria Vu, Magdalena M. Szewczyk, David Y. Nie, Cheryl H. Arrowsmith, Dalia Barsyte-Lovejoy
Small molecule chemical probes are valuable tools for interrogating protein biological functions and relevance as a therapeutic target. Rigorous validation of chemical probe parameters such as cellular potency and selectivity is critical to unequivocally linking biological and phenotypic data resulting from treatment with a chemical probe to the function of a specific target protein. A variety of modern
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The Initiation of Eukaryotic DNA Replication Annu. Rev. Biochem. (IF 16.6) Pub Date : 2022-03-23 Alessandro Costa, John F.X. Diffley
DNA replication in eukaryotic cells initiates from large numbers of sites called replication origins. Initiation of replication from these origins must be tightly controlled to ensure the entire genome is precisely duplicated in each cell cycle. This is accomplished through the regulation of the first two steps in replication: loading and activation of the replicative DNA helicase. Here we describe
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Driving E3 Ligase Substrate Specificity for Targeted Protein Degradation: Lessons from Nature and the Laboratory Annu. Rev. Biochem. (IF 16.6) Pub Date : 2022-03-23 Angus D. Cowan, Alessio Ciulli
Methods to direct the degradation of protein targets with proximity-inducing molecules that coopt the cellular degradation machinery are advancing in leaps and bounds, and diverse modalities are emerging. The most used and well-studied approach is to hijack E3 ligases of the ubiquitin–proteasome system. E3 ligases use specific molecular recognition to determine which proteins in the cell are ubiquitinated
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Structure and Mechanism of the Lipid Flippase MurJ Annu. Rev. Biochem. (IF 16.6) Pub Date : 2022-03-23 Alvin C.Y. Kuk, Aili Hao, Seok-Yong Lee
Biosynthesis of many important polysaccharides (including peptidoglycan, lipopolysaccharide, and N-linked glycans) necessitates the transport of lipid-linked oligosaccharides (LLO) across membranes from their cytosolic site of synthesis to their sites of utilization. Much of our current understanding of LLO transport comes from genetic, biochemical, and structural studies of the multidrug/oligosac
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Emerging Chemical Diversity and Potential Applications of Enzymes in the DMSO Reductase Superfamily Annu. Rev. Biochem. (IF 16.6) Pub Date : 2022-03-23 Chi (Chip) Le, Minwoo Bae, Sina Kiamehr, Emily P. Balskus
Molybdenum- and tungsten-dependent proteins catalyze essential processes in living organisms and biogeochemical cycles. Among these enzymes, members of the dimethyl sulfoxide (DMSO) reductase superfamily are considered the most diverse, facilitating a wide range of chemical transformations that can be categorized as oxygen atom installation, removal, and transfer. Importantly, DMSO reductase enzymes
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Better, Faster, Cheaper: Recent Advances in Cryo–Electron Microscopy Annu. Rev. Biochem. (IF 16.6) Pub Date : 2022-03-23 Eugene Y.D. Chua, Joshua H. Mendez, Micah Rapp, Serban L. Ilca, Yong Zi Tan, Kashyap Maruthi, Huihui Kuang, Christina M. Zimanyi, Anchi Cheng, Edward T. Eng, Alex J. Noble, Clinton S. Potter, Bridget Carragher
Cryo–electron microscopy (cryo-EM) continues its remarkable growth as a method for visualizing biological objects, which has been driven by advances across the entire pipeline. Developments in both single-particle analysis and in situ tomography have enabled more structures to be imaged and determined to better resolutions, at faster speeds, and with more scientists having improved access. This review
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The Purinosome: A Case Study for a Mammalian Metabolon Annu. Rev. Biochem. (IF 16.6) Pub Date : 2022-03-23 Anthony M. Pedley, Vidhi Pareek, Stephen J. Benkovic
Over the past fifteen years, we have unveiled a new mechanism by which cells achieve greater efficiency in de novo purine biosynthesis. This mechanism relies on the compartmentalization of de novo purine biosynthetic enzymes into a dynamic complex called the purinosome. In this review, we highlight our current understanding of the purinosome with emphasis on its biophysical properties and function
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Encapsulins Annu. Rev. Biochem. (IF 16.6) Pub Date : 2022-03-19 Tobias W. Giessen
Subcellular compartmentalization is a defining feature of all cells. In prokaryotes, compartmentalization is generally achieved via protein-based strategies. The two main classes of microbial protein compartments are bacterial microcompartments and encapsulin nanocompartments. Encapsulins self-assemble into proteinaceous shells with diameters between 24 and 42 nm and are defined by the viral HK97-fold
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DNA–Protein Crosslinks and Their Resolution Annu. Rev. Biochem. (IF 16.6) Pub Date : 2022-03-19 Pedro Weickert, Julian Stingele
Covalent DNA–protein crosslinks (DPCs) are pervasive DNA lesions that interfere with essential chromatin processes such as transcription or replication. This review strives to provide an overview of the sources and principles of cellular DPC formation. DPCs are caused by endogenous reactive metabolites and various chemotherapeutic agents. However, in certain conditions DPCs also arise physiologically
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The Wnt Pathway: From Signaling Mechanisms to Synthetic Modulators Annu. Rev. Biochem. (IF 16.6) Pub Date : 2022-03-19 Ellen Youngsoo Rim, Hans Clevers, Roel Nusse
The Wnt pathway is central to a host of developmental and disease-related processes. The remarkable conservation of this intercellular signaling cascade throughout metazoan lineages indicates that it coevolved with multicellularity to regulate the generation and spatial arrangement of distinct cell types. By regulating cell fate specification, mitotic activity, and cell polarity, Wnt signaling orchestrates
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Metalloproteomics for Biomedical Research: Methodology and Applications Annu. Rev. Biochem. (IF 16.6) Pub Date : 2022-03-19 Ying Zhou, Hongyan Li, Hongzhe Sun
Metals are essential components in life processes and participate in many important biological processes. Dysregulation of metal homeostasis is correlated with many diseases. Metals are also frequently incorporated into diagnosis and therapeutics. Understanding of metal homeostasis under (patho)physiological conditions and the molecular mechanisms of action of metallodrugs in biological systems has
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Managing the Steady State Chromatin Landscape by Nucleosome Dynamics Annu. Rev. Biochem. (IF 16.6) Pub Date : 2022-03-19 Kami Ahmad, Steven Henikoff, Srinivas Ramachandran
Gene regulation arises out of dynamic competition between nucleosomes, transcription factors, and other chromatin proteins for the opportunity to bind genomic DNA. The timescales of nucleosome assembly and binding of factors to DNA determine the outcomes of this competition at any given locus. Here, we review how these properties of chromatin proteins and the interplay between the dynamics of different
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The Role of DEAD-Box ATPases in Gene Expression and the Regulation of RNA–Protein Condensates Annu. Rev. Biochem. (IF 16.6) Pub Date : 2022-03-19 Karsten Weis, Maria Hondele
DEAD-box ATPases constitute a very large protein family present in all cells, often in great abundance. From bacteria to humans, they play critical roles in many aspects of RNA metabolism, and due to their widespread importance in RNA biology, they have been characterized in great detail at both the structural and biochemical levels. DEAD-box proteins function as RNA-dependent ATPases that can unwind
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MAPK-Activated Protein Kinases: Servant or Partner? Annu. Rev. Biochem. (IF 16.6) Pub Date : 2022-03-19 Natalia Ronkina, Matthias Gaestel
Mitogen-activated protein kinase (MAPK)-activated protein kinases (MAPKAPKs) are defined by their exclusive activation by MAPKs. They can be activated by classical and atypical MAPKs that have been stimulated by mitogens and various stresses. Genetic deletions of MAPKAPKs and availability of highly specific small-molecule inhibitors have continuously increased our functional understanding of these
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Lipoproteins in the Central Nervous System: From Biology to Pathobiology Annu. Rev. Biochem. (IF 16.6) Pub Date : 2022-03-19 Ana-Caroline Raulin, Yuka A. Martens, Guojun Bu
The brain, as one of the most lipid-rich organs, heavily relies on lipid transport and distribution to maintain homeostasis and neuronal function. Lipid transport mediated by lipoprotein particles, which are complex structures composed of apolipoproteins and lipids, has been thoroughly characterized in the periphery. Although lipoproteins in the central nervous system (CNS) were reported over half
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Macrocyclization and Backbone Modification in RiPP Biosynthesis Annu. Rev. Biochem. (IF 16.6) Pub Date : 2022-03-19 Hyunji Lee, Wilfred A. van der Donk
The past decade has seen impressive advances in understanding the biosynthesis of ribosomally synthesized and posttranslationally modified peptides (RiPPs). One of the most common modifications found in these natural products is macrocyclization, a strategy also used by medicinal chemists to improve metabolic stability and target affinity and specificity. Another tool of the peptide chemist, modification
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The Structural Dynamics of Translation Annu. Rev. Biochem. (IF 16.6) Pub Date : 2022-03-15 Andrei A. Korostelev
Accurate protein synthesis (translation) relies on translation factors that rectify ribosome fluctuations into a unidirectional process. Understanding this process requires structural characterization of the ribosome and translation-factor dynamics. In the 2000s, crystallographic studies determined high-resolution structures of ribosomes stalled with translation factors, providing a starting point
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High-Resolution Single-Molecule Magnetic Tweezers Annu. Rev. Biochem. (IF 16.6) Pub Date : 2022-03-15 Hyun-Kyu Choi, Hyun Gyu Kim, Min Ju Shon, Tae-Young Yoon
Single-molecule magnetic tweezers deliver magnetic force and torque to single target molecules, permitting the study of dynamic changes in biomolecular structures and their interactions. Because the magnetic tweezer setups can generate magnetic fields that vary slowly over tens of millimeters—far larger than the nanometer scale of the single molecule events being observed—this technique can maintain
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Influence of Nonspecific Interactions on Protein Associations: Implications for Biochemistry In Vivo Annu. Rev. Biochem. (IF 16.6) Pub Date : 2022-03-15 Germán Rivas, Allen P. Minton
The cellular interior is composed of a variety of microenvironments defined by distinct local compositions and composition-dependent intermolecular interactions. We review the various types of nonspecific interactions between proteins and between proteins and other macromolecules and supramolecular structures that influence the state of association and functional properties of a given protein existing
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The Function, Structure, and Origins of the ER Membrane Protein Complex Annu. Rev. Biochem. (IF 16.6) Pub Date : 2022-03-15 Ramanujan S. Hegde
The endoplasmic reticulum (ER) is the site of membrane protein insertion, folding, and assembly in eukaryotes. Over the past few years, a combination of genetic and biochemical studies have implicated an abundant factor termed the ER membrane protein complex (EMC) in several aspects of membrane protein biogenesis. This large nine-protein complex is built around a deeply conserved core formed by the
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Biochemistry, Cell Biology, and Pathophysiology of the Innate Immune cGAS–cGAMP–STING Pathway Annu. Rev. Biochem. (IF 16.6) Pub Date : 2022-03-15 Christopher Ritchie, Jacqueline A. Carozza, Lingyin Li
In the decade since the discovery of the innate immune cyclic GMP–AMP synthase (cGAS)–2′3′-cyclic GMP–AMP (cGAMP)–stimulator of interferon genes (STING) pathway, its proper activation and dysregulation have been rapidly implicated in many aspects of human disease. Understanding the biochemical, cellular, and regulatory mechanisms of this pathway is critical to developing therapeutic strategies that
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Sensory TRP Channels in Three Dimensions Annu. Rev. Biochem. (IF 16.6) Pub Date : 2022-03-15 Melinda M. Diver, John V. Lin King, David Julius, Yifan Cheng
Transient receptor potential (TRP) ion channels are sophisticated signaling machines that detect a wide variety of environmental and physiological signals. Every cell in the body expresses one or more members of the extended TRP channel family, which consists of over 30 subtypes, each likely possessing distinct pharmacological, biophysical, and/or structural attributes. While the function of some TRP
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Role of the TOM Complex in Protein Import into Mitochondria: Structural Views Annu. Rev. Biochem. (IF 16.6) Pub Date : 2022-03-15 Yuhei Araiso, Kenichiro Imai, Toshiya Endo
Mitochondria are central to energy production, metabolism and signaling, and apoptosis. To make new mitochondria from preexisting mitochondria, the cell needs to import mitochondrial proteins from the cytosol into the mitochondria with the aid of translocators in the mitochondrial membranes. The translocase of the outer membrane (TOM) complex, an outer membrane translocator, functions as an entry gate
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Ribonucleotide Incorporation by Eukaryotic B-Family Replicases and Its Implications for Genome Stability Annu. Rev. Biochem. (IF 16.6) Pub Date : 2022-03-15 Jessica S. Williams, Thomas A. Kunkel
Our current view of how DNA-based genomes are efficiently and accurately replicated continues to evolve as new details emerge on the presence of ribonucleotides in DNA. Ribonucleotides are incorporated during eukaryotic DNA replication at rates that make them the most common noncanonical nucleotide placed into the nuclear genome, they are efficiently repaired, and their removal impacts genome integrity
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Evolutionary Dynamics and Molecular Mechanisms of HORMA Domain Protein Signaling Annu. Rev. Biochem. (IF 16.6) Pub Date : 2022-01-18 Yajie Gu, Arshad Desai, Kevin D. Corbett
Controlled assembly and disassembly of multi-protein complexes is central to cellular signaling. Proteins of the widespread and functionally diverse HORMA family nucleate assembly of signaling complexes by binding short peptide motifs through a distinctive safety-belt mechanism. HORMA proteins are now understood as key signaling proteins across kingdoms, serving as infection sensors in a bacterial
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Glycyl Radical Enzymes and Sulfonate Metabolism in the Microbiome Annu. Rev. Biochem. (IF 16.6) Pub Date : 2021-06-21 Yifeng Wei, Yan Zhang
Sulfonates include diverse natural products and anthropogenic chemicals and are widespread in the environment. Many bacteria can degrade sulfonates and obtain sulfur, carbon, and energy for growth, playing important roles in the biogeochemical sulfur cycle. Cleavage of the inert sulfonate C–S bond involves a variety of enzymes, cofactors, and oxygen-dependent and oxygen-independent catalytic mechanisms
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Molecules from the Microbiome Annu. Rev. Biochem. (IF 16.6) Pub Date : 2021-06-21 Emilee E. Shine, Jason M. Crawford
The human microbiome encodes a second genome that dwarfs the genetic capacity of the host. Microbiota-derived small molecules can directly target human cells and their receptors or indirectly modulate host responses through functional interactions with other microbes in their ecological niche. Their biochemical complexity has profound implications for nutrition, immune system development, disease progression
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A Natural Product Chemist's Guide to Unlocking Silent Biosynthetic Gene Clusters Annu. Rev. Biochem. (IF 16.6) Pub Date : 2021-06-21 Brett C. Covington, Fei Xu, Mohammad R. Seyedsayamdost
Microbial natural products have provided an important source of therapeutic leads and motivated research and innovation in diverse scientific disciplines. In recent years, it has become evident that bacteria harbor a large, hidden reservoir of potential natural products in the form of silent or cryptic biosynthetic gene clusters (BGCs). These can be readily identified in microbial genome sequences
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Structural Insights Accelerate the Discovery of Opioid Alternatives Annu. Rev. Biochem. (IF 16.6) Pub Date : 2021-06-21 Tao Che, Bryan L. Roth
Opioids such as morphine and oxycodone are analgesics frequently prescribed for the treatment of moderate or severe pain. Unfortunately, these medications are associated with exceptionally high abuse potentials and often cause fatal side effects, mainly through the μ-opioid receptor (MOR). Efforts to discover novel, safer, and more efficacious analgesics targeting MOR have encountered challenges. In
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Mechanisms for Regulating and Organizing Receptor Signaling by Endocytosis Annu. Rev. Biochem. (IF 16.6) Pub Date : 2021-06-21 Mark von Zastrow, Alexander Sorkin
Intricate relationships between endocytosis and cellular signaling, first recognized nearly 40 years ago through the study of tyrosine kinase growth factor receptors, are now known to exist for multiple receptor classes and to affect myriad physiological and developmental processes. This review summarizes our present understanding of how endocytosis orchestrates cellular signaling networks, with an
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PI(4,5)P2 Clustering and Its Impact on Biological Functions Annu. Rev. Biochem. (IF 16.6) Pub Date : 2021-06-21 Yi Wen, Volker M. Vogt, Gerald W. Feigenson
Located at the inner leaflet of the plasma membrane (PM), phosphatidyl-inositol 4,5-bisphosphate [PI(4,5)P2] composes only 1–2 mol% of total PM lipids. With its synthesis and turnover both spatially and temporally regulated, PI(4,5)P2 recruits and interacts with hundreds of cellular proteins to support a broad spectrum of cellular functions. Several factors contribute to the versatile and dynamic distribution
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Posttranslational Regulation of HMG CoA Reductase, the Rate-Limiting Enzyme in Synthesis of Cholesterol Annu. Rev. Biochem. (IF 16.6) Pub Date : 2021-06-21 Marc M. Schumacher, Russell A. DeBose-Boyd
The polytopic, endoplasmic reticulum (ER) membrane protein 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase produces mevalonate, the key intermediate in the synthesis of cholesterol and many nonsterol isoprenoids including geranylgeranyl pyrophosphate (GGpp). Transcriptional, translational, and posttranslational feedback mechanisms converge on this reductase to ensure cells maintain a sufficient
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Quality Control of Procollagen in Cells Annu. Rev. Biochem. (IF 16.6) Pub Date : 2021-06-21 Shinya Ito, Kazuhiro Nagata
Collagen is the most abundant protein in mammals. A unique feature of collagen is its triple-helical structure formed by the Gly-Xaa-Yaa repeats. Three single chains of procollagen make a trimer, and the triple-helical structure is then folded in the endoplasmic reticulum (ER). This unique structure is essential for collagen's functions in vivo, including imparting bone strength, allowing signal transduction
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Tunnels for Protein Export from the Endoplasmic Reticulum Annu. Rev. Biochem. (IF 16.6) Pub Date : 2021-06-21 I. Raote, V. Malhotra
The functions of coat protein complex II (COPII) coats in cargo packaging and the creation of vesicles at the endoplasmic reticulum are conserved in eukaryotic protein secretion. Standard COPII vesicles, however, cannot handle the secretion of metazoan-specific cargoes such as procollagens, apolipoproteins, and mucins. Metazoans have thus evolved modules centered on proteins like TANGO1 (transport
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Chaperoning SNARE Folding and Assembly Annu. Rev. Biochem. (IF 16.6) Pub Date : 2021-06-21 Yongli Zhang, Frederick M. Hughson
SNARE proteins and Sec1/Munc18 (SM) proteins constitute the core molecular engine that drives nearly all intracellular membrane fusion and exocytosis. While SNAREs are known to couple their folding and assembly to membrane fusion, the physiological pathways of SNARE assembly and the mechanistic roles of SM proteins have long been enigmatic. Here, we review recent advances in understanding the SNARE–SM