Nature structural & molecular biology最新文献_第3页

Structure and catalytic mechanism of exogenous fatty acid recycling by AasS, a versatile acyl-ACP synthetase 多用途酰基- acp合成酶AasS对外源脂肪酸回收的结构及催化机理

Nature structural & molecular biology Pub Date : 2025-01-10 DOI: 10.1038/s41594-024-01464-7

Haomin Huang, Chen Wang, Shenghai Chang, Tao Cui, Yongchang Xu, Man Huang, Huimin Zhang, Chun Zhou, Xing Zhang, Youjun Feng

{"title":"Structure and catalytic mechanism of exogenous fatty acid recycling by AasS, a versatile acyl-ACP synthetase","authors":"Haomin Huang, Chen Wang, Shenghai Chang, Tao Cui, Yongchang Xu, Man Huang, Huimin Zhang, Chun Zhou, Xing Zhang, Youjun Feng","doi":"10.1038/s41594-024-01464-7","DOIUrl":"https://doi.org/10.1038/s41594-024-01464-7","url":null,"abstract":"Fatty acids (FAs) are essential building blocks for all the domains of life, of which bacterial de novo synthesis, called type II FA synthesis (FAS II), is energetically expensive. The recycling of exogenous FAs (eFAs) partially relieves the FAS II demand and, therefore, compromises the efficacy of FAS II-directed antimicrobials. The versatile acyl-acyl carrier protein (ACP) synthetase, AasS, enables bacterial channeling of diverse eFA nutrients through holo-ACP, an activated form of ACP. However, the molecular mechanism for AasS catalysis is not fully understood. Here we report a series of cryo-electron microscopy structures of AasS from the bioluminescent bacterium Vibrio harveyi to provide insights into the catalytic cycle. AasS forms a ring-shaped hexamer, with each protomer folding into two distinct domains. Biochemical and structural analysis suggests that AasS accommodates distinct eFA substrates and the conserved W230 residue has a gating role. Adenosine triphosphate and Mg2+ binding converts the AasS hexamer to a tetramer, which is likely needed for the acyl adenylate intermediate formation. Afterward, AasS reverts to the hexamer conformation in adaption to acyl-ACP production. The complete landscape for eFA scavenging lays a foundation for exploiting the versatility of AasS in biopharmaceuticals.","PeriodicalId":18822,"journal":{"name":"Nature structural & molecular biology","volume":"6 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-01-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142961492","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 multivalent engagement of ENL with MOZ ENL与MOZ的多价结合

Nature structural & molecular biology Pub Date : 2025-01-10 DOI: 10.1038/s41594-024-01455-8

Dustin C. Becht, Karthik Selvam, Catherine Lachance, Valérie Côté, Kuai Li, Minh Chau Nguyen, Akshay Pareek, Xiaobing Shi, Hong Wen, M. Andres Blanco, Jacques Côté, Tatiana G. Kutateladze

引用次数: 0

DARPin-induced reactivation of p53 in HPV-positive cells darpin诱导hpv阳性细胞中p53的再激活

Nature structural & molecular biology Pub Date : 2025-01-09 DOI: 10.1038/s41594-024-01456-7

Philipp Münick, Alexander Strubel, Dimitrios-Ilias Balourdas, Julianne S. Funk, Marco Mernberger, Christian Osterburg, Birgit Dreier, Jonas V. Schaefer, Marcel Tuppi, Büşra Yüksel, Birgit Schäfer, Stefan Knapp, Andreas Plückthun, Thorsten Stiewe, Andreas C. Joerger, Volker Dötsch

{"title":"DARPin-induced reactivation of p53 in HPV-positive cells","authors":"Philipp Münick, Alexander Strubel, Dimitrios-Ilias Balourdas, Julianne S. Funk, Marco Mernberger, Christian Osterburg, Birgit Dreier, Jonas V. Schaefer, Marcel Tuppi, Büşra Yüksel, Birgit Schäfer, Stefan Knapp, Andreas Plückthun, Thorsten Stiewe, Andreas C. Joerger, Volker Dötsch","doi":"10.1038/s41594-024-01456-7","DOIUrl":"https://doi.org/10.1038/s41594-024-01456-7","url":null,"abstract":"Infection of cells with high-risk strains of the human papillomavirus (HPV) causes cancer in various types of epithelial tissue. HPV infections are responsible for ~4.5% of all cancers worldwide. Tumorigenesis is based on the inactivation of key cellular control mechanisms by the viral proteins E6 and E7. The HPV E6 protein interacts with the cellular E3 ligase E6AP, and this complex binds to the p53 DNA-binding domain, which results in degradation of p53. Inhibition of this interaction has the potential to reactivate p53, thus preventing oncogenic transformation. Here we describe the characterization of a designed ankyrin repeat protein that binds to the same site as the HPV E6 protein, thereby displacing the E3 ligase and stabilizing p53. Interaction with the designed ankyrin repeat protein does not affect p53 DNA binding or the crucial MDM2 negative feedback loop but reactivates a p53-dependent transcriptional program in HeLa (HPV18-positive) and SiHa (HPV16-positive) cells, suggesting a potential therapeutic use.","PeriodicalId":18822,"journal":{"name":"Nature structural & molecular biology","volume":"31 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-01-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142937022","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

Capturing eukaryotic ribosome dynamics in situ at high resolution 高分辨率原位捕获真核核糖体动力学

Nature structural & molecular biology Pub Date : 2025-01-09 DOI: 10.1038/s41594-024-01454-9

Jing Cheng, Chunling Wu, Junxi Li, Qi Yang, Mingjie Zhao, Xinzheng Zhang

引用次数: 0

RapA opens the RNA polymerase clamp to disrupt post-termination complexes and prevent cytotoxic R-loop formation RapA打开RNA聚合酶夹，破坏后终止复合物，防止细胞毒性r环的形成

Nature structural & molecular biology Pub Date : 2025-01-08 DOI: 10.1038/s41594-024-01447-8

Joshua J. Brewer, Koe Inlow, Rachel A. Mooney, Barbara Bosch, Paul Dominic B. Olinares, Leandro Pimentel Marcelino, Brian T. Chait, Robert Landick, Jeff Gelles, Elizabeth A. Campbell, Seth A. Darst

{"title":"RapA opens the RNA polymerase clamp to disrupt post-termination complexes and prevent cytotoxic R-loop formation","authors":"Joshua J. Brewer, Koe Inlow, Rachel A. Mooney, Barbara Bosch, Paul Dominic B. Olinares, Leandro Pimentel Marcelino, Brian T. Chait, Robert Landick, Jeff Gelles, Elizabeth A. Campbell, Seth A. Darst","doi":"10.1038/s41594-024-01447-8","DOIUrl":"https://doi.org/10.1038/s41594-024-01447-8","url":null,"abstract":"Following transcript release during intrinsic termination, Escherichia coli RNA polymerase (RNAP) often remains associated with DNA in a post-termination complex (PTC). RNAPs in PTCs are removed from the DNA by the SWI2/SNF2 adenosine triphosphatase (ATPase) RapA. Here we determined PTC structures on negatively supercoiled DNA and with RapA engaged to dislodge the PTC. We found that core RNAP in the PTC can unwind DNA and initiate RNA synthesis but is prone to producing R-loops. Nucleotide binding to RapA triggers a conformational change that opens the RNAP clamp, allowing DNA in the RNAP cleft to reanneal and dissociate. We show that RapA helps to control cytotoxic R-loop formation in vivo, likely by disrupting PTCs. We suggest that analogous ATPases acting on PTCs to suppress transcriptional noise and R-loop formation may be widespread. These results hold importance for the bacterial transcription cycle and highlight a role for RapA in maintaining genome stability.","PeriodicalId":18822,"journal":{"name":"Nature structural & molecular biology","volume":"80 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-01-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142935887","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

Inherent asymmetry of Rpd3S coordinates its nucleosome engagement and association with elongating RNA polymerase II Rpd3S固有的不对称性协调了其核小体与延长RNA聚合酶II的结合

Nature structural & molecular biology Pub Date : 2025-01-08 DOI: 10.1038/s41594-024-01453-w

Yixuan Pan, Meiyang Liu, Chun Ruan, Mengyuan Peng, Min Hao, Qi Zhang, Jingdong Xue, Yanling Niu, Ningzhe Li, Haipeng Guan, Pei Wang, Mingqian Hu, Haitao Li, Wenjuan Wang, Juan Song, Yanhua Yao, Yimin Lao, Bing Li

{"title":"Inherent asymmetry of Rpd3S coordinates its nucleosome engagement and association with elongating RNA polymerase II","authors":"Yixuan Pan, Meiyang Liu, Chun Ruan, Mengyuan Peng, Min Hao, Qi Zhang, Jingdong Xue, Yanling Niu, Ningzhe Li, Haipeng Guan, Pei Wang, Mingqian Hu, Haitao Li, Wenjuan Wang, Juan Song, Yanhua Yao, Yimin Lao, Bing Li","doi":"10.1038/s41594-024-01453-w","DOIUrl":"https://doi.org/10.1038/s41594-024-01453-w","url":null,"abstract":"The Rpd3S histone deacetylase complex has a crucial role in genomic integrity by deacetylating transcribed nucleosomes following RNA polymerase (Pol) II passage. Cryo-EM studies highlight the importance of asymmetrical Rco1–Eaf3 dimers in nucleosome binding, yet the interaction dynamics with nucleosomal substrates alongside elongating Pol II are poorly understood. Here we demonstrate the essential function of the Rco1 N-terminal intrinsically disordered region (IDR) in modulating Pol II association, in which K/R mutations within the Rco1 IDR impair interaction of Rpd3S with the C-terminal domain (CTD) of Rpb1, without affecting nucleosome recognition or complex integrity. We also identify the Rco1-PHD1 and Eaf3-CHD domains as crucial for specific binding to Ser5-phosphorylated CTD. The Rco1 IDR alleviates autoinhibition from its C terminus, facilitating PHD1-CHD engagement with phosphorylated CTD. Furthermore, we reveal a conserved mechanism by which asymmetrical Rco1–Eaf3 dimers coordinate nucleosome engagement and Pol II interaction, enhancing understanding of epigenetic complexes associated with transcriptional machinery.","PeriodicalId":18822,"journal":{"name":"Nature structural & molecular biology","volume":"56 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-01-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142935888","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

Importance of an N-terminal structural switch in the distinction between small RNA-bound and free ARGONAUTE n端结构开关在区分小rna结合和自由ARGONAUTE中的重要性

Nature structural & molecular biology Pub Date : 2025-01-07 DOI: 10.1038/s41594-024-01446-9

Simon Bressendorff, Ida Marie Zobbe Sjøgaard, Andreas Prestel, Vasileios Voutsinos, Martin D. Jansson, Patrice Ménard, Anders H. Lund, Rasmus Hartmann-Petersen, Birthe B. Kragelund, Christian Poulsen, Peter Brodersen

{"title":"Importance of an N-terminal structural switch in the distinction between small RNA-bound and free ARGONAUTE","authors":"Simon Bressendorff, Ida Marie Zobbe Sjøgaard, Andreas Prestel, Vasileios Voutsinos, Martin D. Jansson, Patrice Ménard, Anders H. Lund, Rasmus Hartmann-Petersen, Birthe B. Kragelund, Christian Poulsen, Peter Brodersen","doi":"10.1038/s41594-024-01446-9","DOIUrl":"https://doi.org/10.1038/s41594-024-01446-9","url":null,"abstract":"ARGONAUTE (AGO) proteins bind to small non-coding RNAs to form RNA-induced silencing complexes. In the RNA-bound state, AGO is stable while RNA-free AGO turns over rapidly. Molecular features unique to RNA-free AGO that allow its specific recognition and degradation remain unknown. Here, we identify a confined, linear region in Arabidopsis AGO1 and human Ago2, the N-coil, as a structural switch with preferential accessibility in the RNA-free state. RNA-free Arabidopsis AGO1 interacts with the autophagy cargo receptor ATI1 by direct contact with specific N-coil amino acid residues whose mutation reduces the degradation rate of RNA-free AGO1 in vivo. The N-coil of human Ago2 has similar degron activity dependent on residues in positions equivalent to those required for the Arabidopsis AGO1–ATI1 interaction. These results elucidate the molecular basis for specific recognition and degradation of the RNA-free state of eukaryotic AGO proteins.","PeriodicalId":18822,"journal":{"name":"Nature structural & molecular biology","volume":"1 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-01-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142934964","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

Structural basis for the inhibition of PRC2 by active transcription histone posttranslational modifications 活性转录组蛋白翻译后修饰抑制PRC2的结构基础

Nature structural & molecular biology Pub Date : 2025-01-07 DOI: 10.1038/s41594-024-01452-x

Trinity Cookis, Alexandria Lydecker, Paul Sauer, Vignesh Kasinath, Eva Nogales

引用次数: 0

Capture, mutual inhibition and release mechanism for aPKC–Par6 and its multisite polarity substrate Lgl aPKC-Par6及其多位点极性底物Lgl的捕获、相互抑制和释放机制

Nature structural & molecular biology Pub Date : 2025-01-06 DOI: 10.1038/s41594-024-01425-0

Christopher P. Earl, Mathias Cobbaut, André Barros-Carvalho, Marina E. Ivanova, David C. Briggs, Eurico Morais-de-Sá, Peter J. Parker, Neil Q. McDonald

{"title":"Capture, mutual inhibition and release mechanism for aPKC–Par6 and its multisite polarity substrate Lgl","authors":"Christopher P. Earl, Mathias Cobbaut, André Barros-Carvalho, Marina E. Ivanova, David C. Briggs, Eurico Morais-de-Sá, Peter J. Parker, Neil Q. McDonald","doi":"10.1038/s41594-024-01425-0","DOIUrl":"https://doi.org/10.1038/s41594-024-01425-0","url":null,"abstract":"The mutually antagonistic relationship of atypical protein kinase C (aPKC) and partitioning-defective protein 6 (Par6) with the substrate lethal (2) giant larvae (Lgl) is essential for regulating polarity across many cell types. Although aPKC–Par6 phosphorylates Lgl at three serine sites to exclude it from the apical domain, aPKC–Par6 and Lgl paradoxically form a stable kinase–substrate complex, with conflicting roles proposed for Par6. We report the structure of human aPKCι–Par6α bound to full-length Llgl1, captured through an aPKCι docking site and a Par6PDZ contact. This complex traps a phospho-S663 Llgl1 intermediate bridging between aPKC and Par6, impeding phosphorylation progression. Thus, aPKCι is effectively inhibited by Llgl1pS663 while Llgl1 is captured by aPKCι–Par6. Mutational disruption of the Lgl–aPKC interaction impedes complex assembly and Lgl phosphorylation, whereas disrupting the Lgl–Par6PDZ contact promotes complex dissociation and Lgl phosphorylation. We demonstrate a Par6PDZ-regulated substrate capture-and-release model requiring binding by active Cdc42 and the apical partner Crumbs to drive complex disassembly. Our results suggest a mechanism for mutual regulation and spatial control of aPKC–Par6 and Lgl activities.","PeriodicalId":18822,"journal":{"name":"Nature structural & molecular biology","volume":"82 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-01-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142929714","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

Mechanism of mammalian transcriptional repression by noncoding RNA 非编码RNA抑制哺乳动物转录的机制

Nature structural & molecular biology Pub Date : 2025-01-06 DOI: 10.1038/s41594-024-01448-7

Katarína Tlučková, Beata Kaczmarek, Anita Salmazo, Carrie Bernecky

引用次数: 0