Nature chemical biology最新文献_第8页

Plasma membrane-associated ARAF condensates fuel RAS-related cancer drug resistance 质膜相关的ARAF凝聚物促进ras相关癌症耐药

IF 14.8 1区生物学

Nature chemical biology Pub Date : 2025-01-27 DOI: 10.1038/s41589-024-01826-8

Wen Li, Xiaoxian Shi, Caiwei Tan, Zhaodi Jiang, Mingyi Li, Zhiheng Ji, Jing Zhou, Mengxin Luo, Zuyan Fan, Zhifan Ding, Yue Fang, Jun Sun, Junjun Ding, Huasong Lu, Weirui Ma, Wei Xie, Wenjing Su

{"title":"Plasma membrane-associated ARAF condensates fuel RAS-related cancer drug resistance","authors":"Wen Li, Xiaoxian Shi, Caiwei Tan, Zhaodi Jiang, Mingyi Li, Zhiheng Ji, Jing Zhou, Mengxin Luo, Zuyan Fan, Zhifan Ding, Yue Fang, Jun Sun, Junjun Ding, Huasong Lu, Weirui Ma, Wei Xie, Wenjing Su","doi":"10.1038/s41589-024-01826-8","DOIUrl":"https://doi.org/10.1038/s41589-024-01826-8","url":null,"abstract":"RAF protein kinases are major RAS effectors that function by phosphorylating MEK. Although all three RAF isoforms share a conserved RAS binding domain and bind to GTP-loaded RAS, only ARAF uniquely enhances RAS activity. Here we uncovered the molecular basis of ARAF in regulating RAS activation. The disordered N-terminal sequence of ARAF drives self-assembly, forming ARAF–RAS condensates tethered to the plasma membrane. These structures concentrate active RAS locally, impeding NF1-mediated negative regulation of RAS, thereby fostering receptor tyrosine kinase (RTK)-triggered RAS activation. In RAS-mutant tumors, loss of the ARAF N terminus sensitizes tumor cells to pan-RAF inhibition. In hormone-sensitive cancers, increased ARAF condensates drive endocrine therapy resistance, whereas ARAF depletion reverses RTK-dependent resistance. Our findings delineate ARAF–RAS protein condensates as distinct subcellular structures sustaining RAS activity and facilitating oncogenic RAS signaling. Targeting ARAF–RAS condensation may offer a strategy to overcome drug resistance in both wild-type and mutant ARAF-mediated scenarios.<figure></figure>","PeriodicalId":18832,"journal":{"name":"Nature chemical biology","volume":"20 1","pages":""},"PeriodicalIF":14.8,"publicationDate":"2025-01-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143044126","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}

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The ISC machinery assembles [2Fe–2S] clusters by formation and fusion of [1Fe–1S] precursors ISC机制通过[1Fe-1S]前体的形成和融合来组装[2Fe-2S]簇

IF 14.8 1区生物学

Nature chemical biology Pub Date : 2025-01-27 DOI: 10.1038/s41589-024-01818-8

Sylvain Gervason, Rafal Dutkiewicz, Kristian Want, Rania Benazza, Rémi Mor-Gautier, Aneta Grabinska-Rogala, Christina Sizun, Oscar Hernandez-Alba, Sarah Cianferani, Bruno Guigliarelli, Bénédicte Burlat, Benoit D’Autréaux

{"title":"The ISC machinery assembles [2Fe–2S] clusters by formation and fusion of [1Fe–1S] precursors","authors":"Sylvain Gervason, Rafal Dutkiewicz, Kristian Want, Rania Benazza, Rémi Mor-Gautier, Aneta Grabinska-Rogala, Christina Sizun, Oscar Hernandez-Alba, Sarah Cianferani, Bruno Guigliarelli, Bénédicte Burlat, Benoit D’Autréaux","doi":"10.1038/s41589-024-01818-8","DOIUrl":"https://doi.org/10.1038/s41589-024-01818-8","url":null,"abstract":"Iron–sulfur clusters are essential metallocofactors synthesized by multiprotein machineries via an unclear multistep process. Here we report a step-by-step dissection of the [2Fe–2S] cluster assembly process by the Escherichia coli iron–sulfur cluster (ISC) assembly machinery using an in vitro reconstituted system and a combination of biochemical and spectroscopic techniques. We show that this process is initiated by iron binding to the scaffold protein IscU, which triggers persulfide insertion by the cysteine desulfurase IscS upon the formation of a complex with IscU. Then, the persulfide is cleaved into sulfide by the ferredoxin Fdx, leading to a [1Fe–1S] precursor. IscU dissociates from IscS, dimerizes and generates a bridging [2Fe–2S] cluster by fusion of two [1Fe–1S] precursors. The IscU dimer ultimately dissociates into a monomer, ready to transfer its [2Fe–2S] cluster to acceptors. These data provide a comprehensive description of the [2Fe–2S] cluster assembly process by the ISC assembly machinery, highlighting the formation of key intermediates through a tightly concerted process.<figure></figure>","PeriodicalId":18832,"journal":{"name":"Nature chemical biology","volume":"4 1","pages":""},"PeriodicalIF":14.8,"publicationDate":"2025-01-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143044125","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

Implications of frequent hitter E3 ligases in targeted protein degradation screens 频繁攻击者E3连接酶在靶向蛋白降解筛选中的意义

IF 12.9 1区生物学

Nature chemical biology Pub Date : 2025-01-27 DOI: 10.1038/s41589-024-01821-z

Xiaoyu Zhang, Gabriel M. Simon, Benjamin F. Cravatt

{"title":"Implications of frequent hitter E3 ligases in targeted protein degradation screens","authors":"Xiaoyu Zhang, Gabriel M. Simon, Benjamin F. Cravatt","doi":"10.1038/s41589-024-01821-z","DOIUrl":"10.1038/s41589-024-01821-z","url":null,"abstract":"Targeted protein degradation (TPD) offers a promising approach for chemical probe and drug discovery that uses small molecules or biologics to direct proteins to the cellular machinery for destruction. Among the >600 human E3 ligases, CRBN and VHL have served as workhorses for ubiquitin–proteasome system-dependent TPD. Identification of additional E3 ligases capable of supporting TPD would unlock the full potential of this mechanism for both research and pharmaceutical applications. This perspective discusses recent strategies to expand the scope of TPD and the surprising convergence of these diverse screening efforts on a handful of E3 ligases, specifically DCAF16, DCAF11 and FBXO22. We speculate that a combination of properties, including superficial ligandability, potential for promiscuous substrate interactions and high occupancy in Cullin–RING complexes, may position these E3 ligases as ‘low-hanging fruit’ in TPD screens. We also discuss complementary approaches that might further expand the E3 ligase landscape supporting TPD. This Perspective discusses recent strategies to expand the scope of targeted protein degradation (TPD) and the implications of unexpected convergence of diverse screening efforts on a small subset of TPD-competent E3 ligases in the human proteome.","PeriodicalId":18832,"journal":{"name":"Nature chemical biology","volume":"21 4","pages":"474-481"},"PeriodicalIF":12.9,"publicationDate":"2025-01-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143044127","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

An influenza mutation switch 流感突变开关

IF 12.9 1区生物学

Nature chemical biology Pub Date : 2025-01-23 DOI: 10.1038/s41589-025-01839-x

Francesco Zamberlan

引用次数: 0

Rolling toward circular solutions 滚向圆形解

IF 12.9 1区生物学

Nature chemical biology Pub Date : 2025-01-23 DOI: 10.1038/s41589-025-01837-z

Yiyun Song

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TRIMming the nuclear pore 修整核孔

IF 12.9 1区生物学

Nature chemical biology Pub Date : 2025-01-23 DOI: 10.1038/s41589-025-01838-y

Grant Miura

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Hashing the message with cells 用单元格对消息进行散列

IF 12.9 1区生物学

Nature chemical biology Pub Date : 2025-01-20 DOI: 10.1038/s41589-024-01830-y

Jongmin Kim, Elisa Franco

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Continuous selection in E. coli to identify cyclic peptide inhibitors of protein aggregation 连续筛选大肠杆菌中环状肽蛋白聚集抑制剂的鉴定

IF 12.9 1区生物学

Nature chemical biology Pub Date : 2025-01-17 DOI: 10.1038/s41589-024-01824-w

引用次数: 0

A DNA phosphorothioation pathway via adenylated intermediate modulates Tdp machinery DNA磷酸化途径通过腺苷化中间体调节Tdp机制

IF 14.8 1区生物学

Nature chemical biology Pub Date : 2025-01-16 DOI: 10.1038/s41589-024-01832-w

Tianchen An, Qian Tan, Lixu Jiang, Li Liu, Xing Jiang, Liying Liu, Xiaofei Chang, Xihao Tian, Zixin Deng, Shuai Gao, Lianrong Wang, Shi Chen

{"title":"A DNA phosphorothioation pathway via adenylated intermediate modulates Tdp machinery","authors":"Tianchen An, Qian Tan, Lixu Jiang, Li Liu, Xing Jiang, Liying Liu, Xiaofei Chang, Xihao Tian, Zixin Deng, Shuai Gao, Lianrong Wang, Shi Chen","doi":"10.1038/s41589-024-01832-w","DOIUrl":"https://doi.org/10.1038/s41589-024-01832-w","url":null,"abstract":"In prokaryotes, the non-bridging oxygen in the DNA sugar-phosphate backbone can be enzymatically replaced by a sulfur atom, resulting in phosphorothioate (PT) modification. However, the mechanism underlying the oxygen-to-sulfur substitution remains enigmatic. In this study, we discovered a hypercompact DNA phosphorothioation system, TdpABC, in extreme thermophiles. This DNA sulfuration process occurs through two sequential steps: an initial activation step by ATP to form an adenylated intermediate, followed by a substitution step where the adenyl group is replaced with a sulfur atom. Together with the TdpA–TdpB, the TdpABC system provides anti-phage defense by degrading PT-free phage DNA. Cryogenic electron microscopy structural analysis revealed that the TdpA hexamer binds one strand of encircled duplex DNA via hydrogen bonds arranged in a spiral staircase conformation. Nevertheless, the TdpAB–DNA interaction was sensitive to the hydrophobicity of the PT sulfur. PTs inhibit ATP-driven translocation and nuclease activity of TdpAB on self-DNA, thereby preventing autoimmunity.<figure></figure>","PeriodicalId":18832,"journal":{"name":"Nature chemical biology","volume":"15 1","pages":""},"PeriodicalIF":14.8,"publicationDate":"2025-01-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142986759","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

PROTAR Vaccine 2.0 generates influenza vaccines by degrading multiple viral proteins PROTAR疫苗2.0通过降解多种病毒蛋白产生流感疫苗

IF 14.8 1区生物学

Nature chemical biology Pub Date : 2025-01-15 DOI: 10.1038/s41589-024-01813-z

Chunhe Zhang, Jihuan Hou, Zhen Li, Quan Shen, Haiqing Bai, Li Chen, Jinying Shen, Ping Wang, Yinlei Su, Jing Li, Qisi Zhang, Chengyao Liu, Xuetong Xi, Fei Qi, Yuting Chen, Xin Xie, Adam Yongxin Ye, Xiaoheng Liu, Roberto Plebani, George Church, Longlong Si

{"title":"PROTAR Vaccine 2.0 generates influenza vaccines by degrading multiple viral proteins","authors":"Chunhe Zhang, Jihuan Hou, Zhen Li, Quan Shen, Haiqing Bai, Li Chen, Jinying Shen, Ping Wang, Yinlei Su, Jing Li, Qisi Zhang, Chengyao Liu, Xuetong Xi, Fei Qi, Yuting Chen, Xin Xie, Adam Yongxin Ye, Xiaoheng Liu, Roberto Plebani, George Church, Longlong Si","doi":"10.1038/s41589-024-01813-z","DOIUrl":"https://doi.org/10.1038/s41589-024-01813-z","url":null,"abstract":"Manipulating viral protein stability using the cellular ubiquitin-proteasome system (UPS) represents a promising approach for developing live-attenuated vaccines. The first-generation proteolysis-targeting (PROTAR) vaccine had limitations, as it incorporates proteasome-targeting degrons (PTDs) at only the terminal ends of viral proteins, potentially restricting its broad application. Here we developed the next-generation PROTAR vaccine approach, referred to as PROTAR 2.0, which enabled flexible incorporation of PTDs at various genomic loci of influenza viruses, including internal regions and terminal ends. The PROTAR 2.0 influenza viruses maintained efficient replication in UPS-deficient cells for large-scale production but were attenuated by PTD-mediated proteasomal degradation of viral proteins in conventional cells. Incorporation of multiple PTDs into one virus generated optimized PROTAR 2.0 vaccine candidates. In animal models, PROTAR 2.0 vaccine candidates were highly attenuated and a single-dose intranasal immunization induced robust and broad immune responses that provided complete cross-reactive protection against both homologous and heterologous viral challenges.<figure></figure>","PeriodicalId":18832,"journal":{"name":"Nature chemical biology","volume":"1 1","pages":""},"PeriodicalIF":14.8,"publicationDate":"2025-01-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142981369","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