Nature Structural &Molecular Biology最新文献

Alternative splicing fine-tunes modular protein interfaces to control protein localization. 选择性剪接微调模块蛋白质接口，以控制蛋白质定位。

IF 10.1 1区生物学

Nature Structural &Molecular Biology Pub Date : 2026-10-14 DOI: 10.1038/s41594-026-01875-8

Peter Kjer-Hansen, Karina Pazaky, Daisy Kavanagh, Helen E King, Savannah O'Connell, Gabriela Santos-Rodriguez, Abigail K Grootveld, Helaine Graziele Santos Vieira, Scott Berry, Javier Fernandez-Chamorro, Robert J Weatheritt

{"title":"Alternative splicing fine-tunes modular protein interfaces to control protein localization.","authors":"Peter Kjer-Hansen, Karina Pazaky, Daisy Kavanagh, Helen E King, Savannah O'Connell, Gabriela Santos-Rodriguez, Abigail K Grootveld, Helaine Graziele Santos Vieira, Scott Berry, Javier Fernandez-Chamorro, Robert J Weatheritt","doi":"10.1038/s41594-026-01875-8","DOIUrl":"https://doi.org/10.1038/s41594-026-01875-8","url":null,"abstract":"Alternative splicing provides a pervasive means to expand proteome complexity, yet how it reorganizes protein interactions and cellular localization remains unclear. Here, we show that tissue-regulated longer exons preferably reshape local interaction patterns, whereas microexons fine-tune key interfaces linking distinct cellular processes. Integration of subcellular localization data further indicates that such rewiring can redistribute proteins within cells. By using a high-content imaging approach to systematically evaluate the influence of individual exons on protein localization, we show that 38% of the tested isoform pairs alter localization, with microexons, albeit typically shorter than five amino acids, accounting for a substantial proportion of these effects. Bioinformatic and structural analyses demonstrate that microexons can extend secondary structural regions and reposition charged residues, suggesting a potential to modulate local electrostatic environments. Consistent with this, biochemical analysis of a 4-aa microexon in sorting nexin 2, identified in our screen, confirms that residue insertion rather than side-chain chemistry drives key differences in protein localization through repositioning of a flanking, charged residue. Together, these findings suggest that tissue-regulated alternative splicing fine-tunes interface architecture, thus regulating protein assembly, localization and proteome organization.","PeriodicalId":18836,"journal":{"name":"Nature Structural &Molecular Biology","volume":" ","pages":""},"PeriodicalIF":10.1,"publicationDate":"2026-10-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149183192","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}

引用次数: 0

Glycosylated RNAs travel with extracellular vesicles and shape intercellular communication. 糖基化的rna与细胞外囊泡一起旅行并形成细胞间的通讯。

IF 10.1 1区生物学

Nature Structural &Molecular Biology Pub Date : 2026-10-06 DOI: 10.1038/s41594-026-01896-3

引用次数: 0

Profiling extracellular vesicle glycoRNAs defines their function in vesicular communication. 分析细胞外囊泡糖rna定义了它们在囊泡通讯中的功能。

IF 10.1 1区生物学

Nature Structural &Molecular Biology Pub Date : 2026-09-28 DOI: 10.1038/s41594-026-01897-2

Ximing Chen, Chaojie Hao, Xiaodie Chen, Ting Chen, Weirong Xiao, Jiaheng Zhu, Jialu Zhang, Yuqian Zhang, Mingying Chen, Hongyu Lin, Yanling Song

{"title":"Profiling extracellular vesicle glycoRNAs defines their function in vesicular communication.","authors":"Ximing Chen, Chaojie Hao, Xiaodie Chen, Ting Chen, Weirong Xiao, Jiaheng Zhu, Jialu Zhang, Yuqian Zhang, Mingying Chen, Hongyu Lin, Yanling Song","doi":"10.1038/s41594-026-01897-2","DOIUrl":"https://doi.org/10.1038/s41594-026-01897-2","url":null,"abstract":"Glycosylated RNAs (glycoRNAs) reside on the cell surface with their functions largely unexplored. Here, we show that extracellular vesicles (EVs) carry glycoRNAs with distinct sequence diversity, vesicle type specificity and transfer dynamics. By metabolically tagging glycoRNAs with bioorthogonal handles, we selectively enrich and sequence EV-associated glycoRNAs, identifying specific glycoRNA species and expanding the EV glycoRNA landscape. We further develop a proximity-based imaging strategy to track glycoRNAs, revealing that glycoRNA repertoires in large EVs vary with cell type and passage, whereas small EVs display distinct profiles indicative of vesicle-specific sorting. Functionally, EVs deliver glycoRNAs into recipient cells and glycoRNAs are subsequently detected in recipient cell-derived EVs, reflecting contributions from newly synthesized glycoRNAs and others that may be associated with donor EVs. Notably, hybridization-based glycoRNA blockade can heavily reduce EV uptake, highlighting glycoRNAs as potentially actionable targets for modulating EV-cell communication. These findings expand the glycoRNA landscape and suggest EV glycoRNAs are biomarkers of cell state and regulators of vesicle tropism.","PeriodicalId":18836,"journal":{"name":"Nature Structural &Molecular Biology","volume":" ","pages":""},"PeriodicalIF":10.1,"publicationDate":"2026-09-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149075430","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}

引用次数: 0

Cotranslational membrane protein biogenesis by an EMC-bound translocon. emc结合转座子的共翻译膜蛋白生物发生。

IF 10.1 1区生物学

Nature Structural &Molecular Biology Pub Date : 2026-09-28 DOI: 10.1038/s41594-026-01889-2

Madeline G Rollins, Josephine Tang, Yu Wan, Arunkumar Sundaram, Haoxi Wu, Qianru Li, Juliette Fedry, Ramanujan S Hegde, Zhe Ji, Robert J Keenan

{"title":"Cotranslational membrane protein biogenesis by an EMC-bound translocon.","authors":"Madeline G Rollins, Josephine Tang, Yu Wan, Arunkumar Sundaram, Haoxi Wu, Qianru Li, Juliette Fedry, Ramanujan S Hegde, Zhe Ji, Robert J Keenan","doi":"10.1038/s41594-026-01889-2","DOIUrl":"https://doi.org/10.1038/s41594-026-01889-2","url":null,"abstract":"Secretory and membrane protein biogenesis occurs at ribosome-bound translocons in the endoplasmic reticulum (ER) membrane. Translocons consist of the Sec61 protein-conducting channel and various maturation factors including chaperones, modification enzymes and membrane insertases, which assemble dynamically in response to the biogenesis needs of a nascent polypeptide. In human cells, nascent multipass membrane proteins utilize the ER membrane protein complex (EMC) and the multipass translocon (MPT), but how these factors are deployed during biogenesis is unknown. Here we combine selective ribosome profiling, cryo-electron tomography and site-specific photocrosslinking to reveal the substrate range, timing and mechanism of EMC recruitment. We show that multipass proteins initially engage the MPT for insertion and chaperoning, with EMC being recruited when substrates begin to exceed the cytosolic or intramembrane capacity of MPT. Substrate-engaged EMC is observed at the interface between the MPT's protected membrane cavity and the bulk ER membrane, where it is poised for insertion, chaperoning and assembly. These results show how EMC and MPT cooperate at the ribosome-bound translocon to facilitate multipass membrane protein biogenesis.","PeriodicalId":18836,"journal":{"name":"Nature Structural &Molecular Biology","volume":" ","pages":""},"PeriodicalIF":10.1,"publicationDate":"2026-09-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149075284","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}

引用次数: 0

Sculpting semisynthetic conducting protein pores by de novo design. 通过从头设计雕刻半合成导电蛋白孔。

IF 10.1 1区生物学

Nature Structural &Molecular Biology Pub Date : 2026-09-22 DOI: 10.1038/s41594-026-01880-x

引用次数: 0

Mechanistic insights into phosphorylation-driven activation and therapeutic inhibition of human ATR-ATRIP. 磷酸化驱动的人类ATR-ATRIP激活和治疗性抑制的机制见解。

IF 10.1 1区生物学

Nature Structural &Molecular Biology Pub Date : 2026-09-17 DOI: 10.1038/s41594-026-01887-4

Lingling Wang, Mo Wang, Liang Zhao, Qinhui Rao, Hao Wu, Boya Ma, Jingwen Wang, Jian Zheng, Yi Li, Youping Xu, Jiangtao Guo, Jingdong Cheng, Shuai Qiao

{"title":"Mechanistic insights into phosphorylation-driven activation and therapeutic inhibition of human ATR-ATRIP.","authors":"Lingling Wang, Mo Wang, Liang Zhao, Qinhui Rao, Hao Wu, Boya Ma, Jingwen Wang, Jian Zheng, Yi Li, Youping Xu, Jiangtao Guo, Jingdong Cheng, Shuai Qiao","doi":"10.1038/s41594-026-01887-4","DOIUrl":"https://doi.org/10.1038/s41594-026-01887-4","url":null,"abstract":"The ATR-ATRIP complex regulates the DNA replication stress and is targeted in cancer therapy, but the molecular mechanisms of its activation and inhibition have remained unclear. Here, we present high-resolution cryo-electron microscopy structures of the human ATR-ATRIP complex in distinct functional states, including two ATPγS-bound precatalytic states, a Chk1-bound catalytic state, a TopBP1-bound activated catalytic state and four inhibitor-bound states with gartisertib, berzosertib, ceralasertib and elimusertib. These structures show that ATPγS binding alone can prime the ATR kinase catalytic center for catalysis and position Chk1 without major conformational rearrangements. TopBP1 engages the ATR-ATRIP HEAT-repeat scaffold to reorganize the dimer into a near-symmetric conformation that promotes ATR-ATRIP autophosphorylation and efficient Chk1 phosphorylation. Notably, the phosphorylated ATR-ATRIP complex remains active toward Chk1 after TopBP1 dissociation while adopting an asymmetric conformation, indicating that catalytic activity is compatible with both near-symmetric and asymmetric conformations. In addition, inhibitor-bound structures reveal how potent and selective ATR inhibition is achieved through multipocket engagement and exploitation of active-site conformational plasticity. Together, our findings provide a structural framework for understanding multiple routes of ATR activation and inhibition, offering insights for developing next-generation ATR-targeted cancer therapies.","PeriodicalId":18836,"journal":{"name":"Nature Structural &Molecular Biology","volume":" ","pages":""},"PeriodicalIF":10.1,"publicationDate":"2026-09-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148990691","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}

引用次数: 0

Capturing ATR-ATRIP in the act of activation. 捕捉ATR-ATRIP的激活行为。

IF 10.1 1区生物学

Nature Structural &Molecular Biology Pub Date : 2026-09-17 DOI: 10.1038/s41594-026-01899-0

Lee Zou

引用次数: 0

Structure-guided discovery and engineering of miniature CRISPR-Cas12m for epigenome editing. 用于表观基因组编辑的微型CRISPR-Cas12m的结构导向发现和工程。

IF 10.1 1区生物学

Nature Structural &Molecular Biology Pub Date : 2026-09-16 DOI: 10.1038/s41594-026-01890-9

Tao Yu, Meng Ji, Donglin Yu, Zhao Guan, Rongyi Zhu, Yunpeng Jiang, Zhiyi Yang, Lizhen Qiu, Ziyi Zhang, Jiawei Mu, Fengbiao Mao, Kuanhui Xiang, Lin Bai, Kailong Li

{"title":"Structure-guided discovery and engineering of miniature CRISPR-Cas12m for epigenome editing.","authors":"Tao Yu, Meng Ji, Donglin Yu, Zhao Guan, Rongyi Zhu, Yunpeng Jiang, Zhiyi Yang, Lizhen Qiu, Ziyi Zhang, Jiawei Mu, Fengbiao Mao, Kuanhui Xiang, Lin Bai, Kailong Li","doi":"10.1038/s41594-026-01890-9","DOIUrl":"https://doi.org/10.1038/s41594-026-01890-9","url":null,"abstract":"CRISPR-based epigenome editing represents a programmable strategy to precisely modulate gene expression, holding promise for therapeutic applications. However, the large size of dCas proteins substantially impedes delivery using adeno-associated virus (AAV) vectors. Here, through iterative bioinformatics analysis, structure-guided predictions and functional assays, we identified and characterized a miniature subtype V-M CRISPR-Cas12m from Pelomicrobium methylotrophicum. PmCas12m exhibited flexible 5'-YTN-3' PAM-dependent recognition and robust double-stranded DNA-binding properties while lacking DNA cleavage activity, thus rendering it a valuable tool for epigenome editing. Cryo-electron microscopy structures of PmCas12m unveiled its molecular mechanism of target DNA binding. Guided by these structural insights, we used deep mutational scanning and protein engineering to develop xCas12m, a hypercompact variant with highly potent and specific epigenome-editing capabilities in human cells. We further constructed the xCas12m-CRISPRoff platform in a single AAV vector, which achieved durable epigenetic silencing and effective inhibition of hepatitis B virus infection in a mouse model. Collectively, these findings establish xCas12m as a versatile epigenome-editing platform with notable potential for treating diseases, paving the way for clinical translation of epigenetic therapies.","PeriodicalId":18836,"journal":{"name":"Nature Structural &Molecular Biology","volume":" ","pages":""},"PeriodicalIF":10.1,"publicationDate":"2026-09-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148982801","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}

引用次数: 0

Beyond equilibrium in biomolecular phase separation. 生物分子相分离中的超越平衡。

IF 10.1 1区生物学

Nature Structural &Molecular Biology Pub Date : 2026-08-12 DOI: 10.1038/s41594-026-01859-8

Tapas Paul, Sunghyun Cho, Sua Myong

引用次数: 0

Structural basis for Parkinson’s disease-linked LRRK2’s binding to microtubules 帕金森病相关LRRK2与微管结合的结构基础

IF 16.8 1区生物学

Nature Structural &Molecular Biology Pub Date : 2022-01-22 DOI: 10.1101/2022.01.21.477284

D. Snead, M. Matyszewski, Andrea M. Dickey, Yu Lin, A. Leschziner, Samara L. Reck-Peterson

引用次数: 11