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Structural insights into the functional mechanism of the ubiquitin ligase E6AP

文献类型：期刊论文

作者Wang, Zhen7; Fan, Fengying6,7; Li, Zhihai5,6; Ye, Fei4; Wang, Qingxia3; Gao, Rongchao3; Qiu, Jiaxuan6,7; Lv, Yixin5,6; Lin, Min4; Xu, Wenwen6,7
刊名NATURE COMMUNICATIONS
出版日期2024-04-26
卷号15期号:1页码:13
DOI10.1038/s41467-024-47586-w
通讯作者Luo, Cheng(cluo@simm.ac.cn) ; Yu, Xuekui(xkyu@simm.ac.cn)
英文摘要E6AP dysfunction is associated with Angelman syndrome and Autism spectrum disorder. Additionally, the host E6AP is hijacked by the high-risk HPV E6 to aberrantly ubiquitinate the tumor suppressor p53, which is linked with development of multiple types of cancer, including most cervical cancers. Here we show that E6AP and the E6AP/E6 complex exist, respectively, as a monomer and a dimer of the E6AP/E6 protomer. The short alpha 1-helix of E6AP transforms into a longer helical structure when in complex with E6. The extended alpha 1-helices of the dimer intersect symmetrically and contribute to the dimerization. The two protomers sway around the crossed region of the two alpha 1-helices to promote the attachment and detachment of substrates to the catalytic C-lobe of E6AP, thus facilitating ubiquitin transfer. These findings, complemented by mutagenesis analysis, suggest that the alpha 1-helix, through conformational transformations, controls the transition between the inactive monomer and the active dimer of E6AP. The human papillomavirus (HPV) E6 oncoprotein hijacks the ligase activity of the host E6AP to ubiquitinate the tumor suppressor p53. Here, the authors show how the presence of the HPV E6 oncoprotein transforms the inactive E6AP monomer into an active dimer, providing a structural understanding of the physiological and pathophysiological mechanisms of E6AP function.
WOS关键词HUMAN-PAPILLOMAVIRUS TYPE-16 ; ANGELMAN SYNDROME ; PROTEIN LIGASE ; AUTISM ; E6-AP ; ONCOPROTEIN ; P53 ; ASSOCIATION ; PREDICTION ; CATALYSIS
资助项目National Natural Science Foundation of China (National Science Foundation of China) ; Shanghai Institute of Material Medica[2022YFC3400500] ; Shanghai Institute of Material Medica[2021ZD0203900] ; Shanghai Institute of Material Medica[2022YFC2804800] ; National Key Research and Development Program of China[LG202103-02-08] ; Hundred Talents Program of the Chinese Academy of Sciences[TZX022021007] ; Shanghai Municipal Science and Technology Major Project[32000896] ; Shanghai Municipal Science and Technology Major Project[81821005] ; Shanghai Municipal Science and Technology Major Project[92253303] ; National Natural Science Foundation of China[2019B090904008] ; High-level New RD Institute[2021B0909050003] ; High-level Innovative Research Institute ; Department of Science and Technology of Guangdong Province ; SANOFI Scholarship Program[LY23H190002] ; Zhejiang Provincial Natural Science Foundation of China[2022ZZ01010] ; Research Funds from Hangzhou Institute for Advanced Study[22042292-Y] ; Fundamental Research Funds of Zhejiang Sci-Tech University
WOS研究方向Science & Technology - Other Topics
语种英语
WOS记录号WOS:001210969800014
出版者NATURE PORTFOLIO
源URL[http://119.78.100.183/handle/2S10ELR8/312261]  
专题新药研究国家重点实验室
通讯作者Luo, Cheng; Yu, Xuekui
作者单位1.Guiyang Univ Tradit Chinese Med, Dept Pharm, South Dong Qing Rd, Huaxi Dist 550025, Guizhou, Peoples R China
2.Chinese Acad Sci, Zhongshan Inst Drug Discovery, Shanghai Inst Mat Med, Zhongshan 528437, Peoples R China
3.Chinese Acad Sci, Shanghai Inst Mat Med, Cryo Electron Microscopy Res Ctr, Shanghai 201203, Peoples R China
4.Zhejiang Sci Tech Univ, Coll Life Sci & Med, Hangzhou 310018, Peoples R China
5.Univ Chinese Acad Sci, Hangzhou Inst Adv Study, Sch Pharmaceut Sci & Technol, Hangzhou 310024, Peoples R China
6.Univ Chinese Acad Sci, Beijing 100049, Peoples R China
7.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Shanghai 201203, Peoples R China
推荐引用方式
GB/T 7714		 Wang, Zhen,Fan, Fengying,Li, Zhihai,et al. Structural insights into the functional mechanism of the ubiquitin ligase E6AP[J]. NATURE COMMUNICATIONS,2024,15(1):13.
APA Wang, Zhen.,Fan, Fengying.,Li, Zhihai.,Ye, Fei.,Wang, Qingxia.,...&Yu, Xuekui.(2024).Structural insights into the functional mechanism of the ubiquitin ligase E6AP.NATURE COMMUNICATIONS,15(1),13.
MLA Wang, Zhen,et al."Structural insights into the functional mechanism of the ubiquitin ligase E6AP".NATURE COMMUNICATIONS 15.1(2024):13.

入库方式： OAI收割

来源：上海药物研究所

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