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

作　　者：Yuejia Huang Lin Lin Xing Liu Sheng Ye Phil Y. Yao Wenwen Wang Fengrui Yang Xinjiao Gao Junying Li Yin Zhang Jiancun Zhang Zhihong Yang Xu Liu Zhenye Yang Jianye Zang Maikun Teng Zhiyong Wang Ke Ruan Xia Ding Lin Li Don W. Cleveland Rongguang Zhang Xuebiao 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》2019年第7期562-578,共17页细胞研究（英文版）

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 

分 类 号：Q[生物学]