Chloé Van Leene , Laura Van Moortel , Karolien De Bosscher , Kris Gevaert
{"title":"Exploring protein conformations with limited proteolysis coupled to mass spectrometry","authors":"Chloé Van Leene , Laura Van Moortel , Karolien De Bosscher , Kris Gevaert","doi":"10.1016/j.tibs.2024.11.005","DOIUrl":"10.1016/j.tibs.2024.11.005","url":null,"abstract":"<div><div>Limited proteolysis coupled to mass spectrometry (LiP-MS) has emerged as a powerful proteomic tool for studying protein conformations. Since its introduction in 2014, LiP-MS has expanded its scope to explore complex biological systems and shed light on disease mechanisms, and has been used for protein drug research. This review discusses the evolution of the technique, recent technical advances, including enhanced protocols and integration of machine learning, and diverse applications across various experimental models. Despite its achievements, challenges in protein extraction and conformotypic peptide identification remain. Ongoing methodological refinements will be crucial to overcome these challenges and enhance the capabilities of the technique. However, LiP-MS offers significant potential for future discoveries in structural proteomics and medical research.</div></div>","PeriodicalId":440,"journal":{"name":"Trends in Biochemical Sciences","volume":"50 2","pages":"Pages 143-155"},"PeriodicalIF":11.6,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142871016","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":"Routes to molecular glue degrader discovery","authors":"Yanfen Liu , Jieyun Bai , Dong Li , Yong Cang","doi":"10.1016/j.tibs.2024.12.006","DOIUrl":"10.1016/j.tibs.2024.12.006","url":null,"abstract":"<div><div>Molecular glue degraders (MGDs) represent a unique class of targeted protein degradation (TPD) modalities. By facilitating protein–protein interactions between E3 ubiquitin ligases and neo-substrates, MGDs offer a novel approach to target previously undruggable or insufficiently drugged disease-causing proteins. Here, we present an overview of recently reported MGDs, highlighting their diverse mechanisms, and we discuss mechanism-based strategies to discover new MGDs and neo-substrates. These strategies include repurposing existing E3 ubiquitin ligase-targeting ligands, screening for novel binders to proteins of interest, and leveraging functional genomics and quantitative proteomics to probe the MGD mechanism of action. Despite their historically serendipitous discovery, MGDs are on their way to being rationally designed to deplete undesired proteins by purposely altering the evolutionarily conserved ligase:substrate interactions.</div></div>","PeriodicalId":440,"journal":{"name":"Trends in Biochemical Sciences","volume":"50 2","pages":"Pages 134-142"},"PeriodicalIF":11.6,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142926136","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":"Crabtree effect in yeast: a phosphate tug-of-war between fermentation and respiration","authors":"Ananda Krishnan Manoj , Aswathy Valsalakumari Saradanandan , Vijay Jayaraman","doi":"10.1016/j.tibs.2024.12.001","DOIUrl":"10.1016/j.tibs.2024.12.001","url":null,"abstract":"<div><div>The Crabtree effect in yeast, where cells prefer fermentation over respiration in high -glucose environments, is associated with mitochondrial repression, but the molecular mechanisms were previously unclear. Recently, <span><span>Vengayil <em>et al</em>.</span><svg><path></path></svg></span> revealed that knocking out the ubp3 gene, encoding a deubiquitinase enzyme, mitigates the Crabtree effect by increasing mitochondrial phosphate levels.</div></div>","PeriodicalId":440,"journal":{"name":"Trends in Biochemical Sciences","volume":"50 2","pages":"Pages 89-91"},"PeriodicalIF":11.6,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142871015","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}
Hanadi Hoblos , Wayne Cawthorne , André L. Samson , James M. Murphy
{"title":"Protein shapeshifting in necroptotic cell death signaling","authors":"Hanadi Hoblos , Wayne Cawthorne , André L. Samson , James M. Murphy","doi":"10.1016/j.tibs.2024.11.006","DOIUrl":"10.1016/j.tibs.2024.11.006","url":null,"abstract":"<div><div>Necroptosis is a mode of programmed cell death executed by the mixed lineage kinase domain-like (MLKL) pseudokinase following its activation by the upstream receptor-interacting protein kinase-3 (RIPK3), subsequent to activation of death, Toll-like, and pathogen receptors. The pathway originates in innate immunity, although interest has surged in therapeutically targeting necroptosis owing to its dysregulation in inflammatory diseases. Here, we explore how protein conformation and higher order assembly of the pathway effectors – Z-DNA-binding protein-1 (ZBP1), RIPK1, RIPK3, and MLKL – can be modulated by post-translational modifications, such as phosphorylation, ubiquitylation, and lipidation, and intermolecular interactions to tune activities and modulate necroptotic signaling flux. As molecular level knowledge of cell death signaling grows, we anticipate targeting the conformations of key necrosomal effector proteins will emerge as new avenues for drug development.</div></div>","PeriodicalId":440,"journal":{"name":"Trends in Biochemical Sciences","volume":"50 2","pages":"Pages 92-105"},"PeriodicalIF":11.6,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142891263","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}
Ella Catherall , Sabina Musial , Nicky Atkinson , Charlotte E. Walker , Luke C.M. Mackinder , Alistair J. McCormick
{"title":"From algae to plants: understanding pyrenoid-based CO2-concentrating mechanisms","authors":"Ella Catherall , Sabina Musial , Nicky Atkinson , Charlotte E. Walker , Luke C.M. Mackinder , Alistair J. McCormick","doi":"10.1016/j.tibs.2024.10.010","DOIUrl":"10.1016/j.tibs.2024.10.010","url":null,"abstract":"<div><div>Pyrenoids are the key component of one of the most abundant biological CO<sub>2</sub> concentration mechanisms found in nature. Pyrenoid-based CO<sub>2</sub>-concentrating mechanisms (pCCMs) are estimated to account for one third of global photosynthetic CO<sub>2</sub> capture. Our molecular understanding of how pyrenoids work is based largely on work in the green algae <em>Chlamydomonas reinhardtii</em>. Here, we review recent advances in our fundamental knowledge of the biogenesis, architecture, and function of pyrenoids in <em>Chlamydomonas</em> and ongoing engineering biology efforts to introduce a functional pCCM into chloroplasts of vascular plants, which, if successful, has the potential to enhance crop productivity and resilience to climate change.</div></div>","PeriodicalId":440,"journal":{"name":"Trends in Biochemical Sciences","volume":"50 1","pages":"Pages 33-45"},"PeriodicalIF":11.6,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142724555","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":"Surviving the heat: the role of macromolecular assemblies in promoting cellular shutdown","authors":"Christine Desroches Altamirano , Simon Alberti","doi":"10.1016/j.tibs.2024.09.008","DOIUrl":"10.1016/j.tibs.2024.09.008","url":null,"abstract":"<div><div>During heat shock (HS), cells orchestrate a gene expression program that promotes the synthesis of HS proteins (HSPs) while simultaneously repressing the synthesis of other proteins, including growth-promoting housekeeping proteins. Recent studies show that mRNAs encoding housekeeping proteins, along with associated processing factors, form macromolecular assemblies during HS. These assemblies inhibit transcription, nuclear export, and translation of housekeeping mRNAs, and coincide with structural rearrangements in proteins. These findings reveal a mechanism linking temperature sensitivity through structural rearrangements and macromolecular assembly to the ‘shut down’ of housekeeping protein synthesis. This review delves into recent findings in yeast, with a focus on macromolecular assembly, offering perspectives into mechanisms that regulate gene expression during HS and how these processes may be conserved.</div></div>","PeriodicalId":440,"journal":{"name":"Trends in Biochemical Sciences","volume":"50 1","pages":"Pages 18-32"},"PeriodicalIF":11.6,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142542735","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":"Confronting PFAS persistence: enzymes catalyzing C–F bond cleavage","authors":"Lawrence P. Wackett","doi":"10.1016/j.tibs.2024.11.001","DOIUrl":"10.1016/j.tibs.2024.11.001","url":null,"abstract":"<div><div>Studies of enzymes catalyzing carbon–fluorine (C–F) bond cleavage have focused largely on a limited number of native microbial hydrolases that are reactive with the natural product fluoroacetate. Driven by widespread interest in biodegrading commercial fluorinated compounds, many of which are known as per- and polyfluorinated alkyl substances (PFAS), it is necessary to identify and engineer new enzymes. For example, some hydrolases react with –CF<sub>2</sub>– moieties, a common functionality in PFAS. Additional enzymatic C–F cleaving mechanisms catalyzed by reductases, lyases, and oxygenases have been identified via screening. Screening and evolving PFAS defluorination in bacteria is inhibited by the obligate release of toxic fluoride from C–F cleavage. Engineering greater fluoride tolerance in bacteria is a problem that must be solved in tandem with enzyme improvement.</div></div>","PeriodicalId":440,"journal":{"name":"Trends in Biochemical Sciences","volume":"50 1","pages":"Pages 71-83"},"PeriodicalIF":11.6,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142790894","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}
Larissa O. Silva , Anuradha V. Wijesekara , Matthew T. Eddy
{"title":"NMR spectroscopy reveals insights into mechanisms of GPCR signaling","authors":"Larissa O. Silva , Anuradha V. Wijesekara , Matthew T. Eddy","doi":"10.1016/j.tibs.2024.10.007","DOIUrl":"10.1016/j.tibs.2024.10.007","url":null,"abstract":"","PeriodicalId":440,"journal":{"name":"Trends in Biochemical Sciences","volume":"50 1","pages":"Pages 84-85"},"PeriodicalIF":11.6,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142611617","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":"ERK-dependent protein phosphorylation in KRAS-mutant cancer: a mix of the expected and surprising","authors":"Kevin Huang , Yubao Wang , Thomas M. Roberts","doi":"10.1016/j.tibs.2024.10.011","DOIUrl":"10.1016/j.tibs.2024.10.011","url":null,"abstract":"<div><div>Recently developed KRAS inhibitors have delivered clinical benefits but their antitumor efficacy remains limited. A recent study by <span><span>Klomp <em>et al</em>.</span><svg><path></path></svg></span> reports an unprecedentedly comprehensive profiling of protein phosphorylation dependent on the KRAS pathway and generates new insights and directions to improve the efficacy of KRAS-targeted therapies.</div></div>","PeriodicalId":440,"journal":{"name":"Trends in Biochemical Sciences","volume":"50 1","pages":"Pages 6-8"},"PeriodicalIF":11.6,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142646724","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":"Endomembrane GPCR signaling: 15 years on, the quest continues","authors":"Davide Calebiro , Tamara Miljus , Shannon O’Brien","doi":"10.1016/j.tibs.2024.10.006","DOIUrl":"10.1016/j.tibs.2024.10.006","url":null,"abstract":"<div><div>G-protein-coupled receptors (GPCRs) are the largest family of cell receptors. They mediate the effects of a multitude of endogenous and exogenous cues, are deeply involved in human physiology and disease, and are major pharmacological targets. Whereas GPCRs were long thought to signal exclusively at the plasma membrane, research over the past 15 years has revealed that they also signal via classical G-protein-mediated pathways on membranes of intracellular organelles such as endosomes and the Golgi complex. This review provides an overview of recent advances and emerging concepts related to endomembrane GPCR signaling, as well as ongoing research aimed at a better understanding of its mechanisms, physiological relevance, and potential therapeutic applications.</div></div>","PeriodicalId":440,"journal":{"name":"Trends in Biochemical Sciences","volume":"50 1","pages":"Pages 46-60"},"PeriodicalIF":11.6,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142611611","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}