Nature structural & molecular biology最新文献

Nuclear pore passage of the HIV capsid is driven by its unusual surface amino acid composition. HIV衣壳的核孔通过是由其不寻常的表面氨基酸组成驱动的。

Nature structural & molecular biology Pub Date : 2025-10-09 DOI: 10.1038/s41594-025-01684-5

Liran Fu,Shiya Cheng,Dietmar Riedel,Leonie Kopecny,Melina Schuh,Dirk Görlich

{"title":"Nuclear pore passage of the HIV capsid is driven by its unusual surface amino acid composition.","authors":"Liran Fu,Shiya Cheng,Dietmar Riedel,Leonie Kopecny,Melina Schuh,Dirk Görlich","doi":"10.1038/s41594-025-01684-5","DOIUrl":"https://doi.org/10.1038/s41594-025-01684-5","url":null,"abstract":"Nuclear transport receptors (NTRs) carry cargo across the permeability barrier of nuclear pore complexes (NPCs)-an FG phase condensed from disordered but cohesive FG-repeat domains. This phase repels inert macromolecules but allows NTR passage. When the human immunodeficiency virus (HIV) infects nondividing cells, its capsid is transported into nuclei not like a cargo but crosses NPCs like an NTR. Here we uncovered the molecular determinants of the capsid's NTR behavior. The FG-binding pocket is insufficient. Hexameric and pentameric capsomers contribute. The highly exposed outer capsid surface is key. It lacks FG-repulsive charged residues (K, D and E) that are very abundant on other protein surfaces. FG-attractive residues dominate the capsid surface instead. Introducing FG-repulsive amino acids impedes FG phase partitioning, NPC targeting and NPC passage of assembled capsids. Capsids are, thus, made soluble in the FG phase by a myriad of transient FG-attractive interactions originating from individual surface side chains. We propose that CPSF6 releases the capsid from NPCs by masking its FG-attractive surface and switching the capsid to an FG-repulsive species.","PeriodicalId":18822,"journal":{"name":"Nature structural & molecular biology","volume":"9 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145254766","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

Returning home: a story of chromatin and community. 回家：一个关于染色质和社区的故事。

Nature structural & molecular biology Pub Date : 2025-10-06 DOI: 10.1038/s41594-025-01645-y

Mayra Furlan-Magaril

引用次数: 0

Reporter CRISPR screens decipher cis-regulatory and trans-regulatory principles at the Xist locus. 报道型CRISPR筛选破译了Xist位点的顺式调控和跨式调控原理。

Nature structural & molecular biology Pub Date : 2025-10-06 DOI: 10.1038/s41594-025-01686-3

Till Schwämmle,Gemma Noviello,Eleni Kanata,Jonathan J Froehlich,Melissa Bothe,Alexandra Martitz,Aybuge Altay,Jade Scouarnec,Vivi-Yun Feng,Heleen Mallie,Martin Vingron,Edda G Schulz

{"title":"Reporter CRISPR screens decipher cis-regulatory and trans-regulatory principles at the Xist locus.","authors":"Till Schwämmle,Gemma Noviello,Eleni Kanata,Jonathan J Froehlich,Melissa Bothe,Alexandra Martitz,Aybuge Altay,Jade Scouarnec,Vivi-Yun Feng,Heleen Mallie,Martin Vingron,Edda G Schulz","doi":"10.1038/s41594-025-01686-3","DOIUrl":"https://doi.org/10.1038/s41594-025-01686-3","url":null,"abstract":"Developmental genes are controlled by an ensemble of cis-acting regulatory elements (REs), which in turn respond to multiple trans-acting transcription factors (TFs). Understanding how a cis-regulatory landscape integrates information from many dynamically expressed TFs has remained a challenge. Here we develop a combined CRISPR screening approach using endogenous RNA and RE reporters as readouts. Applied to the murine Xist locus, which is crucial for X-chromosome inactivation in females, this method allows us to comprehensively identify Xist-controlling TFs and map their TF-RE wiring. We find a group of transiently upregulated TFs, including ZIC3, that regulate proximal REs, driving the binary activation of Xist expression. These basal activators are more highly expressed in cells with two X chromosomes, potentially governing female-specific Xist upregulation. A second set of developmental TFs that include OTX2 is upregulated later during differentiation and targets distal REs. This regulatory axis is crucial to achieve high levels of Xist RNA, which is necessary for X-chromosome inactivation. OCT4 emerges as the strongest activator overall, regulating both proximal and distal elements. Our findings support a model for developmental gene regulation, in which factors targeting proximal REs drive binary on-off decisions, whereas factors interacting with distal REs control the transcription output.","PeriodicalId":18822,"journal":{"name":"Nature structural & molecular biology","volume":"8 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-10-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145235665","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

Molecular basis for the activation of outer dynein arms in cilia. 纤毛外动力蛋白臂激活的分子基础。

Nature structural & molecular biology Pub Date : 2025-09-29 DOI: 10.1038/s41594-025-01680-9

Karim Housseini B Issa,Muyang Ren,Bradley Burnet,Hao Lu,Charlotte Melia,Kate Heesom,Anthony J Roberts,Sudipto Roy,Girish R Mali

{"title":"Molecular basis for the activation of outer dynein arms in cilia.","authors":"Karim Housseini B Issa,Muyang Ren,Bradley Burnet,Hao Lu,Charlotte Melia,Kate Heesom,Anthony J Roberts,Sudipto Roy,Girish R Mali","doi":"10.1038/s41594-025-01680-9","DOIUrl":"https://doi.org/10.1038/s41594-025-01680-9","url":null,"abstract":"Multiciliogenesis requires large-scale biosynthesis of motility-powering axonemal inner and outer dynein arm motors (IDAs and ODAs) before their intraflagellar transport (IFT) into cilia. ODAs are inhibited by the packaging chaperone Shulin during ciliogenesis in Tetrahymena thermophila. How Shulin is released for ODAs to become active inside cilia remains unclear. Here we uncover a molecular mechanism for ODA activation. We establish interactions between DNAAF9 (human Shulin) and mammalian ODA subunits, IFT proteins and the ciliary small guanosine triphosphatase (GTPase) ARL3 using proteomics and in vitro reconstitutions. Mutagenesis combined with biochemical and structural studies reveal that DNAAF9 and Shulin preferentially bind active Arl3-GTP highlighting a cross-species conservation of this interaction. GTP-loaded Arl3 can access, bind and displace Shulin from the packaged ODA-Shulin complex. We propose that, once the inhibited ODA complex enters growing cilia, Arl3-GTP displaces Shulin (DNAAF9) and sequesters it away from ODAs, promoting activation of their motility specifically inside cilia.","PeriodicalId":18822,"journal":{"name":"Nature structural & molecular biology","volume":"68 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-09-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145189271","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 guide to using small-molecule ferroptosis inhibitors. 小分子铁下垂抑制剂的使用指南。

Nature structural & molecular biology Pub Date : 2025-09-26 DOI: 10.1038/s41594-025-01682-7

Derek A Pratt,Scott J Dixon

引用次数: 0

Cryo-EM structures reveal the molecular mechanism of SUMO E1-E2 thioester transfer. 低温电镜结构揭示了SUMO E1-E2硫酯转移的分子机制。

Nature structural & molecular biology Pub Date : 2025-09-25 DOI: 10.1038/s41594-025-01681-8

Anindita Nayak,Digant Nayak,Lijia Jia,Eliza A Ruben,Suryavathi Viswanadhapalli,Priscila Dos Santos Bury,Khaled Mohamed Nassar,Corey H Yu,Anna A Tumanova,Caleb M Stratton,Pirouz Ebadi,Dmitri N Ivanov,Patrick Sung,Ratna K Vadlamudi,Elizabeth V Wasmuth,Shaun K Olsen

{"title":"Cryo-EM structures reveal the molecular mechanism of SUMO E1-E2 thioester transfer.","authors":"Anindita Nayak,Digant Nayak,Lijia Jia,Eliza A Ruben,Suryavathi Viswanadhapalli,Priscila Dos Santos Bury,Khaled Mohamed Nassar,Corey H Yu,Anna A Tumanova,Caleb M Stratton,Pirouz Ebadi,Dmitri N Ivanov,Patrick Sung,Ratna K Vadlamudi,Elizabeth V Wasmuth,Shaun K Olsen","doi":"10.1038/s41594-025-01681-8","DOIUrl":"https://doi.org/10.1038/s41594-025-01681-8","url":null,"abstract":"Post-translational modification of proteins by SUMO (small ubiquitin-like modifier) regulates fundamental cellular processes and occurs through the sequential interactions and activities of three enzymes: E1, E2 and E3. SUMO E1 activates SUMO in a two-step process involving adenylation and thioester bond formation, followed by transfer of SUMO to its dedicated E2 enzyme, UBC9. This process is termed E1-E2 thioester transfer (or transthioesterification). Despite its fundamental importance, the molecular basis for SUMO E1-UBC9 thioester transfer and the molecular rules governing SUMO E1-UBC9 specificity are poorly understood. Here we present cryo-EM reconstructions of human SUMO E1 in complex with UBC9, SUMO1 adenylate and SUMO1 thioester intermediate. Our structures reveal drastic conformational changes that accompany thioester transfer, providing insights into the molecular recognition of UBC9 by SUMO E1 and delineating the rules that govern SUMO E1-UBC9 specificity. Collectively, our structural, biochemical and cell-based studies elucidate the molecular mechanisms by which SUMOylation exerts its essential biological functions.","PeriodicalId":18822,"journal":{"name":"Nature structural & molecular biology","volume":"41 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145140445","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 small molecule stabilizer rescues the surface expression of nearly all missense variants in a GPCR. 一种小分子稳定剂可以挽救GPCR中几乎所有错义变异的表面表达。

Nature structural & molecular biology Pub Date : 2025-09-22 DOI: 10.1038/s41594-025-01659-6

Taylor L Mighell,Ben Lehner

{"title":"A small molecule stabilizer rescues the surface expression of nearly all missense variants in a GPCR.","authors":"Taylor L Mighell,Ben Lehner","doi":"10.1038/s41594-025-01659-6","DOIUrl":"https://doi.org/10.1038/s41594-025-01659-6","url":null,"abstract":"Reduced protein abundance is the most frequent mechanism by which rare missense variants cause disease. A promising therapeutic avenue for treating reduced abundance variants is pharmacological chaperones (PCs, also known as correctors or stabilizers), small molecules that bind to and stabilize target proteins. PCs have been approved as clinical treatments for specific variants, but protein energetics suggest their effects might be much more general. To comprehensively assess PC efficacy for variation in a given protein, it is necessary to first assign the molecular mechanism explaining all pathogenic variants, then measure the response to the PC. Here we establish such a framework for the vasopressin 2 receptor (V2R), a G-protein-coupled receptor in which loss-of-function variants cause nephrogenic diabetes insipidus (NDI). Our data show that more than half of NDI variants are poorly expressed, highlighting loss of stability as the major pathogenic mechanism. Treatment with a PC rescues the expression of 87% of destabilized variants. The non-rescued variants identify the drug's predicted binding site. Our results provide proof-of-principle that small molecule binding can rescue destabilizing variants throughout a protein's structure. The application of this principle to other proteins should allow the development of effective therapies for many different rare diseases.","PeriodicalId":18822,"journal":{"name":"Nature structural & molecular biology","volume":"10 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-09-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145117045","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

Towards a molecular and structural definition of cell death. 迈向细胞死亡的分子和结构定义。

Nature structural & molecular biology Pub Date : 2025-09-18 DOI: 10.1038/s41594-025-01646-x

Eli Arama,Katia Cosentino,Peter E Czabotar,Boyi Gan,Elizabeth Hartland,Xuejun Jiang,Jonathan C Kagan,Shigekazu Nagata,Kate Schroder,Liming Sun,Daichao Xu,Junying Yuan

引用次数: 0

Phase separation promotes Atg8 lipidation and vesicle condensation for autophagy progression 相分离促进at8脂化和囊泡凝聚，促进自噬进程

Nature structural & molecular biology Pub Date : 2025-09-16 DOI: 10.1038/s41594-025-01678-3

Yuko Fujioka, Takuma Tsuji, Tetsuya Kotani, Hiroyuki Kumeta, Chika Kakuta, Junko Shimasaki, Toyoshi Fujimoto, Hitoshi Nakatogawa, Nobuo N. Noda

{"title":"Phase separation promotes Atg8 lipidation and vesicle condensation for autophagy progression","authors":"Yuko Fujioka, Takuma Tsuji, Tetsuya Kotani, Hiroyuki Kumeta, Chika Kakuta, Junko Shimasaki, Toyoshi Fujimoto, Hitoshi Nakatogawa, Nobuo N. Noda","doi":"10.1038/s41594-025-01678-3","DOIUrl":"https://doi.org/10.1038/s41594-025-01678-3","url":null,"abstract":"<p>Upon starvation, the autophagy-initiating Atg1 complex undergoes phase separation to organize the preautophagosomal structure (PAS) in <i>Saccharomyces cerevisiae</i>, from which autophagosome formation is considered to proceed. However, the physiological roles of the PAS droplet remain unclear. Here we show that core Atg proteins are recruited into early PAS droplets that are formed by phase separation of the Atg1 complex with different efficiencies in vitro. The Atg12–Atg5–Atg16 E3 ligase complex for Atg8 lipidation is the most efficiently condensed in the droplets through specific Atg12–Atg17 interaction, which is also important for the PAS targeting of the E3 complex in vivo. In vitro reconstitution demonstrates that E3-enriched early PAS droplets promote Atg8 lipidation and that Atg8 coating of the vesicle membrane is both necessary and sufficient for their condensation into the droplets. These data suggest that the PAS functions as an efficient production site for lipidated Atg8 and pools membrane seeds to drive autophagosome formation.</p>","PeriodicalId":18822,"journal":{"name":"Nature structural & molecular biology","volume":"71 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-09-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145067759","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

Arp2/3-mediated bidirectional actin assembly by SPIN90 dimers 通过SPIN90二聚体介导的arp2 /3双向肌动蛋白组装

Nature structural & molecular biology Pub Date : 2025-09-15 DOI: 10.1038/s41594-025-01665-8

Tianyang Liu, Luyan Cao, Miroslav Mladenov, Guillaume Romet-Lemonne, Michael Way, Carolyn A. Moores

引用次数: 0