Nature structural & molecular biology最新文献_第5页

Regulation of kinesin-2 motility by its β-hairpin motif β-发夹基序对运动蛋白-2运动的调控

Nature structural & molecular biology Pub Date : 2025-07-29 DOI: 10.1038/s41594-025-01630-5

Stephanie Webb, Katerina Toropova, Aakash G. Mukhopadhyay, Stephanie D. Nofal, Anthony J. Roberts

{"title":"Regulation of kinesin-2 motility by its β-hairpin motif","authors":"Stephanie Webb, Katerina Toropova, Aakash G. Mukhopadhyay, Stephanie D. Nofal, Anthony J. Roberts","doi":"10.1038/s41594-025-01630-5","DOIUrl":"https://doi.org/10.1038/s41594-025-01630-5","url":null,"abstract":"Members of the kinesin-2 family coordinate with other motors to power diverse physiological processes, but the structural mechanisms regulating kinesin-2 activity have been unknown. Distinctively, kinesin-2s canonically function as heterotrimers of two different motor subunits (for example Kif3A and Kif3B in humans) and Kap3, but the role of heterotrimerization has yet to fully emerge. Here, we combine structural, cell biological and single-molecule approaches to dissect kinesin-2 regulation as a heterodimer, heterotrimer and quaternary complex with a cargo adaptor (APC). We identify a conserved motif in the tail of kinesin-2s (the β-hairpin motif) that, in conjunction with the adjacent coiled coil, controls kinesin-2 motility by sequestering the motor domains away from their microtubule track. Our data reveal how Kap3 binds via a multipartite interface with Kif3A and Kif3B. Rather than activating motility directly, Kap3 provides a platform on which cargo adaptors can engage and occlude the β-hairpin motif. Together, these data articulate a structural framework for kinesin-2 activation, recycling by dynein and adaptation for different biological functions.","PeriodicalId":18822,"journal":{"name":"Nature structural & molecular biology","volume":"12 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-07-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144719678","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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Returning home to navigate challenges and meet potential in Poland 回国迎接挑战，挖掘波兰的潜力

Nature structural & molecular biology Pub Date : 2025-07-29 DOI: 10.1038/s41594-025-01641-2

Lidia Wrobel

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eIF1 and eIF5 dynamically control translation start site fidelity eIF1和eIF5动态控制翻译起始站点保真度

Nature structural & molecular biology Pub Date : 2025-07-28 DOI: 10.1038/s41594-025-01629-y

Rosslyn Grosely, Carlos Alvarado, Ivaylo P. Ivanov, Oliver B. Nicholson, Joseph D. Puglisi, Thomas E. Dever, Christopher P. Lapointe

{"title":"eIF1 and eIF5 dynamically control translation start site fidelity","authors":"Rosslyn Grosely, Carlos Alvarado, Ivaylo P. Ivanov, Oliver B. Nicholson, Joseph D. Puglisi, Thomas E. Dever, Christopher P. Lapointe","doi":"10.1038/s41594-025-01629-y","DOIUrl":"https://doi.org/10.1038/s41594-025-01629-y","url":null,"abstract":"Human translation initiation requires accurate recognition of translation start sites. While AUG codons are canonical start sites, non-AUG codons are also used, typically with lower efficiency. The initiator tRNA and initiation factors eIF1 and eIF5 control recognition. How they distinguish different start sites yet allow flexible recognition remains unclear. Here we used real-time single-molecule assays and an in vitro reconstituted human system to reveal how eIF1 and eIF5 direct start site selection. eIF1 binds initiation complexes in two modes: stable binding during scanning, followed by transient, concentration-dependent rebinding after start site recognition. Termination of eIF1 rebinding requires transient and concentration-dependent binding by eIF5, which allows the formation of translation competent ribosomes. Non-AUG start sites differentially stabilize eIF1 and destabilize eIF5 binding, blocking initiation at multiple points. We confirmed these opposing effects in human cells. Collectively, our findings uncover that eIF1 and eIF5 directly compete to bind initiation complexes and illuminate how their dynamic interplay tunes the fidelity of start site recognition, which has broad connections to health and disease.","PeriodicalId":18822,"journal":{"name":"Nature structural & molecular biology","volume":"52 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-07-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144715264","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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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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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}

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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