{"title":"Understanding the dynamic design of the spliceosome","authors":"Irene Beusch , Hiten D. Madhani","doi":"10.1016/j.tibs.2024.03.012","DOIUrl":"10.1016/j.tibs.2024.03.012","url":null,"abstract":"<div><p>The spliceosome catalyzes the splicing of pre-mRNAs. Although the spliceosome evolved from a prokaryotic self-splicing intron and an associated protein, it is a vastly more complex and dynamic ribonucleoprotein (RNP) whose function requires at least eight ATPases and multiple RNA rearrangements. These features afford stepwise opportunities for multiple inspections of the intron substrate, coupled with spliceosome disassembly for substrates that fail inspection. Early work using splicing-defective pre-mRNAs or small nuclear (sn)RNAs in <em>Saccharomyces cerevisiae</em> demonstrated that such checks could occur in catalytically active spliceosomes. We review recent results on pre-mRNA splicing in various systems, including humans, suggesting that earlier steps in spliceosome assembly are also subject to such quality control. The inspection–rejection framework helps explain the dynamic nature of the spliceosome.</p></div>","PeriodicalId":440,"journal":{"name":"Trends in Biochemical Sciences","volume":"49 7","pages":"Pages 583-595"},"PeriodicalIF":11.6,"publicationDate":"2024-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S0968000424000781/pdfft?md5=bbb6aeb7e63838ff600a8cb1ff1d8071&pid=1-s2.0-S0968000424000781-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140776366","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Advisory Board and Contents","authors":"","doi":"10.1016/S0968-0004(24)00139-7","DOIUrl":"https://doi.org/10.1016/S0968-0004(24)00139-7","url":null,"abstract":"","PeriodicalId":440,"journal":{"name":"Trends in Biochemical Sciences","volume":"49 7","pages":"Pages i-ii"},"PeriodicalIF":11.6,"publicationDate":"2024-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S0968000424001397/pdfft?md5=f6dd74a40dda1b1e9174b0f103373d8c&pid=1-s2.0-S0968000424001397-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141595513","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Beneath the surface: endosomal GPCR signaling","authors":"Emmanuel Flores-Espinoza , Alex R.B. Thomsen","doi":"10.1016/j.tibs.2024.03.006","DOIUrl":"10.1016/j.tibs.2024.03.006","url":null,"abstract":"<div><p>G protein-coupled receptors (GPCRs) located at the cell surface bind extracellular ligands and convey intracellular signals via activation of heterotrimeric G proteins. Traditionally, G protein signaling was viewed to occur exclusively at this subcellular region followed by rapid desensitization facilitated by β-arrestin (βarr)-mediated G protein uncoupling and receptor internalization. However, emerging evidence over the past 15 years suggests that these βarr-mediated events do not necessarily terminate receptor signaling and that some GPCRs continue to activate G proteins after having been internalized into endosomes. Here, we review the recently elucidated mechanistic basis underlying endosomal GPCR signaling and discuss physiological implications and pharmacological targeting of this newly appreciated signaling mode.</p></div>","PeriodicalId":440,"journal":{"name":"Trends in Biochemical Sciences","volume":"49 6","pages":"Pages 520-531"},"PeriodicalIF":13.8,"publicationDate":"2024-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140760577","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Thiol dioxygenases: from structures to functions","authors":"Monica Perri , Francesco Licausi","doi":"10.1016/j.tibs.2024.03.007","DOIUrl":"10.1016/j.tibs.2024.03.007","url":null,"abstract":"<div><p>Thiol oxidation to dioxygenated sulfinic acid is catalyzed by an enzyme family characterized by a cupin fold. These proteins act on free thiol-containing molecules to generate central metabolism precursors and signaling compounds in bacteria, fungi, and animal cells. In plants and animals, they also oxidize exposed N-cysteinyl residues, directing proteins to proteolysis. Enzyme kinetics, X-ray crystallography, and spectroscopy studies prompted the formulation and testing of hypotheses about the mechanism of action and the different substrate specificity of these enzymes. Concomitantly, the physiological role of thiol dioxygenation in prokaryotes and eukaryotes has been studied through genetic and physiological approaches. Further structural characterization is necessary to enable precise and safe manipulation of thiol dioxygenases (TDOs) for therapeutic, industrial, and agricultural applications.</p></div>","PeriodicalId":440,"journal":{"name":"Trends in Biochemical Sciences","volume":"49 6","pages":"Pages 545-556"},"PeriodicalIF":13.8,"publicationDate":"2024-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S0968000424000732/pdfft?md5=c3a169ce954c4a136b6d347c6f9b1923&pid=1-s2.0-S0968000424000732-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140789320","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"ULK/Atg1: phasing in and out of autophagy","authors":"Bo Wang , Gautam Pareek , Mondira Kundu","doi":"10.1016/j.tibs.2024.03.004","DOIUrl":"10.1016/j.tibs.2024.03.004","url":null,"abstract":"<div><p>Autophagy – a highly regulated intracellular degradation process – is pivotal in maintaining cellular homeostasis. Liquid–liquid phase separation (LLPS) is a fundamental mechanism regulating the formation and function of membrane-less compartments. Recent research has unveiled connections between LLPS and autophagy, suggesting that phase separation events may orchestrate the spatiotemporal organization of autophagic machinery and cargo sequestration. The Unc-51-like kinase (ULK)/autophagy-related 1 (Atg1) family of proteins is best known for its regulatory role in initiating autophagy, but there is growing evidence that the functional spectrum of ULK/Atg1 extends beyond autophagy regulation. In this review, we explore the spatial and temporal regulation of the ULK/Atg1 family of kinases, focusing on their recruitment to LLPS-driven compartments, and highlighting their multifaceted functions beyond their traditional role.</p></div>","PeriodicalId":440,"journal":{"name":"Trends in Biochemical Sciences","volume":"49 6","pages":"Pages 494-505"},"PeriodicalIF":13.8,"publicationDate":"2024-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140761128","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Matthias S. Leisegang , Timothy Warwick , Julia Stötzel , Ralf P. Brandes
{"title":"RNA-DNA triplexes: molecular mechanisms and functional relevance","authors":"Matthias S. Leisegang , Timothy Warwick , Julia Stötzel , Ralf P. Brandes","doi":"10.1016/j.tibs.2024.03.009","DOIUrl":"10.1016/j.tibs.2024.03.009","url":null,"abstract":"<div><p>Interactions of RNA with DNA are principles of gene expression control that have recently gained considerable attention. Among RNA–DNA interactions are R-loops and RNA-DNA hybrid G-quadruplexes, as well as RNA-DNA triplexes. It is proposed that RNA-DNA triplexes guide RNA-associated regulatory proteins to specific genomic locations, influencing transcription and epigenetic decision making. Although triplex formation initially was considered solely an <em>in vitro</em> event, recent progress in computational, biochemical, and biophysical methods support <em>in vivo</em> functionality with relevance for gene expression control. Here, we review the central methodology and biology of triplexes, outline paradigms required for triplex function, and provide examples of physiologically important triplex-forming long non-coding RNAs.</p></div>","PeriodicalId":440,"journal":{"name":"Trends in Biochemical Sciences","volume":"49 6","pages":"Pages 532-544"},"PeriodicalIF":13.8,"publicationDate":"2024-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S0968000424000756/pdfft?md5=9f9f4aef9e9e02cd88e4b181cdfc399e&pid=1-s2.0-S0968000424000756-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140773597","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Advisory Board and Contents","authors":"","doi":"10.1016/S0968-0004(24)00123-3","DOIUrl":"https://doi.org/10.1016/S0968-0004(24)00123-3","url":null,"abstract":"","PeriodicalId":440,"journal":{"name":"Trends in Biochemical Sciences","volume":"49 6","pages":"Pages i-ii"},"PeriodicalIF":13.8,"publicationDate":"2024-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S0968000424001233/pdfft?md5=051918d74506a4a0a0028f9adba942e8&pid=1-s2.0-S0968000424001233-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141263806","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Macromolecular crowding sensing during osmotic stress in plants","authors":"G.I. Meneses-Reyes , D.L. Rodriguez-Bustos , C.L. Cuevas-Velazquez","doi":"10.1016/j.tibs.2024.02.002","DOIUrl":"10.1016/j.tibs.2024.02.002","url":null,"abstract":"<div><p>Osmotic stress conditions occur at multiple stages of plant life. Changes in water availability caused by osmotic stress induce alterations in the mechanical properties of the plasma membrane, its interaction with the cell wall, and the concentration of macromolecules in the cytoplasm. We summarize the reported players involved in the sensing mechanisms of osmotic stress in plants. We discuss how changes in macromolecular crowding are perceived intracellularly by intrinsically disordered regions (IDRs) in proteins. Finally, we review methods for dynamically monitoring macromolecular crowding in living cells and discuss why their implementation is required for the discovery of new plant osmosensors. Elucidating the osmosensing mechanisms will be essential for designing strategies to improve plant productivity in the face of climate change.</p></div>","PeriodicalId":440,"journal":{"name":"Trends in Biochemical Sciences","volume":"49 6","pages":"Pages 480-493"},"PeriodicalIF":13.8,"publicationDate":"2024-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S0968000424000380/pdfft?md5=3672c7f0acf7914d4916e59542eaed4e&pid=1-s2.0-S0968000424000380-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140183410","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Limitations in membrane protein structure determination by lipid nanodiscs","authors":"Chen Zhao","doi":"10.1016/j.tibs.2024.03.010","DOIUrl":"10.1016/j.tibs.2024.03.010","url":null,"abstract":"<div><p>Lipid nanodiscs are popular mimetics of biological membranes for determining membrane protein structures. However, a recent study revealed that the choice of nanodisc scaffold directly influenced the structure of an ion channel. This finding prompts us to be cautious and calls for improved membrane mimetics for structure determination.</p></div>","PeriodicalId":440,"journal":{"name":"Trends in Biochemical Sciences","volume":"49 6","pages":"Pages 475-476"},"PeriodicalIF":13.8,"publicationDate":"2024-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140304293","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Scott A. Jones , Jonathan J. Ruprecht , Paul G. Crichton , Edmund R.S. Kunji
{"title":"Structural mechanisms of mitochondrial uncoupling protein 1 regulation in thermogenesis","authors":"Scott A. Jones , Jonathan J. Ruprecht , Paul G. Crichton , Edmund R.S. Kunji","doi":"10.1016/j.tibs.2024.03.005","DOIUrl":"10.1016/j.tibs.2024.03.005","url":null,"abstract":"<div><p>In mitochondria, the oxidation of nutrients is coupled to ATP synthesis by the generation of a protonmotive force across the mitochondrial inner membrane. In mammalian brown adipose tissue (BAT), uncoupling protein 1 (UCP1, SLC25A7), a member of the SLC25 mitochondrial carrier family, dissipates the protonmotive force by facilitating the return of protons to the mitochondrial matrix. This process short-circuits the mitochondrion, generating heat for non-shivering thermogenesis. Recent cryo-electron microscopy (cryo-EM) structures of human UCP1 have provided new molecular insights into the inhibition and activation of thermogenesis. Here, we discuss these structures, describing how purine nucleotides lock UCP1 in a proton-impermeable conformation and rationalizing potential conformational changes of this carrier in response to fatty acid activators that enable proton leak for thermogenesis.</p></div>","PeriodicalId":440,"journal":{"name":"Trends in Biochemical Sciences","volume":"49 6","pages":"Pages 506-519"},"PeriodicalIF":13.8,"publicationDate":"2024-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S0968000424000719/pdfft?md5=4275e31dee205ccf724ae3979e5131c3&pid=1-s2.0-S0968000424000719-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140771367","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}