气候变化领域集成服务门户(CCPortal): Double inhibition and activation mechanisms of Ephexin family RhoGEFs

CCPortal

DOI	10.1073/pnas.2024465118
	Double inhibition and activation mechanisms of Ephexin family RhoGEFs
	Zhang M.; Lin L.; Wang C.; Zhu J.
发表日期	2021
ISSN	00278424
卷号	118 期号:8
英文摘要	Ephexin family guanine nucleotide exchange factors (GEFs) transfer signals from Eph tyrosine kinase receptors to Rho GTPases, which play critical roles in diverse cellular processes, as well as cancers and brain disorders. Here, we elucidate the molecular basis underlying inhibition and activation of Ephexin family RhoGEFs. The crystal structures of partially and fully autoinhibited Ephexin4 reveal that the complete autoinhibition requires both N- and C-terminal inhibitory modes, which can operate independently to impede Ras homolog family member G (RhoG) access. This double inhibition mechanism is commonly employed by other Ephexins and SGEF, another RhoGEF for RhoG. Structural, enzymatic, and cell biological analyses show that phosphorylation of a conserved tyrosine residue in its N-terminal inhibitory domain and association of PDZ proteins with its C-terminal PDZ-binding motif may respectively relieve the two autoinhibitory modes in Ephexin4. Our study provides a mechanistic framework for understanding the fine-tuning regulation of Ephexin4 GEF activity and offers possible clues for its pathological dysfunction. © 2021 National Academy of Sciences. All rights reserved.
英文关键词	Autoinhibition; Crystal structure; Ephexin; RhoGEF
语种	英语
scopus关键词	ephexin; ephexin 4; PDZ protein; Rho guanine nucleotide exchange factor; SGEF protein; tyrosine; unclassified drug; allosterism; amino terminal sequence; Article; autoinhibition; C terminal inhibition; carboxy terminal sequence; cell migration; controlled study; crystal structure; enzyme active site; HeLa cell line; mutation; N terminal inhibition; PDZ domain; priority journal; protein phosphorylation
来源期刊	Proceedings of the National Academy of Sciences of the United States of America
文献类型	期刊论文
条目标识符	http://gcip.llas.ac.cn/handle/2XKMVOVA/180581
作者单位	Ministry of Education Key Laboratory for Membraneless Organelles and Cellular Dynamics, Hefei National Laboratory for Physical Sciences at the Microscale, School of Life Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, 230027, China; Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders, Ministry of Education, Shanghai Jiao Tong University, Shanghai, 200240, China
推荐引用方式 GB/T 7714	Zhang M.,Lin L.,Wang C.,et al. Double inhibition and activation mechanisms of Ephexin family RhoGEFs[J],2021,118(8).
APA	Zhang M.,Lin L.,Wang C.,&Zhu J..(2021).Double inhibition and activation mechanisms of Ephexin family RhoGEFs.Proceedings of the National Academy of Sciences of the United States of America,118(8).
MLA	Zhang M.,et al."Double inhibition and activation mechanisms of Ephexin family RhoGEFs".Proceedings of the National Academy of Sciences of the United States of America 118.8(2021).