Nature structural & molecular biology最新文献_第2页

Activation of Arp2/3 complex by a SPIN90 dimer in linear actin-filament nucleation 在线状肌动蛋白丝成核过程中，SPIN90二聚体对Arp2/3复合物的激活

Nature structural & molecular biology Pub Date : 2025-09-15 DOI: 10.1038/s41594-025-01673-8

Justus Francis, Achyutha Krishna Pathri, Kankipati Teja Shyam, Sridhar Sripada, Rishav Mitra, Heidy Y. Narvaez-Ortiz, Kiran Vyshnav Eliyan, Brad J. Nolen, Saikat Chowdhury

{"title":"Activation of Arp2/3 complex by a SPIN90 dimer in linear actin-filament nucleation","authors":"Justus Francis, Achyutha Krishna Pathri, Kankipati Teja Shyam, Sridhar Sripada, Rishav Mitra, Heidy Y. Narvaez-Ortiz, Kiran Vyshnav Eliyan, Brad J. Nolen, Saikat Chowdhury","doi":"10.1038/s41594-025-01673-8","DOIUrl":"https://doi.org/10.1038/s41594-025-01673-8","url":null,"abstract":"Arp2/3 complex is a key nucleator of actin filaments. It requires activation by nucleation-promoting factors (NPFs). WISH/DIP1/SPIN90 (WDS) proteins represent a unique class of NPFs that activate the Arp2/3 complex independently of preexisting filaments, promoting linear actin-filament nucleation. In fission yeast, Dip1 binds to the clamp subunits in Arp2/3 complex to induce the short-pitch conformation, where Arp2 moves closer to Arp3 to mimic a filamentous actin dimer. However, how WDS proteins stimulate subunit flattening in Arp subunits, a ‘scissor-like’ conformational change akin to what is observed in an actin monomer during filament formation, remained unclear. Here we present cryo-electron microscopy structures of human SPIN90 bound to activated bovine Arp2/3 complex on an actin filament pointed end. The structures show that SPIN90 dimerizes through a metazoan-specific domain in the middle segment, engaging both the clamp and the Arp3/ARPC3 interface, to drive the activating conformational changes in Arp2/3 complex. Remarkably, a single SPIN90 dimer can also bridge two Arp2/3 complexes, enabling bidirectional actin nucleation and suggesting a mechanism for rapidly assembling complex actin network architectures.","PeriodicalId":18822,"journal":{"name":"Nature structural & molecular biology","volume":"36 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-09-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145059293","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

GluA4 AMPA receptor gating mechanisms and modulation by auxiliary proteins GluA4 AMPA受体的门控机制及辅助蛋白的调控

Nature structural & molecular biology Pub Date : 2025-09-15 DOI: 10.1038/s41594-025-01666-7

Carlos Vega-Gutiérrez, Javier Picañol-Párraga, Irene Sánchez-Valls, Victoria del Pilar Ribón-Fuster, David Soto, Beatriz Herguedas

{"title":"GluA4 AMPA receptor gating mechanisms and modulation by auxiliary proteins","authors":"Carlos Vega-Gutiérrez, Javier Picañol-Párraga, Irene Sánchez-Valls, Victoria del Pilar Ribón-Fuster, David Soto, Beatriz Herguedas","doi":"10.1038/s41594-025-01666-7","DOIUrl":"https://doi.org/10.1038/s41594-025-01666-7","url":null,"abstract":"AMPA-type glutamate receptors, fundamental ion channels for fast excitatory neurotransmission and synaptic plasticity, contain a GluA tetrameric core surrounded by auxiliary proteins such as transmembrane AMPA receptor regulatory proteins (TARPs) or Cornichons. Their exact composition and stoichiometry govern functional properties, including kinetics, calcium permeability and trafficking. The GluA1–GluA3 subunits predominate in the adult forebrain and are well characterized. However, we lack structural information on full-length GluA4-containing AMPARs, a subtype that has specific roles in brain development and specific cell types in mammals. Here we present the cryo-electron microscopy structures of rat GluA4:TARP-γ2 trapped in active, resting and desensitized states, covering a full gating cycle. Additionally, we describe the structure of GluA4 alone, which displays a classical Y-shaped conformation. In resting conditions, GluA4:TARP-γ2 adopts two conformations, one resembling the desensitized states of other GluA subunits. Moreover, we identify a regulatory site for TARP-γ2 in the ligand-binding domain that modulates gating kinetics. Our findings uncover distinct features of GluA4, highlighting how subunit composition and auxiliary proteins shape receptor structure and dynamics, expanding glutamatergic signaling diversity.","PeriodicalId":18822,"journal":{"name":"Nature structural & molecular biology","volume":"4 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-09-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145059292","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

Computational design of sequence-specific DNA-binding proteins 序列特异性dna结合蛋白的计算设计

Nature structural & molecular biology Pub Date : 2025-09-12 DOI: 10.1038/s41594-025-01669-4

Cameron J. Glasscock, Robert J. Pecoraro, Ryan McHugh, Lindsey A. Doyle, Wei Chen, Olivier Boivin, Beau Lonnquist, Emily Na, Yuliya Politanska, Hugh K. Haddox, David Cox, Christoffer Norn, Brian Coventry, Inna Goreshnik, Dionne Vafeados, Gyu Rie Lee, Raluca Gordân, Barry L. Stoddard, Frank DiMaio, David Baker

{"title":"Computational design of sequence-specific DNA-binding proteins","authors":"Cameron J. Glasscock, Robert J. Pecoraro, Ryan McHugh, Lindsey A. Doyle, Wei Chen, Olivier Boivin, Beau Lonnquist, Emily Na, Yuliya Politanska, Hugh K. Haddox, David Cox, Christoffer Norn, Brian Coventry, Inna Goreshnik, Dionne Vafeados, Gyu Rie Lee, Raluca Gordân, Barry L. Stoddard, Frank DiMaio, David Baker","doi":"10.1038/s41594-025-01669-4","DOIUrl":"https://doi.org/10.1038/s41594-025-01669-4","url":null,"abstract":"Sequence-specific DNA-binding proteins (DBPs) have critical roles in biology and biotechnology and there has been considerable interest in the engineering of DBPs with new or altered specificities for genome editing and other applications. While there has been some success in reprogramming naturally occurring DBPs using selection methods, the computational design of new DBPs that recognize arbitrary target sites remains an outstanding challenge. We describe a computational method for the design of small DBPs that recognize short specific target sequences through interactions with bases in the major groove and use this method to generate binders for five distinct DNA targets with mid-nanomolar to high-nanomolar affinities. The individual binding modules have specificity closely matching the computational models at as many as six base-pair positions and higher-order specificity can be achieved by rigidly positioning the binders along the DNA double helix using RFdiffusion. The crystal structure of a designed DBP–target site complex is in close agreement with the design model and the designed DBPs function in both Escherichia coli and mammalian cells to repress and activate transcription of neighboring genes. Our method provides a route to small and, hence, readily deliverable sequence-specific DBPs for gene regulation and editing.","PeriodicalId":18822,"journal":{"name":"Nature structural & molecular biology","volume":"33 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-09-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145035119","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

Host transfer RNA guides assembly of viral RNA polymerase 宿主转移RNA引导病毒RNA聚合酶的组装

Nature structural & molecular biology Pub Date : 2025-09-10 DOI: 10.1038/s41594-025-01654-x

引用次数: 0

m6A and the NEXT complex direct Xist RNA turnover and X-inactivation dynamics m6A和NEXT复合体直接Xist RNA的转换和x -失活动力学

Nature structural & molecular biology Pub Date : 2025-09-09 DOI: 10.1038/s41594-025-01663-w

Guifeng Wei, Heather Coker, Lisa Rodermund, Mafalda Almeida, Holly L. Roach, Tatyana B. Nesterova, Neil Brockdorff

{"title":"m6A and the NEXT complex direct Xist RNA turnover and X-inactivation dynamics","authors":"Guifeng Wei, Heather Coker, Lisa Rodermund, Mafalda Almeida, Holly L. Roach, Tatyana B. Nesterova, Neil Brockdorff","doi":"10.1038/s41594-025-01663-w","DOIUrl":"https://doi.org/10.1038/s41594-025-01663-w","url":null,"abstract":"X-chromosome inactivation (XCI) in mammals is orchestrated by the noncoding RNA X-inactive-specific transcript (Xist) that, together with specific interacting proteins, functions in cis to silence an entire X chromosome. Defined sites on Xist RNA carry the N6-methyladenosine (m6A) modification and perturbation of the m6A writer complex has been found to abrogate Xist-mediated gene silencing. However, the relative contribution of m6A and its mechanism of action remain unclear. Here we investigate the role of m6A in XCI by applying rapid degron-mediated depletion of METTL3, the catalytic subunit of the m6A writer complex, an approach that minimizes indirect effects because of transcriptome-wide depletion of m6A. We find that acute loss of METTL3 and m6A accelerates Xist-mediated gene silencing and this correlates with increased levels and stability of Xist transcripts. We show that Xist RNA turnover is mediated by the nuclear exosome targeting complex but is independent of the principal nuclear m6A reader protein YTHDC1. Our findings demonstrate that the primary function of m6A on Xist RNA is to promote Xist RNA turnover, which in turn regulates XCI dynamics.","PeriodicalId":18822,"journal":{"name":"Nature structural & molecular biology","volume":"32 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-09-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145018088","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

Redundant and cooperative interactions between the genome and nuclear lamina 基因组与核层之间的冗余和合作相互作用

Nature structural & molecular biology Pub Date : 2025-09-08 DOI: 10.1038/s41594-025-01670-x

引用次数: 0

tRNA as an assembly chaperone for a macromolecular transcription-processing complex tRNA作为大分子转录加工复合物的装配伴侣

Nature structural & molecular biology Pub Date : 2025-09-04 DOI: 10.1038/s41594-025-01653-y

Julia Bartuli, Stefan Jungwirth, Manisha Dixit, Takumi Okuda, Johannes Patrick Zimmermann, Matthias Erlacher, Tao Pan, Asisa Volz, Alexander Hüttenhofer, Bettina Warscheid, Claudia Höbartner, Clemens Grimm, Utz Fischer

{"title":"tRNA as an assembly chaperone for a macromolecular transcription-processing complex","authors":"Julia Bartuli, Stefan Jungwirth, Manisha Dixit, Takumi Okuda, Johannes Patrick Zimmermann, Matthias Erlacher, Tao Pan, Asisa Volz, Alexander Hüttenhofer, Bettina Warscheid, Claudia Höbartner, Clemens Grimm, Utz Fischer","doi":"10.1038/s41594-025-01653-y","DOIUrl":"https://doi.org/10.1038/s41594-025-01653-y","url":null,"abstract":"Transfer RNAs (tRNAs) are widely recognized for their role in translation. Here, we describe a previously unidentified function of tRNA as an assembly chaperone. During poxviral infection, tRNAGln/Arg lacking the anticodon mcm5s2U34 modification is specifically sequestered from the cellular tRNA pool to promote formation of a multisubunit poxviral RNA polymerase complex (vRNAP). Cryo-electron microscopy analysis of assembly intermediates illustrates how tRNAGln/Arg orchestrates the recruitment of transcription and mRNA processing factors to vRNAP where it controls the transition to the preinitiation complex. This is achieved by an induced fit mechanism that internalizes anticodon base G36 into the anticodon stem, creating a noncanonical tRNA structure and selecting a defined tRNA modification pattern. The role of tRNA as an assembly chaperone extends to the pathogenic Mpox virus, which features a similar vRNAP.","PeriodicalId":18822,"journal":{"name":"Nature structural & molecular biology","volume":"15 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-09-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144983399","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

Two dynamically competing factors determine the translation start site 两个动态竞争的因素决定了翻译的起始地点

Nature structural & molecular biology Pub Date : 2025-09-02 DOI: 10.1038/s41594-025-01664-9

Yi-Lan Chen, Jin-Der Wen

引用次数: 0

Interactions between the genome and the nuclear lamina are multivalent and cooperative 基因组与核层之间的相互作用是多价的和合作的

Nature structural & molecular biology Pub Date : 2025-09-01 DOI: 10.1038/s41594-025-01655-w

Lise Dauban, Mathias Eder, Marcel de Haas, Vinícius H. Franceschini-Santos, J. Omar Yañez-Cuna, Moreno Martinovic, Tom van Schaik, Christ Leemans, Hans Teunissen, Koen Rademaker, Miguel Martinez Ara, Martijn Verkuilen, Elzo de Wit, Bas van Steensel

{"title":"Interactions between the genome and the nuclear lamina are multivalent and cooperative","authors":"Lise Dauban, Mathias Eder, Marcel de Haas, Vinícius H. Franceschini-Santos, J. Omar Yañez-Cuna, Moreno Martinovic, Tom van Schaik, Christ Leemans, Hans Teunissen, Koen Rademaker, Miguel Martinez Ara, Martijn Verkuilen, Elzo de Wit, Bas van Steensel","doi":"10.1038/s41594-025-01655-w","DOIUrl":"https://doi.org/10.1038/s41594-025-01655-w","url":null,"abstract":"Lamina-associated domains (LADs) are megabase-sized genomic regions that interact with the nuclear lamina (NL). It is not yet understood how their interactions with the NL are encoded in their DNA. Here we designed an efficient LAD ‘scrambling’ approach, based on transposon-mediated local hopping of loxP recombination sites, to generate series of large deletions and inversions that span LADs and flanking sequences. Mapping of NL interactions in these rearrangements revealed that, in mouse embryonic stem cells, a single LAD contacts the NL through multiple regions that act cooperatively or redundantly; some have more affinity for the NL than others and can pull neighboring sequences to the NL. Genes drawn toward the NL showed often but not always reduced expression and increased H3K9me3 levels. Furthermore, neighboring LADs can cooperatively interact with the NL when placed close enough to each other. These results elucidate principles that govern the positioning of megabase-sized genomic regions inside the cell nucleus.","PeriodicalId":18822,"journal":{"name":"Nature structural & molecular biology","volume":"12 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144924213","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

Dynamic TOM–TIM23 supercomplex directs mitochondrial protein translocation and sorting 动态TOM-TIM23超复合体指导线粒体蛋白易位和分选

Nature structural & molecular biology Pub Date : 2025-08-28 DOI: 10.1038/s41594-025-01662-x

Yuqi Yang, Shanshan Wang, Guopeng Wang, Yuke Lian, Lingfeng Xue, Wenhong Jiang, Qiang Guo, Chen Song, Long Li

{"title":"Dynamic TOM–TIM23 supercomplex directs mitochondrial protein translocation and sorting","authors":"Yuqi Yang, Shanshan Wang, Guopeng Wang, Yuke Lian, Lingfeng Xue, Wenhong Jiang, Qiang Guo, Chen Song, Long Li","doi":"10.1038/s41594-025-01662-x","DOIUrl":"https://doi.org/10.1038/s41594-025-01662-x","url":null,"abstract":"The mitochondrial translocase of the outer membrane (TOM) and translocase of the inner membrane 23 (TIM23) complexes are coupled to control protein import across the outer and inner membranes, respectively. However, the mechanisms of protein recognition and sorting in the TOM–TIM23 pathway remain unclear. Here we report cryo-electron microscopy structures of a translocating polypeptide substrate captured in the active TOM–TIM23 supercomplex from Saccharomyces cerevisiae. In the TOM complex, the polypeptide substrate adopts multiple conformations stabilized by hydrophilic residues from distinct regions of the Tom40 channel. In the TIM23 complex, the Tim17 and Mgr2 subunits create the translocation pathway, with a central restriction formed by four highly conserved hydrophobic residues. The substrate primarily interacts with hydrophobic residues along the Tim17–Mgr2 pathway. Substrate hydrophobicity modulates the association of Mgr2 with Tim17, enabling dynamic regulation of protein sorting toward either the matrix or membrane. These findings reveal a sophisticated translocation mechanism of the TOM–TIM23 supercomplex that ensures the efficient import of diverse mitochondrial proteins.","PeriodicalId":18822,"journal":{"name":"Nature structural & molecular biology","volume":"0 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-08-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144910708","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