Nature Structural & Molecular Biology最新文献_第5页

A competitive regulatory mechanism of the Chd1 remodeler is integral to distorting nucleosomal DNA Chd1重塑器的竞争性调控机制是扭曲核小体DNA的组成部分

IF 10.1 1区生物学

Nature Structural & Molecular Biology Pub Date : 2025-05-28 DOI: 10.1038/s41594-025-01556-y

Ilana M. Nodelman, Heather J. Folkwein, Wesley S. Glime, Jean-Paul Armache, Gregory D. Bowman

{"title":"A competitive regulatory mechanism of the Chd1 remodeler is integral to distorting nucleosomal DNA","authors":"Ilana M. Nodelman, Heather J. Folkwein, Wesley S. Glime, Jean-Paul Armache, Gregory D. Bowman","doi":"10.1038/s41594-025-01556-y","DOIUrl":"10.1038/s41594-025-01556-y","url":null,"abstract":"The Chd1 chromatin remodeler repositions nucleosomes into evenly spaced arrays, a characteristic of most eukaryotic genes. Here we show that the yeast Chd1 remodeler requires two activating segments to distort nucleosomal DNA into an A-form-like conformation, a critical first step in nucleosome sliding. As shown by cryo-electron microscopy, these two activating segments together pack against the ATPase motor, where they are poised to stabilize the central ATPase cleft. These activating elements contact the ATPase at locations that are incompatible with binding of NegC, an autoinhibitory segment located between the two activators. NegC inhibits sliding by antagonizing the activators through steric competition and constraining activator placement, giving rise to directional nucleosome sliding. Given that activator reinforcement of the ATPase cleft is needed for DNA distortion, this first step in remodeling appears to provide a natural checkpoint for regulation of chromatin remodeler activity. Nodelman, Folkwein et al. define a regulatory region in Chd1 containing adjacent inhibitor and activator elements that compete for binding to the remodeler ATPase. The competition between these elements shows how remodeler regulation is integrated into the nucleosome sliding cycle.","PeriodicalId":49141,"journal":{"name":"Nature Structural & Molecular Biology","volume":"32 8","pages":"1445-1455"},"PeriodicalIF":10.1,"publicationDate":"2025-05-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144164779","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

Akt-phosphorylated UFL1 UFMylates ArpC4 to promote metastasis akt磷酸化的UFL1 ufmylate ArpC4促进转移

IF 10.1 1区生物学

Nature Structural & Molecular Biology Pub Date : 2025-05-26 DOI: 10.1038/s41594-025-01576-8

Kailiang Zhao, Hao Hu, Debao Fang, Mingran Xie, Jiasheng Chen, Shan Zhang, Suyun Tang, Mingsheng Wu, Xiaorui Guo, Ning Yu, Bao Yao, Wenli Jiang, Chao Wang, Yide Mei

{"title":"Akt-phosphorylated UFL1 UFMylates ArpC4 to promote metastasis","authors":"Kailiang Zhao, Hao Hu, Debao Fang, Mingran Xie, Jiasheng Chen, Shan Zhang, Suyun Tang, Mingsheng Wu, Xiaorui Guo, Ning Yu, Bao Yao, Wenli Jiang, Chao Wang, Yide Mei","doi":"10.1038/s41594-025-01576-8","DOIUrl":"10.1038/s41594-025-01576-8","url":null,"abstract":"The role of modification by ubiquitin-fold modifier (‘UFMylation’) in regulating metastasis has remained enigmatic. Cell migration, a critical step in metastasis, is driven by actin polymerization mediated by actin-related proteins 2 and 3 (Arp2/3) at the leading edge of lamellipodia. Here, we report that UFM1-specific E3 ligase 1 (UFL1) interacts with and catalyzes the UFMylation of ArpC4, a core subunit of the Arp2/3 complex. Akt has a key role in this process, which involves phosphorylating UFL1 at T426, thereby enhancing its interaction with ArpC4 and inducing ArpC4 UFMylation. Through ArpC4 UFMylation and potentially other targets, UFL1 facilitates lamellipodia formation and promotes cell migration, invasion and metastasis, making UFL1 an attractive therapeutic target for cancer. Zhao et al. show that Akt-mediated phosphorylation of ubiquitin-fold modifier 1 (UFM1)-specific E3 ligase 1 (UFL1) catalyzes the UFMylation of ArpC4, a core subunit of actin-related proteins 2 and 3. Through ArpC4 UFMylation, UFL1 promotes lamellipodia formation and enhances cell migration, invasion and metastasis.","PeriodicalId":49141,"journal":{"name":"Nature Structural & Molecular Biology","volume":"32 8","pages":"1528-1541"},"PeriodicalIF":10.1,"publicationDate":"2025-05-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144137156","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

UFMylation of ARPC4 facilitates lamellipodia formation and promotes cancer metastasis ARPC4的ufmy化促进板足形成，促进肿瘤转移

IF 10.1 1区生物学

Nature Structural & Molecular Biology Pub Date : 2025-05-26 DOI: 10.1038/s41594-025-01577-7

Miao Wang, Yu-Sheng Cong

引用次数: 0

TRIP12 structures reveal HECT E3 formation of K29 linkages and branched ubiquitin chains TRIP12结构揭示了K29键和分支泛素链的HECT E3形成

IF 10.1 1区生物学

Nature Structural & Molecular Biology Pub Date : 2025-05-26 DOI: 10.1038/s41594-025-01561-1

Samuel A. Maiwald, Laura A. Schneider, Ronnald Vollrath, Joanna Liwocha, Matthew D. Maletic, Kirby N. Swatek, Monique P. C. Mulder, Brenda A. Schulman

{"title":"TRIP12 structures reveal HECT E3 formation of K29 linkages and branched ubiquitin chains","authors":"Samuel A. Maiwald, Laura A. Schneider, Ronnald Vollrath, Joanna Liwocha, Matthew D. Maletic, Kirby N. Swatek, Monique P. C. Mulder, Brenda A. Schulman","doi":"10.1038/s41594-025-01561-1","DOIUrl":"10.1038/s41594-025-01561-1","url":null,"abstract":"Regulation by ubiquitin depends on E3 ligases forging chains of specific topologies, yet the mechanisms underlying the generation of atypical linkages remain largely elusive. Here we utilize biochemistry, chemistry, and cryo-EM to define the catalytic architecture producing K29 linkages and K29/K48 branches for the human HECT E3 TRIP12. TRIP12 resembles a pincer. One pincer side comprises tandem ubiquitin-binding domains, engaging the proximal ubiquitin to direct its K29 towards the ubiquitylation active site, and selectively capturing a distal ubiquitin from a K48-linked chain. The opposite pincer side—the HECT domain—precisely juxtaposes the ubiquitins to be joined, further ensuring K29 linkage specificity. Comparison to the prior structure visualizing K48-linked chain formation by UBR5 reveals a similar mechanism shared by two human HECT enzymes: parallel features of the E3s, donor and acceptor ubiquitins configure the active site around the targeted lysine, with E3-specific domains buttressing the acceptor for linkage-specific polyubiquitylation. Using biochemistry, chemical biology, and cryo-EM, Maiwald et al. elucidate how TRIP12 forms K29 linkages and K29/K48-linked branched ubiquitin chains, revealing a mechanism for polyubiquitylation shared by some HECT E3s.","PeriodicalId":49141,"journal":{"name":"Nature Structural & Molecular Biology","volume":"32 9","pages":"1766-1775"},"PeriodicalIF":10.1,"publicationDate":"2025-05-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41594-025-01561-1.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144137155","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

TRIMming centrosomal assemblies 修整中心体组件

IF 10.1 1区生物学

Nature Structural & Molecular Biology Pub Date : 2025-05-25 DOI: 10.1038/s41594-025-01549-x

Renata Basto

引用次数: 0

TRIM37 prevents ectopic spindle pole assembly by peptide motif recognition and substrate-dependent oligomerization TRIM37通过肽基序识别和底物依赖性寡聚化防止异位纺锤极组装

IF 10.1 1区生物学

Nature Structural & Molecular Biology Pub Date : 2025-05-25 DOI: 10.1038/s41594-025-01562-0

Andrew Bellaart, Amanda Brambila, Jiawei Xu, Francisco Mendez Diaz, Amar Deep, John Anzola, Franz Meitinger, Midori Ohta, Kevin D. Corbett, Arshad Desai, Karen Oegema

{"title":"TRIM37 prevents ectopic spindle pole assembly by peptide motif recognition and substrate-dependent oligomerization","authors":"Andrew Bellaart, Amanda Brambila, Jiawei Xu, Francisco Mendez Diaz, Amar Deep, John Anzola, Franz Meitinger, Midori Ohta, Kevin D. Corbett, Arshad Desai, Karen Oegema","doi":"10.1038/s41594-025-01562-0","DOIUrl":"10.1038/s41594-025-01562-0","url":null,"abstract":"Tightly controlled duplication of centrosomes, the primary microtubule-organizing centers of animal cells, ensures bipolarity of the mitotic spindle and accurate chromosome segregation. The RING–B-box–coiled coil ubiquitin ligase tripartite motif-containing protein 37 (TRIM37), whose loss is associated with elevated chromosome missegregation and the tumor-prone human developmental disorder Mulibrey nanism, prevents the formation of ectopic spindle poles assembling around structured condensates that contain the centrosomal protein centrobin. Here, we show that TRIM37’s tumor necrosis factor receptor-associated factor (TRAF) domain, which is unique in the extended TRIM family, engages peptide motifs in centrobin to suppress condensate formation. TRIM family proteins form antiparallel coiled-coil dimers with RING–B-box domains at each end. Oligomerization resulting from RING–RING interactions and conformational regulation through B-box 2–B-box 2 interfaces are essential for TRIM37 to suppress centrobin condensate formation. These results indicate that, similar to antiviral TRIM ligases, TRIM37 activation is coupled to detection of oligomerized substrates, facilitated by recognition of specific motifs in the substrate, to enforce ubiquitination-mediated clearance of ectopic centrosomal protein assemblies. Bellaart et al. address how the ubiquitin ligase tripartite motif-containing protein 37, the gene for which is mutated in Mulibrey nanism, uses peptide motif recognition and substrate-directed oligomerization to prevent the formation of ectopic spindle poles that cause chromosome missegregation.","PeriodicalId":49141,"journal":{"name":"Nature Structural & Molecular Biology","volume":"32 9","pages":"1800-1811"},"PeriodicalIF":10.1,"publicationDate":"2025-05-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144133595","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

Mesoscale regulation of microtubule-organizing centers by the E3 ligase TRIM37 E3连接酶TRIM37对微管组织中心的中尺度调控

IF 10.1 1区生物学

Nature Structural & Molecular Biology Pub Date : 2025-05-25 DOI: 10.1038/s41594-025-01540-6

Zhong Y. Yeow, Sonia Sarju, Fang-Chi Chang, Lance Y. Xu, Mark van Breugel, Andrew J. Holland

{"title":"Mesoscale regulation of microtubule-organizing centers by the E3 ligase TRIM37","authors":"Zhong Y. Yeow, Sonia Sarju, Fang-Chi Chang, Lance Y. Xu, Mark van Breugel, Andrew J. Holland","doi":"10.1038/s41594-025-01540-6","DOIUrl":"10.1038/s41594-025-01540-6","url":null,"abstract":"Centrosomes ensure accurate chromosome segregation during cell division. Although the regulation of centrosome number is well established, less is known about the suppression of noncentrosomal microtubule-organizing centers (ncMTOCs). The E3 ligase TRIM37, implicated in Mulibrey nanism and 17q23-amplified cancers, has emerged as a key regulator of both centrosomes and ncMTOCs. Yet, the mechanism by which TRIM37 achieves enzymatic activation to target these mesoscale structures had thus far remained unknown. Here we elucidate the activation process of TRIM37, unveiling a process that initiates with TRAF domain-directed substrate recognition followed by B-box domain-mediated oligomerization and culminates in RING domain dimerization. Using optogenetics, we demonstrate that the E3 activity of TRIM37 is directly coupled to the assembly state of its substrates, being activated only when centrosomal proteins cluster into higher-order assemblies resembling MTOCs. This regulatory framework provides a mechanistic basis for understanding TRIM37-driven pathologies and echoes the restriction of the human immunodeficiency virus capsid by TRIM5, thus unveiling a conserved activation blueprint among TRIM proteins to control turnover of complexes assembled at the mesoscale level. Here Yeow et al. present a model in which TRIM37 regulates microtubule-organizing centers through substrate-templated activation, providing a unifying mechanism for the control of mesoscale assemblies by the TRIM family of E3 ligases.","PeriodicalId":49141,"journal":{"name":"Nature Structural & Molecular Biology","volume":"32 9","pages":"1787-1799"},"PeriodicalIF":10.1,"publicationDate":"2025-05-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144133592","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

Multiple steps of dynein activation by Lis1 visualized by cryo-EM 低温电镜观察Lis1激活动力蛋白的多个步骤

IF 10.1 1区生物学

Nature Structural & Molecular Biology Pub Date : 2025-05-23 DOI: 10.1038/s41594-025-01558-w

Agnieszka A. Kendrick, Kendrick H. V. Nguyen, Wen Ma, Eva P. Karasmanis, Rommie E. Amaro, Samara L. Reck-Peterson, Andres E. Leschziner

{"title":"Multiple steps of dynein activation by Lis1 visualized by cryo-EM","authors":"Agnieszka A. Kendrick, Kendrick H. V. Nguyen, Wen Ma, Eva P. Karasmanis, Rommie E. Amaro, Samara L. Reck-Peterson, Andres E. Leschziner","doi":"10.1038/s41594-025-01558-w","DOIUrl":"10.1038/s41594-025-01558-w","url":null,"abstract":"Cytoplasmic dynein-1 (dynein) is an essential molecular motor controlled in part by autoinhibition. Lis1, a key dynein regulator mutated in the neurodevelopmental disease lissencephaly, plays a role in dynein activation. We recently identified a structure of partially autoinhibited dynein bound to Lis1, which suggests an intermediate state in dynein’s activation pathway. However, other structural information is needed to fully understand how Lis1 activates dynein. Here, we used cryo-EM and yeast dynein and Lis1 incubated with ATP at different time points to reveal conformations that we propose represent additional intermediate states in dynein’s activation pathway. We solved 16 high-resolution structures, including 7 distinct dynein and dynein–Lis1 structures from the same sample. Our data support a model in which Lis1 relieves dynein autoinhibition by increasing its basal ATP hydrolysis rate and promoting conformations compatible with complex assembly and motility. Together, this analysis advances our understanding of dynein activation and the contribution of Lis1 to this process. Using cryo-EM, Kendrick et al. reveal multiple dynein conformations during dynein’s mechanochemical cycle and Lis1 binding that represent intermediate states of dynein’s activation.","PeriodicalId":49141,"journal":{"name":"Nature Structural & Molecular Biology","volume":"32 8","pages":"1434-1444"},"PeriodicalIF":10.1,"publicationDate":"2025-05-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41594-025-01558-w.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144123075","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Structural elucidation of full-length Pfs48/45 in complex with potent monoclonal antibodies isolated from a naturally exposed individual 从自然暴露个体中分离的强效单克隆抗体复合物全长Pfs48/45的结构解析

IF 10.1 1区生物学

Nature Structural & Molecular Biology Pub Date : 2025-05-22 DOI: 10.1038/s41594-025-01532-6

Iga Kucharska, Danton Ivanochko, Sophia Hailemariam, Maartje R. Inklaar, Hee Ryung Kim, Karina Teelen, Rianne Stoter, Marga van de Vegte-Bolmer, Geert-Jan van Gemert, Anthony Semesi, Brandon McLeod, Ahyoung Ki, Won-Kyu Lee, John L. Rubinstein, Matthijs M. Jore, Jean-Philippe Julien

{"title":"Structural elucidation of full-length Pfs48/45 in complex with potent monoclonal antibodies isolated from a naturally exposed individual","authors":"Iga Kucharska, Danton Ivanochko, Sophia Hailemariam, Maartje R. Inklaar, Hee Ryung Kim, Karina Teelen, Rianne Stoter, Marga van de Vegte-Bolmer, Geert-Jan van Gemert, Anthony Semesi, Brandon McLeod, Ahyoung Ki, Won-Kyu Lee, John L. Rubinstein, Matthijs M. Jore, Jean-Philippe Julien","doi":"10.1038/s41594-025-01532-6","DOIUrl":"10.1038/s41594-025-01532-6","url":null,"abstract":"Biomedical interventions that block the transmission of Plasmodium falciparum (Pf) from humans to mosquitoes may be critical for malaria elimination. Pfs48/45, a gamete-surface protein essential for Pf development in the mosquito midgut, is a target of clinical-stage transmission-blocking vaccines and monoclonal antibodies (mAbs) that disrupt Pf transmission to mosquitoes. Antibodies directed to domain 3 of Pfs48/45 have been structurally and functionally described; however, in-depth information about other inhibitory epitopes on Pfs48/45 is currently limited. Here, we present a cryo-electron microscopy structure of full-length Pfs48/45 in complex with potent human mAbs targeting all three domains. Our data indicate that although Pfs48/45 domains 1 and 2 are rigidly coupled, there is substantial conformational flexibility between domains 2 and 3. Characterization of mAbs against domain 1 revealed the presence of a conformational epitope class that is largely conserved across Pf field isolates and is associated with recognition by potent antibodies. Our study provides insights into epitopes across full-length Pfs48/45 and has implications for the design of next-generation malaria interventions. Kucharska, Ivanochko and Hailemariam and colleagues solved cryo-EM structures of Pfs48/45, needed for Plasmodium falciparum development, with potent antibodies. The work revealed conformational epitopes, with implications for design of therapies against malaria.","PeriodicalId":49141,"journal":{"name":"Nature Structural & Molecular Biology","volume":"32 8","pages":"1396-1407"},"PeriodicalIF":10.1,"publicationDate":"2025-05-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41594-025-01532-6.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144113819","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Making 3′ ends meet 收支相抵

IF 10.1 1区生物学

Nature Structural & Molecular Biology Pub Date : 2025-05-22 DOI: 10.1038/s41594-025-01578-6

Sylvie Doublié

引用次数: 0