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Volume 93, 2024
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A Life of Translocations
Vol. 93 (2024), pp. 1–20More LessWriting 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 story, like the political winds that blew me from one continent to the next, involved shifts into different fields. For advice to young scientists, I would suggest: Don't be afraid to start something new, it pays to be persistent, and science is a passion. In addition to telling my own story, this article also provides the opportunity to express my gratitude to my trainees and colleagues and to convey my conviction that we have the best job on earth.
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Replication–Transcription Conflicts: A Perpetual War on the Chromosome
Vol. 93 (2024), pp. 21–46More LessDNA replication and transcription occur in all living cells across all domains of life. Both essential processes occur simultaneously on the same template, leading to conflicts between the macromolecular machines that perform these functions. Numerous studies over the past few decades demonstrate that this is an inevitable problem in both prokaryotic and eukaryotic cells. We have learned that conflicts lead to replication fork reversal, breaks in the DNA, R-loop formation, topological stress, and mutagenesis and can ultimately impact evolution. Recent studies have also provided insight into the various mechanisms that mitigate, resolve, and allow tolerance of conflicts and how conflicts result in pathological consequences across divergent species. In this review, we summarize our current knowledge regarding the outcomes of the encounters between replication and transcription machineries and explore how these clashes are dealt with across species.
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Replication and Transcription of Human Mitochondrial DNA
Vol. 93 (2024), pp. 47–77More LessMammalian mitochondrial DNA (mtDNA) is replicated and transcribed by phage-like DNA and RNA polymerases, and our understanding of these processes has progressed substantially over the last several decades. Molecular mechanisms have been elucidated by biochemistry and structural biology and essential in vivo roles established by cell biology and mouse genetics. Single molecules of mtDNA are packaged by mitochondrial transcription factor A into mitochondrial nucleoids, and their level of compaction influences the initiation of both replication and transcription. Mutations affecting the molecular machineries replicating and transcribing mtDNA are important causes of human mitochondrial disease, reflecting the critical role of the genome in oxidative phosphorylation system biogenesis. Mechanisms controlling mtDNA replication and transcription still need to be clarified, and future research in this area is likely to open novel therapeutic possibilities for treating mitochondrial dysfunction.
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The Story of RNA Unfolded: The Molecular Function of DEAD- and DExH-Box ATPases and Their Complex Relationship with Membraneless Organelles
Vol. 93 (2024), pp. 79–108More LessDEAD- and DExH-box ATPases (DDX/DHXs) are abundant and highly conserved cellular enzymes ubiquitously involved in RNA processing. By remodeling RNA–RNA and RNA–protein interactions, they often function as gatekeepers that control the progression of diverse RNA maturation steps. Intriguingly, most DDX/DHXs localize to membraneless organelles (MLOs) such as nucleoli, nuclear speckles, stress granules, or processing bodies. Recent findings suggest not only that localization to MLOs can promote interaction between DDX/DHXs and their targets but also that DDX/DHXs are key regulators of MLO formation and turnover through their condensation and ATPase activity.
In this review, we describe the molecular function of DDX/DHXs in ribosome biogenesis, messenger RNA splicing, export, translation, and storage or decay as well as their association with prominent MLOs. We discuss how the enzymatic function of DDX/DHXs in RNA processing is linked to DDX/DHX condensation, the accumulation of ribonucleoprotein particles and MLO dynamics. Future research will reveal how these processes orchestrate the RNA life cycle in MLO space and DDX/DHX time.
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How Natural Enzymes and Synthetic Ribozymes Generate Methylated Nucleotides in RNA
Vol. 93 (2024), pp. 109–137More LessMethylation of RNA nucleotides represents an important layer of gene expression regulation, and perturbation of the RNA methylome is associated with pathophysiology. In cells, RNA methylations are installed by RNA methyltransferases (RNMTs) that are specialized to catalyze particular types of methylation (ribose or different base positions). Furthermore, RNMTs must specifically recognize their appropriate target RNAs within the RNA-dense cellular environment. Some RNMTs are catalytically active alone and achieve target specificity via recognition of sequence motifs and/or RNA structures. Others function together with protein cofactors that can influence stability, S-adenosyl-L-methionine binding, and RNA affinity as well as aiding specific recruitment and catalytic activity. Association of RNMTs with guide RNAs represents an alternative mechanism to direct site-specific methylation by an RNMT that lacks intrinsic specificity. Recently, ribozyme-catalyzed methylation of RNA has been achieved in vitro, and here, we compare these different strategies for RNA methylation from structural and mechanistic perspectives.
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Natural and Engineered Guide RNA–Directed Transposition with CRISPR-Associated Tn7-Like Transposons
Vol. 93 (2024), pp. 139–161More LessCRISPR–Cas (clustered regularly interspaced short palindromic repeats–CRISPR-associated nuclease) defense systems have been naturally coopted for guide RNA–directed transposition on multiple occasions. In all cases, cooption occurred with diverse elements related to the bacterial transposon Tn7. Tn7 tightly controls transposition; the transposase is activated only when special targets are recognized by dedicated target-site selection proteins. Tn7 and the Tn7-like elements that coopted CRISPR–Cas systems evolved complementary targeting pathways: one that recognizes a highly conserved site in the chromosome and a second pathway that targets mobile plasmids capable of cell-to-cell transfer. Tn7 and Tn7-like elements deliver a single integration into the site they recognize and also control the orientation of the integration event, providing future potential for use as programmable gene-integration tools. Early work has shown that guide RNA–directed transposition systems can be adapted to diverse hosts, even within microbial communities, suggesting great potential for engineering these systems as powerful gene-editing tools.
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A Cool Look at Positive-Strand RNA Virus Replication Organelles: New Insights from Cryo–Electron Microscopy
Vol. 93 (2024), pp. 163–187More LessPositive-strand RNA viruses encompass a variety of established and emerging eukaryotic pathogens. Their genome replication is confined to specialized cytoplasmic membrane compartments known as replication organelles (ROs). These ROs derive from host membranes, transformed into distinct structures such as invaginated spherules or intricate membrane networks including single- and/or double-membrane vesicles. ROs play a vital role in orchestrating viral RNA synthesis and evading detection by innate immune sensors of the host. In recent years, groundbreaking cryo–electron microscopy studies conducted with several prototypic viruses have significantly advanced our understanding of RO structure and function. Notably, these studies unveiled the presence of crown-shaped multimeric viral protein complexes that seem to actively participate in viral RNA synthesis and regulate the release of newly synthesized RNA into the cytosol for translation and packaging. These findings have shed light on novel viral functions and fascinating macromolecular complexes that delineate promising new avenues for future research.
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Eukaryotic Ribosome Assembly
Vol. 93 (2024), pp. 189–210More LessDuring the last ten years, developments in cryo–electron microscopy have transformed our understanding of eukaryotic ribosome assembly. As a result, the field has advanced from a list of the vast array of ribosome assembly factors toward an emerging molecular movie in which individual frames are represented by structures of stable ribosome assembly intermediates with complementary biochemical and genetic data. In this review, we discuss the mechanisms driving the assembly of yeast and human small and large ribosomal subunits. A particular emphasis is placed on the most recent findings that illustrate key concepts of ribosome assembly, such as folding of preribosomal RNA, the enforced chronology of assembly, enzyme-mediated irreversible transitions, and proofreading of preribosomal particles.
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Molecular Machines that Facilitate Bacterial Outer Membrane Protein Biogenesis
Vol. 93 (2024), pp. 211–231More LessAlmost all outer membrane proteins (OMPs) in Gram-negative bacteria contain a β-barrel domain that spans the outer membrane (OM). To reach the OM, OMPs must be translocated across the inner membrane by the Sec machinery, transported across the crowded periplasmic space through the assistance of molecular chaperones, and finally assembled (folded and inserted into the OM) by the β-barrel assembly machine. In this review, we discuss how considerable new insights into the contributions of these factors to OMP biogenesis have emerged in recent years through the development of novel experimental, computational, and predictive methods. In addition, we describe recent evidence that molecular machines that were thought to function independently might interact to form dynamic intermembrane supercomplexes. Finally, we discuss new results that suggest that OMPs are inserted primarily near the middle of the cell and packed into supramolecular structures (OMP islands) that are distributed throughout the OM.
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ATP-Dependent Steps in Peroxisomal Protein Import
Vol. 93 (2024), pp. 233–259More LessPeroxisomes are organelles that play a central role in lipid metabolism and cellular redox homeostasis. The import of peroxisomal matrix proteins by peroxisomal targeting signal (PTS) receptors is an ATP-dependent mechanism. However, the energy-dependent steps do not occur early during the binding of the receptor–cargo complex to the membrane but late, because they are linked to the peroxisomal export complex for the release of the unloaded receptor. The first ATP-demanding step is the cysteine-dependent monoubiquitination of the PTS receptors, which is required for recognition by the AAA+ peroxins. They execute the second ATP-dependent step by extracting the ubiqitinated PTS receptors from the membrane for release back to the cytosol. After deubiquitination, the PTS receptors regain import competence and can facilitate further rounds of cargo import. Here, we give a general overview and discuss recent data regarding the ATP-dependent steps in peroxisome protein import.
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Leucine-Rich Repeat Kinases
Vol. 93 (2024), pp. 261–287More LessActivating mutations in leucine-rich repeat kinase 2 (LRRK2) represent the most common cause of monogenic Parkinson's disease. LRRK2 is a large multidomain protein kinase that phosphorylates a specific subset of the ∼65 human Rab GTPases, which are master regulators of the secretory and endocytic pathways. After phosphorylation by LRRK2, Rabs lose the capacity to bind cognate effector proteins and guanine nucleotide exchange factors. Moreover, the phosphorylated Rabs cannot interact with their cognate prenyl-binding retrieval proteins (also known as guanine nucleotide dissociation inhibitors) and, thus, they become trapped on membrane surfaces. Instead, they gain the capacity to bind phospho-Rab-specific effector proteins, such as RILPL1, with resulting pathological consequences. Rab proteins also act upstream of LRRK2 by controlling its activation and recruitment onto membranes. LRRK2 signaling is counteracted by the phosphoprotein phosphatase PPM1H, which selectively dephosphorylates phospho-Rab proteins. We present here our current understanding of the structure, biochemical properties, and cell biology of LRRK2 and its related paralog LRRK1 and discuss how this information guides the generation of LRRK2 inhibitors for the potential benefit of patients.
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Signaling from RAS to RAF: The Molecules and Their Mechanisms
Vol. 93 (2024), pp. 289–316More LessRAF 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 complex, and RAF engagement with HSP90–CDC37 chaperone complexes. These studies have important implications for pharmacologic targeting of the pathway. They reveal RAF in distinct regulatory states and show that the functional RAF switch is an integrated complex of RAF with its substrate (MEK) and a 14-3-3 dimer. Here we review these advances, placing them in the context of decades of investigation of RAF regulation. We explore the insights they provide into aberrant activation of the pathway in cancer and RASopathies (developmental syndromes caused by germline mutations in components of the pathway).
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Inositol Pyrophosphates as Versatile Metabolic Messengers
Vol. 93 (2024), pp. 317–338More LessDiscovered in 1993, inositol pyrophosphates are evolutionarily conserved signaling metabolites whose versatile modes of action are being increasingly appreciated. These include their emerging roles as energy regulators, phosphodonors, steric/allosteric regulators, and G protein–coupled receptor messengers. Through studying enzymes that metabolize inositol pyrophosphates, progress has also been made in elucidating the various cellular and physiological functions of these pyrophosphate-containing, energetic molecules. The two main forms of inositol pyrophosphates, 5-IP7 and IP8, synthesized respectively by inositol-hexakisphosphate kinases (IP6Ks) and diphosphoinositol pentakisphosphate kinases (PPIP5Ks), regulate phosphate homeostasis, ATP synthesis, and several other metabolic processes ranging from insulin secretion to cellular energy utilization. Here, we review the current understanding of the catalytic and regulatory mechanisms of IP6Ks and PPIP5Ks, as well as their counteracting phosphatases. We also highlight the genetic and cellular evidence implicating inositol pyrophosphates as essential mediators of mammalian metabolic homeostasis.
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The Nicotinic Acetylcholine Receptor and Its Pentameric Homologs: Toward an Allosteric Mechanism of Signal Transduction at the Atomic Level
Vol. 93 (2024), pp. 339–366More LessThe 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 in the understanding of channel gating by the neurotransmitter. They reveal, at atomic resolution, the diversity and flexibility of the multiple ligand-binding sites, including recently discovered allosteric modulatory sites distinct from the neurotransmitter orthosteric site, and the conformational dynamics of the activation process as a molecular switch linking these multiple sites. The model emerging from these studies paves the way for a new pharmacology based, first, upon the occurrence of an original mode of indirect allosteric modulation, distinct from a steric competition for a single and rigid binding site, and second, the design of drugs that specifically interact with privileged conformations of the receptor such as agonists, antagonists, and desensitizers. Research on nicotinic receptors is still at the forefront of understanding the mode of action of drugs on the nervous system.
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The Endo-Lysosomal Damage Response
Hemmo Meyer, and Bojana KravicVol. 93 (2024), pp. 367–387More LessLysosomes are the degradative endpoints of material delivered by endocytosis and autophagy and are therefore particularly prone to damage. Membrane permeabilization or full rupture of lysosomal or late endosomal compartments is highly deleterious because it threatens cellular homeostasis and can elicit cell death and inflammatory signaling. Cells have developed a complex response to endo-lysosomal damage that largely consists of three branches. Initially, a number of repair pathways are activated to restore the integrity of the lysosomal membrane. If repair fails or if damage is too extensive, lysosomes are isolated and degraded by a form of selective autophagy termed lysophagy. Meanwhile, an mTORC1-governed signaling cascade drives biogenesis and regeneration of new lysosomal components to reestablish the full lysosomal capacity of the cell. This damage response is vital to counteract the effects of various conditions, including neurodegeneration and infection, and can constitute a critical vulnerability in cancer cells.
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The Art and Science of Molecular Docking
Vol. 93 (2024), pp. 389–410More LessMolecular docking has become an essential part of a structural biologist's and medicinal chemist's toolkits. Given a chemical compound and the three-dimensional structure of a molecular target—for example, a protein—docking methods fit the compound into the target, predicting the compound's bound structure and binding energy. Docking can be used to discover novel ligands for a target by screening large virtual compound libraries. Docking can also provide a useful starting point for structure-based ligand optimization or for investigating a ligand's mechanism of action. Advances in computational methods, including both physics-based and machine learning approaches, as well as in complementary experimental techniques, are making docking an even more powerful tool. We review how docking works and how it can drive drug discovery and biological research. We also describe its current limitations and ongoing efforts to overcome them.
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Triumphs and Challenges of Natural Product Discovery in the Postgenomic Era
Vol. 93 (2024), pp. 411–445More LessNatural products have played significant roles as medicine and food throughout human history. Here, we first provide a brief historical overview of natural products, their classification and biosynthetic origins, and the microbiological and genetic methods used for their discovery. We also describe and discuss the technologies that revolutionized the field, which transitioned from classic genetics to genome-centric discovery approximately two decades ago. We then highlight the most recent advancements and approaches in the current postgenomic era, in which genome mining is a standard operation and high-throughput analytical methods allow parallel discovery of genes and molecules at an unprecedented pace. Finally, we discuss the new challenges faced by the field of natural products and the future of systematic heterologous expression and strain-independent discovery, which promises to deliver more molecules in vials than ever before.
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The Bis(monoacylglycero)-phosphate Hypothesis: From Lysosomal Function to Therapeutic Avenues
Vol. 93 (2024), pp. 447–469More LessLysosomes catabolize and recycle lipids and other biological molecules to maintain cellular homeostasis in diverse nutrient environments. Lysosomal lipid catabolism relies on the stimulatory activity of bis(monoacylglycero)phosphate (BMP), an enigmatic lipid whose levels are altered across myriad lysosome-associated diseases. Here, we review the discovery of BMP over half a century ago and its structural properties that facilitate the activation of lipid hydrolases and recruitment of their coactivators. We further discuss the current, yet incomplete, understanding of BMP catabolism and anabolism. To conclude, we discuss its role in lysosome-associated diseases and the potential for modulating its levels by pharmacologically activating and inhibiting the BMP synthase to therapeutically target lysosomal storage disorders, drug-induced phospholipidosis, Alzheimer's disease, Parkinson's disease, frontotemporal dementia, cancer, and viral infection.
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Structure and Mechanisms of Assembly-Line Polyketide Synthases
Vol. 93 (2024), pp. 471–498More LessThree decades of studies on the multifunctional 6-deoxyerythronolide B synthase have laid a foundation for understanding the chemistry and evolution of polyketide antibiotic biosynthesis by a large family of versatile enzymatic assembly lines. Recent progress in applying chemical and structural biology tools to this prototypical assembly-line polyketide synthase (PKS) and related systems has highlighted several features of their catalytic cycles and associated protein dynamics. There is compelling evidence that multiple mechanisms have evolved in this enzyme family to channel growing polyketide chains along uniquely defined sequences of 10–100 active sites, each of which is used only once in the overall catalytic cycle of an assembly-line PKS. Looking forward, one anticipates major advances in our understanding of the mechanisms by which the free energy of a repetitive Claisen-like reaction is harnessed to guide the growing polyketide chain along the assembly line in a manner that is kinetically robust yet evolutionarily adaptable.
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Lipid Quality Control and Ferroptosis: From Concept to Mechanism
Vol. 93 (2024), pp. 499–528More LessCellular 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 as signaling and energy-storage molecules. As with other macromolecules, lipids can be damaged (e.g., oxidized), and cells require quality control systems to ensure that nonfunctional and potentially toxic lipids do not accumulate. Ferroptosis is a form of cell death that results from the failure of lipid quality control and the consequent accumulation of oxidatively damaged phospholipids. In this review, we describe a framework for lipid quality control, using ferroptosis as an illustrative example to highlight concepts related to lipid damage, membrane remodeling, and suppression or detoxification of lipid damage via preemptive and damage-repair lipid quality control pathways.
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Previous Volumes
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Volume 93 (2024)
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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)