Nature structural & molecular biology最新文献_第7页

Multiplex and multimodal mapping of variant effects in secreted proteins via MultiSTEP 通过MultiSTEP对分泌蛋白的变异效应进行多重和多模态定位

Nature structural & molecular biology Pub Date : 2025-06-13 DOI: 10.1038/s41594-025-01582-w

Nicholas A. Popp, Rachel L. Powell, Melinda K. Wheelock, Kristen J. Holmes, Brendan D. Zapp, Kathryn M. Sheldon, Shelley N. Fletcher, Xiaoping Wu, Shawn Fayer, Alan F. Rubin, Kerry W. Lannert, Alexis T. Chang, John P. Sheehan, Jill M. Johnsen, Douglas M. Fowler

{"title":"Multiplex and multimodal mapping of variant effects in secreted proteins via MultiSTEP","authors":"Nicholas A. Popp, Rachel L. Powell, Melinda K. Wheelock, Kristen J. Holmes, Brendan D. Zapp, Kathryn M. Sheldon, Shelley N. Fletcher, Xiaoping Wu, Shawn Fayer, Alan F. Rubin, Kerry W. Lannert, Alexis T. Chang, John P. Sheehan, Jill M. Johnsen, Douglas M. Fowler","doi":"10.1038/s41594-025-01582-w","DOIUrl":"https://doi.org/10.1038/s41594-025-01582-w","url":null,"abstract":"Despite widespread advances in DNA sequencing, the functional consequences of most genetic variants remain poorly understood. Multiplexed assays of variant effect can measure the function of variants at scale but cannot readily be applied to the ~10% of human genes encoding secreted proteins. Here we develop a flexible, scalable human cell surface display method, multiplexed surface tethering of extracellular proteins (MultiSTEP), to study the consequences of missense variation in coagulation factor IX (FIX), a serine protease in which genetic variation can cause hemophilia B. We combine MultiSTEP with a panel of antibodies to detect FIX secretion and post-translational modification (PTM), measuring 44,816 variant effects for 436 synonymous variants and 8,528 of the 8,759 possible F9 missense variants. Almost half of missense variants impact secretion, PTM or both. We also identify functional constraints on secretion within the signal peptide and for nearly all gain or loss of cysteine variants. Secretion scores correlate strongly with FIX levels in hemophilia B and reveal that loss-of-secretion variants are more often associated with severe disease. Integration of the secretion and PTM scores enables reclassification of 63.1% of F9 variants of uncertain significance in the My Life, Our Future hemophilia genotyping project. Lastly, we show that MultiSTEP can be applied to other secreted proteins, thus demonstrating that MultiSTEP is a multiplexed, multimodal and generalizable method for systematically assessing variant effects in secreted proteins at scale.","PeriodicalId":18822,"journal":{"name":"Nature structural & molecular biology","volume":"1 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-06-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144278669","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

H2A.Z is essential for oocyte maturation and fertility in female mouse H2A。Z是雌性小鼠卵母细胞成熟和生育所必需的

Nature structural & molecular biology Pub Date : 2025-06-13 DOI: 10.1038/s41594-025-01580-y

Qianhua Xu, Chunyi Huang, Jia Ming, Xukun Lu, Ling Liu, Zhenhai Du, Zhen Chen, Jie Na, Guohong Li, Yunlong Xiang, Yu Zhang, Wei Xie

{"title":"H2A.Z is essential for oocyte maturation and fertility in female mouse","authors":"Qianhua Xu, Chunyi Huang, Jia Ming, Xukun Lu, Ling Liu, Zhenhai Du, Zhen Chen, Jie Na, Guohong Li, Yunlong Xiang, Yu Zhang, Wei Xie","doi":"10.1038/s41594-025-01580-y","DOIUrl":"https://doi.org/10.1038/s41594-025-01580-y","url":null,"abstract":"Oocyte maturation is essential for both gametogenesis and early development, when large amounts of transcripts are produced without DNA replication. Histone variants, which can be incorporated at cis-regulatory elements in a replication-independent manner, are naturally suited for such regulation. However, their roles during mammalian oocyte maturation remain elusive. Here we show that oocyte-specific depletion of H2A.Z, an evolutionarily conserved histone variant, in female mice results in profound epigenetic and transcriptional alterations, impedes resumption of oocyte meiosis II and causes infertility. Mechanistically, H2A.Z in mouse oocytes is incorporated into chromatin at active promoters and putative enhancers. Interestingly, H2A.Z is depleted from CG-rich silenced promoters, including poised Polycomb target genes, in fully grown oocytes (FGOs), unlike what occurs in growing oocytes, early embryos and mouse embryonic stem cells. In FGOs, the presence of H2A.Z correlates with histone acetylation, except in regions marked by DNA methylation and H3K36me3. Depletion of H2A.Z leads to impaired activities of a subset of promoters and enhancers, correlated with defective gene expression. Consistent with a role in gene activation, H2A.Z in FGOs is widely acetylated at the promoters and enhancers. Together, our findings uncover an essential role of H2A.Z in mammalian oocyte maturation and female fertility.","PeriodicalId":18822,"journal":{"name":"Nature structural & molecular biology","volume":"5 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-06-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144278668","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

H2A.Z reinforces maternal H3K4me3 formation and is essential for meiotic progression in mouse oocytes H2A。Z增强母体H3K4me3的形成，对小鼠卵母细胞的减数分裂进程至关重要

Nature structural & molecular biology Pub Date : 2025-06-13 DOI: 10.1038/s41594-025-01573-x

Hailiang Mei, Ryoya Hayashi, Chisayo Kozuka, Mami Kumon, Haruhiko Koseki, Azusa Inoue

引用次数: 0

Remote on–off switching of protein activity by intrinsically disordered region 内在无序区对蛋白质活性的远程开关

Nature structural & molecular biology Pub Date : 2025-06-04 DOI: 10.1038/s41594-025-01585-7

Tuo Ji, Piao Ge, Shan Zhang, Chanjuan Wan, Hailong Liu, Xiaozhan Qu, Feng Zhu, Qingguo Gong, Weiya Xu, Chao Wang, Yucai Wang, Chengdong Huang

{"title":"Remote on–off switching of protein activity by intrinsically disordered region","authors":"Tuo Ji, Piao Ge, Shan Zhang, Chanjuan Wan, Hailong Liu, Xiaozhan Qu, Feng Zhu, Qingguo Gong, Weiya Xu, Chao Wang, Yucai Wang, Chengdong Huang","doi":"10.1038/s41594-025-01585-7","DOIUrl":"https://doi.org/10.1038/s41594-025-01585-7","url":null,"abstract":"While the regulation of protein function theoretically encompasses alterations in both structural conformation and dynamic properties, the latter aspect, specifically conformational entropy, remains relatively unexplored. Here we show that an intrinsically disordered region (IDR), a prominent component of the proteome, can remotely switch protein activity on or off through a nonbinding, entropy-driven mechanism. Focusing on the disordered C-terminal tail of Sgt2, a chaperone in the guided entry of tail-anchored protein pathway, we demonstrate that it allosterically inhibits the N-terminal domain without direct contact, preventing unproductive chaperone–chaperone interactions. This inhibition is relieved upon client binding. These effects depend on specific IDR sequences but not the intervening regions. Beyond acting as a relay signal, the IDR also forms a dynamic complex with transmembrane domains of tail-anchored clients, serving as an entropic shelter. Moreover, the IDR-mediated activity of Sgt2 correlates with fast internal dynamics, establishing conformational entropy as a key regulatory principle. Our findings reveal IDRs as two-way entropic modulators, enabling distant, on-demand activity switching.","PeriodicalId":18822,"journal":{"name":"Nature structural & molecular biology","volume":"16 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-06-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144211030","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

Epitranscriptome regulation. 上皮转录组调控。

Nature structural & molecular biology Pub Date : 2018-09-28 DOI: 10.1038/s41594-018-0140-7

Dan Dominissini, Gideon Rechavi

引用次数: 0

Intersubunit capture of regulatory segments is a component of cooperative CaMKII activation. 调控片段的亚基间捕获是CaMKII协同激活的一个组成部分。

Nature structural & molecular biology Pub Date : 2010-03-01 Epub Date: 2010-02-07 DOI: 10.1038/nsmb.1751

Luke H Chao, Patricia Pellicena, Sebastian Deindl, Lauren A Barclay, Howard Schulman, John Kuriyan

引用次数: 0

Domain structure of separase and its binding to securin as determined by EM. 分离酶的结构域结构及其与securin的结合。

Nature structural & molecular biology Pub Date : 2005-06-01 Epub Date: 2005-05-08 DOI: 10.1038/nsmb935

Hector Viadiu, Olaf Stemmann, Marc W Kirschner, Thomas Walz

引用次数: 51