Pub Date : 2025-01-01DOI: 10.1016/j.tibs.2024.10.011
Kevin Huang , Yubao Wang , Thomas M. Roberts
Recently developed KRAS inhibitors have delivered clinical benefits but their antitumor efficacy remains limited. A recent study by Klomp et al. 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.
{"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}
Pub Date : 2025-01-01DOI: 10.1016/j.tibs.2024.10.006
Davide Calebiro , Tamara Miljus , Shannon O’Brien
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.
G 蛋白偶联受体（GPCR）是最大的细胞受体家族。它们介导多种内源性和外源性信号的作用，深度参与人体生理和疾病，是主要的药理靶标。长期以来，人们一直认为 GPCR 只在质膜上发出信号，但过去 15 年的研究发现，它们也通过经典的 G 蛋白介导途径在细胞内的细胞器（如内体和高尔基复合体）膜上发出信号。本综述概述了与内膜 GPCR 信号相关的最新进展和新兴概念，以及为更好地了解其机制、生理相关性和潜在治疗应用而正在进行的研究。
{"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}
Pub Date : 2025-01-01DOI: 10.1016/j.tibs.2024.10.008
Philip Cohen , Tom Snelling
Protein kinases regulate many intracellular processes, and their dysregulation causes cancers and other diseases. This review focuses on the atypical alpha-kinase 1 (ALPK1), which is activated in mammalian cells by nucleoside diphosphate heptoses (ADP-heptose, UDP-heptose, and CDP-heptose) produced by microbial pathogens but not by mammalian cells. Mutations in human ALPK1 cause ROSAH syndrome and spiradenoma, which result from an alteration in its specificity for nucleoside diphosphate heptoses, causing aberrant activation by mammalian nucleoside diphosphate sugars without microbial infection. These may be the first diseases caused by altered specificity of an enzyme for its allosteric activators and has suggested ways in which selective drugs could be developed to treat them without compromising the innate immune system.
{"title":"Diseases caused by altered specificity of a protein kinase for its allosteric activators","authors":"Philip Cohen , Tom Snelling","doi":"10.1016/j.tibs.2024.10.008","DOIUrl":"10.1016/j.tibs.2024.10.008","url":null,"abstract":"<div><div>Protein kinases regulate many intracellular processes, and their dysregulation causes cancers and other diseases. This review focuses on the atypical alpha-kinase 1 (ALPK1), which is activated in mammalian cells by nucleoside diphosphate heptoses (ADP-heptose, UDP-heptose, and CDP-heptose) produced by microbial pathogens but not by mammalian cells. Mutations in human ALPK1 cause ROSAH syndrome and spiradenoma, which result from an alteration in its specificity for nucleoside diphosphate heptoses, causing aberrant activation by mammalian nucleoside diphosphate sugars without microbial infection. These may be the first diseases caused by altered specificity of an enzyme for its allosteric activators and has suggested ways in which selective drugs could be developed to treat them without compromising the innate immune system.</div></div>","PeriodicalId":440,"journal":{"name":"Trends in Biochemical Sciences","volume":"50 1","pages":"Pages 61-70"},"PeriodicalIF":11.6,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142694974","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}
Pub Date : 2025-01-01DOI: 10.1016/S0968-0004(24)00289-5
{"title":"Subscription and Copyright Information","authors":"","doi":"10.1016/S0968-0004(24)00289-5","DOIUrl":"10.1016/S0968-0004(24)00289-5","url":null,"abstract":"","PeriodicalId":440,"journal":{"name":"Trends in Biochemical Sciences","volume":"50 1","pages":"Page e1"},"PeriodicalIF":11.6,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143136580","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}
Pub Date : 2025-01-01DOI: 10.1016/j.tibs.2024.10.012
Yuxia Qi , Sho W. Suzuki
DNA is constantly subject to damage from endogenous and exogenous factors, leading to mutations and disease. While DNA is traditionally repaired in the nucleus, Lascaux et al. reveal a novel role for the lysosome in DNA repair, demonstrating that topoisomerase 1 (TOP1) cleavage complex (TOP1cc) DNA lesions are degraded via TEX264-mediated selective autophagy.
DNA 经常受到内源性和外源性因素的损伤，从而导致突变和疾病。DNA 传统上是在细胞核中修复的，而 Lascaux 等人揭示了溶酶体在 DNA 修复中的新作用，证明拓扑异构酶 1（TOP1）裂解复合体（TOP1cc）DNA 病变是通过 TEX264 介导的选择性自噬降解的。
{"title":"TEX264-mediated selective autophagy directs DNA damage repair","authors":"Yuxia Qi , Sho W. Suzuki","doi":"10.1016/j.tibs.2024.10.012","DOIUrl":"10.1016/j.tibs.2024.10.012","url":null,"abstract":"<div><div>DNA is constantly subject to damage from endogenous and exogenous factors, leading to mutations and disease. While DNA is traditionally repaired in the nucleus, <span><span>Lascaux <em>et al.</em></span><svg><path></path></svg></span> reveal a novel role for the lysosome in DNA repair, demonstrating that topoisomerase 1 (TOP1) cleavage complex (TOP1cc) DNA lesions are degraded via TEX264-mediated selective autophagy.</div></div>","PeriodicalId":440,"journal":{"name":"Trends in Biochemical Sciences","volume":"50 1","pages":"Pages 4-5"},"PeriodicalIF":11.6,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142643384","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}
Pub Date : 2025-01-01DOI: 10.1016/j.tibs.2024.11.003
Kayleigh Robichaux , Taylor Billings , Christina Marie Termini
In this piece, we use an antibody inventory system to exemplify the potential benefits of laboratory organization in research environments. We highlight how inventories can support resource accessibility and strengthen a sense of independence for scientists, especially those new to research environments.
{"title":"Inventories invite independence","authors":"Kayleigh Robichaux , Taylor Billings , Christina Marie Termini","doi":"10.1016/j.tibs.2024.11.003","DOIUrl":"10.1016/j.tibs.2024.11.003","url":null,"abstract":"<div><div>In this piece, we use an antibody inventory system to exemplify the potential benefits of laboratory organization in research environments. We highlight how inventories can support resource accessibility and strengthen a sense of independence for scientists, especially those new to research environments.</div></div>","PeriodicalId":440,"journal":{"name":"Trends in Biochemical Sciences","volume":"50 1","pages":"Pages 1-3"},"PeriodicalIF":11.6,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142816889","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}
Pub Date : 2025-01-01DOI: 10.1016/j.tibs.2024.10.009
H. Jane Dyson , Peter E. Wright
Defects in the tumor suppressor protein p53 are found in the majority of cancers. The p53 protein (393 amino acids long) contains the folded DNA-binding domain (DBD) and tetramerization domain (TET), with the remainder of the sequence being intrinsically disordered. Since cancer-causing mutations occur primarily in the DBD, this has been the focus of most of the research on p53. However, recent reports show that the disordered N-terminal activation domain (NTAD) and C-terminal regulatory domain (CTD) function synergistically with the DBD to regulate p53 activity. We propose a mechanistic model in which intermolecular and intramolecular interactions of the disordered regions, modulated by post-translational modifications, perform a central role in the regulation and activation of p53 in response to cellular stress.
大多数癌症都存在肿瘤抑制蛋白 p53 的缺陷。p53 蛋白（长 393 个氨基酸）包含折叠的 DNA 结合结构域（DBD）和四聚合结构域（TET），其余序列为内在无序结构。由于致癌突变主要发生在 DBD 上，因此这一直是大多数 p53 研究的重点。然而，最近的报告显示，紊乱的 N 端激活结构域（NTAD）和 C 端调节结构域（CTD）与 DBD 起着协同调节 p53 活性的作用。我们提出了一个机理模型，在该模型中，无序区域的分子间和分子内相互作用在翻译后修饰的调节下，在 p53 应对细胞压力时的调控和激活过程中发挥着核心作用。
{"title":"How does p53 work? Regulation by the intrinsically disordered domains","authors":"H. Jane Dyson , Peter E. Wright","doi":"10.1016/j.tibs.2024.10.009","DOIUrl":"10.1016/j.tibs.2024.10.009","url":null,"abstract":"<div><div>Defects in the tumor suppressor protein p53 are found in the majority of cancers. The p53 protein (393 amino acids long) contains the folded DNA-binding domain (DBD) and tetramerization domain (TET), with the remainder of the sequence being intrinsically disordered. Since cancer-causing mutations occur primarily in the DBD, this has been the focus of most of the research on p53. However, recent reports show that the disordered N-terminal activation domain (NTAD) and C-terminal regulatory domain (CTD) function synergistically with the DBD to regulate p53 activity. We propose a mechanistic model in which intermolecular and intramolecular interactions of the disordered regions, modulated by post-translational modifications, perform a central role in the regulation and activation of p53 in response to cellular stress.</div></div>","PeriodicalId":440,"journal":{"name":"Trends in Biochemical Sciences","volume":"50 1","pages":"Pages 9-17"},"PeriodicalIF":11.6,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142692447","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}
Pub Date : 2025-01-01DOI: 10.1016/S0968-0004(24)00286-X
{"title":"Advisory Board and Contents","authors":"","doi":"10.1016/S0968-0004(24)00286-X","DOIUrl":"10.1016/S0968-0004(24)00286-X","url":null,"abstract":"","PeriodicalId":440,"journal":{"name":"Trends in Biochemical Sciences","volume":"50 1","pages":"Pages i-ii"},"PeriodicalIF":11.6,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143136579","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}
Pub Date : 2024-12-01DOI: 10.1016/j.tibs.2024.10.004
Sukantha Dey , Rohit Kumar , Rajkumar Mishra , Santu Bera
Amyloids are filamentous protein aggregates that have traditionally been associated with neurodegenerative diseases, although they are also known to play pivotal functional roles across diverse forms of life. Although the cross-β structure has represented the hallmark of amyloidal assemblies, a cross-α structure was recently characterized as a functional microbial amyloid, and further work has shown that de novo designed sequences also assemble into cross-α amyloids, emphasizing cross-α as an alternative paradigm for self-assembly into ordered aggregates. In this review, we summarize recent discoveries of cross-α amyloids both in nature and artificially designed systems, and we describe their fundamental structural organization, self-assembly mechanisms, and biological functions. Finally, we outline the future opportunities for research and development in this potential field.
{"title":"Exploring cross-α amyloids: from functional roles to design innovations","authors":"Sukantha Dey , Rohit Kumar , Rajkumar Mishra , Santu Bera","doi":"10.1016/j.tibs.2024.10.004","DOIUrl":"10.1016/j.tibs.2024.10.004","url":null,"abstract":"<div><div>Amyloids are filamentous protein aggregates that have traditionally been associated with neurodegenerative diseases, although they are also known to play pivotal functional roles across diverse forms of life. Although the cross-β structure has represented the hallmark of amyloidal assemblies, a cross-α structure was recently characterized as a functional microbial amyloid, and further work has shown that <em>de novo</em> designed sequences also assemble into cross-α amyloids, emphasizing cross-α as an alternative paradigm for self-assembly into ordered aggregates. In this review, we summarize recent discoveries of cross-α amyloids both in nature and artificially designed systems, and we describe their fundamental structural organization, self-assembly mechanisms, and biological functions. Finally, we outline the future opportunities for research and development in this potential field.</div></div>","PeriodicalId":440,"journal":{"name":"Trends in Biochemical Sciences","volume":"49 12","pages":"Pages 1097-1110"},"PeriodicalIF":11.6,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142602327","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}
Pub Date : 2024-12-01DOI: 10.1016/j.tibs.2024.08.003
Carsten Peters , Martin Haslbeck , Johannes Buchner
Small heat shock proteins (sHsps) are an important part of the cellular system maintaining protein homeostasis under physiological and stress conditions. As molecular chaperones, they form complexes with different non-native proteins in an ATP-independent manner. Many sHsps populate ensembles of energetically similar but different-sized oligomers. Regulation of chaperone activity occurs by changing the equilibrium of these ensembles. This makes sHsps a versatile and adaptive system for trapping non-native proteins in complexes, allowing recycling with the help of ATP-dependent chaperones. In this review, we discuss progress in our understanding of the structural principles of sHsp oligomers and their functional principles, as well as their roles in aging and eye lens transparency.
小热休克蛋白（sHsps）是在生理和应激条件下维持蛋白质平衡的细胞系统的重要组成部分。作为分子伴侣，它们以不依赖 ATP 的方式与不同的非本源蛋白质形成复合物。许多 sHsps 形成了能量相似但大小不同的寡聚体组合。通过改变这些组合体的平衡来调节伴侣活性。这使得 sHsps 成为一种多功能的适应性系统，可将非本地蛋白质困在复合物中，并在 ATP 依赖性伴侣的帮助下进行回收。在这篇综述中，我们将讨论对 sHsp 寡聚体结构原理及其功能原理的理解进展，以及它们在衰老和眼睛晶状体透明度中的作用。
{"title":"Catchers of folding gone awry: a tale of small heat shock proteins","authors":"Carsten Peters , Martin Haslbeck , Johannes Buchner","doi":"10.1016/j.tibs.2024.08.003","DOIUrl":"10.1016/j.tibs.2024.08.003","url":null,"abstract":"<div><div>Small heat shock proteins (sHsps) are an important part of the cellular system maintaining protein homeostasis under physiological and stress conditions. As molecular chaperones, they form complexes with different non-native proteins in an ATP-independent manner. Many sHsps populate ensembles of energetically similar but different-sized oligomers. Regulation of chaperone activity occurs by changing the equilibrium of these ensembles. This makes sHsps a versatile and adaptive system for trapping non-native proteins in complexes, allowing recycling with the help of ATP-dependent chaperones. In this review, we discuss progress in our understanding of the structural principles of sHsp oligomers and their functional principles, as well as their roles in aging and eye lens transparency.</div></div>","PeriodicalId":440,"journal":{"name":"Trends in Biochemical Sciences","volume":"49 12","pages":"Pages 1063-1078"},"PeriodicalIF":11.6,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142267666","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}
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