BubR1 phosphorylates CENP-E as a switch enabling the transition from lateral association to end-on capture of spindle microtubules

查看全文 作　　者：Yuejia [1]Huang;Lin [2,3]Lin;Xing [1,4]Liu;Sheng [2]Ye;Phil Y. [4]Yao;Wenwen [1,4]Wang;Fengrui [1,4]Yang;Xinjiao [1]Gao;Junying [1]Li;Yin [1,5]Zhang;Jiancun [1]Zhang;Zhihong [1]Yang;Xu [1,4]Liu;Zhenye [1]Yang;Jianye [1]Zang;Maikun [1]Teng;Zhiyong [1]Wang;Ke [1]Ruan;Xia [4,5]Ding;Lin [1,3]Li;Don W. [6]Cleveland;Rongguang [2,3]Zhang;Xuebiao [1]Yao

机构地区：[1]Anhui Key Laboratory for Chemical Biology & MOE Key Laboratory for Cellular Dynamics, CAS Center for Excellence in Molecular Cell Science, School of Life Sciences, Hefei National Laboratory for Physical Sciences at the Mciroscale, University of Science & Technology of China, Hefei, Anhui 230026, China;[2]National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China;[3]National Center for Protein Science Shanghai, Institute for Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China;[4]Department of Physiology, Morehouse School of Medicine, Atlanta, GA 30310, USA;[5]School of Basic Medical Sciences, Beijing University of Chinese Medicine, Beijing 100029, China;[6]Ludwig Institute for Cancer Research, University of California, La Jolla, CA 92093, USA

出　　处：《Cell Research》索引2019年第29卷第7期,共17页

基　　金：We are grateful to Prof. Yunyu Shi for support;to Dr Hongtao Yu for reagents and Drs Guo-Qiang Chen for input. We thank all the members of our laboratories for discussion and Qiaoqiao Zhang for help on several BubRI mutant constructs;initiated by the chemical biology grant PGX-2 from the ProteoGenomics Research Laboratory;supported in part by the National Key Research and Development Program of China (2017YFA0503600, 2017YFA0504901, 2016YFA0100500);National Natural Science Foundation of China (31320103904, 31430054, 91313303, 31621002, 31301120, 91854203, 91853115, 91753000, 31671405, 31470792, 31601097, 21672201, 31600607, and B1661138004);Strategic Priority Research Program' of the Chinese Academy of Sciences (XDB19000000 and XDB08030102);MOE Innovative team (IRT_17R102). 摘　　要：Error-free mitosis depends on accurate chromosome attachment to spindle microtubules, powered congression of those chromosomes, their segregation in anaphase, and assembly of a spindle midzone at mitotic exit. The centromere-associated kinesin motor CENP-E, whose binding partner is BubR1, has been implicated in congression of misaligned chromosomes and the transition from lateral kinetochore-microtubule association to end-on capture. Although previously proposed to be a pseudokinase, here we report the structure of the kinase domain of Drosophila melanogaster BubR1, revealing its folding into a conformation predicted to be catalytically active. BubR1 is shown to be a bona fide kinase whose phosphorylation of CENP-E switches it from a laterally attached microtubule motor to a plus-end microtubule tip tracker. Computational modeling is used to identify bubristatin as a selective BubR1 kinase antagonist that targets the αN1 helix of N-terminal extension and αC helix of the BubR1 kinase domain. Inhibition of CENP-E phosphorylation is shown to prevent proper microtubule capture at kinetochores and, surprisingly, proper assembly of the central spindle at mitotic exit. Thus, BubR1-mediated CENP-E phosphorylation produces a temporal switch that enables transition from lateral to end-on microtubule capture and organization of microtubules into stable midzone arrays. 关键词：MITOSIS BUBR1 arrays

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BubR1 phosphorylates CENP-E as a switch enabling the transition from lateral association to end-on capture of spindle microtubules

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