Nature structural & molecular biology最新文献

A structural switch reveals how to disarm USP30 and unlock mitophagy 一个结构开关揭示了如何解除USP30并解锁有丝分裂

Nature structural & molecular biology Pub Date : 2025-07-25 DOI: 10.1038/s41594-025-01640-3

Julia C. Fitzgerald, Anja Bremm

引用次数: 0

Structural basis for mTORC1 regulation by the CASTOR1–GATOR2 complex CASTOR1-GATOR2复合物调控mTORC1的结构基础

Nature structural & molecular biology Pub Date : 2025-07-25 DOI: 10.1038/s41594-025-01635-0

Rachel M. Jansen, Clément Maghe, Karla Tapia, Selina Wu, Serim Yang, Xuefeng Ren, Roberto Zoncu, James H. Hurley

{"title":"Structural basis for mTORC1 regulation by the CASTOR1–GATOR2 complex","authors":"Rachel M. Jansen, Clément Maghe, Karla Tapia, Selina Wu, Serim Yang, Xuefeng Ren, Roberto Zoncu, James H. Hurley","doi":"10.1038/s41594-025-01635-0","DOIUrl":"https://doi.org/10.1038/s41594-025-01635-0","url":null,"abstract":"Mechanistic target of rapamycin complex 1 (mTORC1) is a nutrient-responsive master regulator of metabolism. Amino acids control the recruitment and activation of mTORC1 at the lysosome through the nucleotide loading state of the heterodimeric Rag GTPases. Under low nutrients, including arginine, the GTPase-activating protein complex GATOR1 promotes GTP hydrolysis on RagA/B, inactivating mTORC1. GATOR1 is regulated by the cage-like GATOR2 complex and cytosolic amino acid sensors. To understand how the arginine sensor CASTOR1 binds to GATOR2 to disinhibit GATOR1 under low cytosolic arginine, we determined the cryo-electron microscopy structure of human GATOR2 bound to CASTOR1 in the absence of arginine. Two MIOS WD40 domain β-propellers of the GATOR2 cage engage with both subunits of a single CASTOR1 homodimer. Each propeller binds to a negatively charged MIOS-binding interface on CASTOR1 that is distal to the arginine pocket. The structure shows how arginine-triggered loop ordering in CASTOR1 blocks the MIOS-binding interface, switches off its binding to GATOR2 and, thus, communicates to downstream mTORC1 activation.","PeriodicalId":18822,"journal":{"name":"Nature structural & molecular biology","volume":"55 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-07-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144701845","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Q&A with Francesca Mattiroli Francesca Mattiroli的问答

Nature structural & molecular biology Pub Date : 2025-07-21 DOI: 10.1038/s41594-025-01620-7

Melina Casadio

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Q&A with Yael David and Charles Rice on using chromatin biology to understand hepatitis 雅艾尔·大卫和查尔斯·赖斯关于用染色质生物学来理解肝炎的问答

Nature structural & molecular biology Pub Date : 2025-07-17 DOI: 10.1038/s41594-025-01613-6

Dimitris Typas

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Structural basis of ClC-3 transporter inhibition by TMEM9 and PtdIns(3,5)P2 TMEM9和PtdIns抑制ClC-3转运蛋白的结构基础（3,5）P2

Nature structural & molecular biology Pub Date : 2025-07-16 DOI: 10.1038/s41594-025-01617-2

Marina Schrecker, Yeeun Son, Rosa Planells-Cases, Sumanta Kar, Viktoriia Vorobeva, Uwe Schulte, Bernd Fakler, Thomas J. Jentsch, Richard K. Hite

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scNanoHi-C2 uncovers dynamic reorganization of 3D chromatin structure in mammalian germ cells scNanoHi-C2揭示了哺乳动物生殖细胞中三维染色质结构的动态重组

Nature structural & molecular biology Pub Date : 2025-07-16 DOI: 10.1038/s41594-025-01603-8

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A conserved coupling of transcriptional ON and OFF periods underlies bursting dynamics 转录ON和OFF周期的保守耦合是爆发动力学的基础

Nature structural & molecular biology Pub Date : 2025-07-15 DOI: 10.1038/s41594-025-01615-4

Po-Ta Chen, Michal Levo, Benjamin Zoller, Thomas Gregor

{"title":"A conserved coupling of transcriptional ON and OFF periods underlies bursting dynamics","authors":"Po-Ta Chen, Michal Levo, Benjamin Zoller, Thomas Gregor","doi":"10.1038/s41594-025-01615-4","DOIUrl":"https://doi.org/10.1038/s41594-025-01615-4","url":null,"abstract":"Transcription commonly occurs in bursts, with alternating productive (ON) and quiescent (OFF) periods determining mRNA production rates. However, how bursting dynamics regulate transcription is not well understood. Here, we conduct real-time measurements of endogenous transcriptional bursting with single-mRNA sensitivity. Using the diverse transcriptional activities present in early Drosophila embryos, we find stringent relationships between bursting parameters. Specifically, ON and OFF durations are tightly coupled, and each level of gene activity is associated with a characteristic combination of these periods. Lowly transcribing alleles primarily adjust OFF periods (burst frequency), while highly transcribing alleles tune ON periods (burst size). These relationships persist across developmental stages, body-axis positions, cis-regulatory or trans-regulatory perturbations and bursting dynamics observed in other species. Our findings suggest a mechanistic constraint that governs bursting dynamics, challenging the view that regulatory processes independently control distinct parameters.","PeriodicalId":18822,"journal":{"name":"Nature structural & molecular biology","volume":"65 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-07-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144629850","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

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Conformational plasticity of a BiP–GRP94 chaperone complex BiP-GRP94伴侣复合物的构象可塑性

Nature structural & molecular biology Pub Date : 2025-07-14 DOI: 10.1038/s41594-025-01619-0

Joel Cyrille Brenner, Linda Charlotte Zirden, Lana Buzuk, Yasser Almeida-Hernandez, Lea Radzuweit, Joao Diamantino, Farnusch Kaschani, Markus Kaiser, Elsa Sanchez-Garcia, Simon Poepsel, Doris Hellerschmied

{"title":"Conformational plasticity of a BiP–GRP94 chaperone complex","authors":"Joel Cyrille Brenner, Linda Charlotte Zirden, Lana Buzuk, Yasser Almeida-Hernandez, Lea Radzuweit, Joao Diamantino, Farnusch Kaschani, Markus Kaiser, Elsa Sanchez-Garcia, Simon Poepsel, Doris Hellerschmied","doi":"10.1038/s41594-025-01619-0","DOIUrl":"https://doi.org/10.1038/s41594-025-01619-0","url":null,"abstract":"Hsp70 and Hsp90 chaperones and their regulatory cochaperones are critical for maintaining protein homeostasis. Glucose-regulated protein 94 (GRP94), the sole Hsp90 chaperone in the secretory pathway of mammalian cells, is essential for the maturation of important secretory and transmembrane proteins. Without the requirement of cochaperones, the Hsp70 protein BiP controls regulatory conformational changes of GRP94, the structural basis of which has remained elusive. Here we biochemically and structurally characterize the formation of a BiP–GRP94 chaperone complex and its transition to a conformation expected to support the loading of substrate proteins from BiP onto GRP94. BiP initially binds to the open GRP94 dimer through an interaction interface that is conserved among Hsp70 and Hsp90 paralogs. Subsequently, binding of a second BiP protein stabilizes a semiclosed GRP94 dimer, thereby advancing the chaperone cycle. Our findings highlight a fundamental mechanism of direct Hsp70–Hsp90 cooperation, independent of cochaperones.","PeriodicalId":18822,"journal":{"name":"Nature structural & molecular biology","volume":"14 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-07-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144622481","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

A heterotrimeric protein complex assembles the metazoan V-ATPase upon dissipation of proton gradients 异三聚体蛋白复合体在质子梯度耗散后组装后生动物v - atp酶

Nature structural & molecular biology Pub Date : 2025-07-11 DOI: 10.1038/s41594-025-01610-9

Christopher Nardone, Julian Mintseris, Dingwei He, Justine C. Rutter, Benjamin L. Ebert, Steven P. Gygi, Tom Rapoport

{"title":"A heterotrimeric protein complex assembles the metazoan V-ATPase upon dissipation of proton gradients","authors":"Christopher Nardone, Julian Mintseris, Dingwei He, Justine C. Rutter, Benjamin L. Ebert, Steven P. Gygi, Tom Rapoport","doi":"10.1038/s41594-025-01610-9","DOIUrl":"https://doi.org/10.1038/s41594-025-01610-9","url":null,"abstract":"Organelles such as lysosomes and synaptic vesicles are acidified by V-ATPases, which consist of a cytosolically oriented V1 complex that hydrolyzes ATP and a membrane-embedded VO complex that pumps protons. In yeast, V1–VO association is facilitated by the RAVE (regulator of H+-ATPase of the vacuolar and endosomal membrane) complex, but how higher eukaryotes assemble V-ATPases remains unclear. Here we identify a metazoan RAVE complex (mRAVE) whose structure and composition are notably divergent from the ancestral counterpart. mRAVE consists of DMXL1 or DMXL2, WDR7 and the central linker ROGDI. DMXL1 and DMXL2 interact with subunits A and D of the inactive, isolated V1. On dissipation of proton gradients, mRAVE binds to V1 and VO, forming a supercomplex on the membrane. mRAVE then catalyzes V1–VO assembly, enabling lysosomal acidification, neurotransmitter loading into vesicles and ATG16L1 recruitment for LC3/ATG8 conjugation onto single membranes. Our findings provide a molecular basis for neurological disorders caused by mRAVE mutations.","PeriodicalId":18822,"journal":{"name":"Nature structural & molecular biology","volume":"15 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-07-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144603102","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Comparative CRISPRi screens reveal a human stem cell dependence on mRNA translation-coupled quality control 比较CRISPRi筛选揭示了人类干细胞对mRNA翻译耦合质量控制的依赖

Nature structural & molecular biology Pub Date : 2025-07-11 DOI: 10.1038/s41594-025-01616-3

Geraldine Rodschinka, Sergio Forcelloni, Felix M. Kühner, Sascha Wani, Henrick Riemenschneider, Dieter Edbauer, Andrew Behrens, Danny D. Nedialkova

{"title":"Comparative CRISPRi screens reveal a human stem cell dependence on mRNA translation-coupled quality control","authors":"Geraldine Rodschinka, Sergio Forcelloni, Felix M. Kühner, Sascha Wani, Henrick Riemenschneider, Dieter Edbauer, Andrew Behrens, Danny D. Nedialkova","doi":"10.1038/s41594-025-01616-3","DOIUrl":"https://doi.org/10.1038/s41594-025-01616-3","url":null,"abstract":"The translation of mRNA into proteins in multicellular organisms needs to be carefully tuned to changing proteome demands in development and differentiation, while defects in translation often have a disproportionate impact in distinct cell types. Here we used inducible CRISPR interference screens to compare the essentiality of genes with functions in mRNA translation in human induced pluripotent stem cells (hiPS cells) and hiPS cell-derived neural and cardiac cells. We find that core components of the mRNA translation machinery are broadly essential but the consequences of perturbing translation-coupled quality control factors are cell type dependent. Human stem cells critically depend on pathways that detect and rescue slow or stalled ribosomes and on the E3 ligase ZNF598 to resolve a distinct type of ribosome collision at translation start sites on endogenous mRNAs with highly efficient initiation. Our findings underscore the importance of cell identity for deciphering the molecular mechanisms of translational control in metazoans.","PeriodicalId":18822,"journal":{"name":"Nature structural & molecular biology","volume":"22 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-07-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144603347","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0