Volume 29, No 7, Jul 2019
ISSN: 1001-0602
EISSN: 1748-7838 2018
impact factor 17.848*
(Clarivate Analytics, 2019)
Volume 29 Issue 7, July 2019: 562-578
ORIGINAL ARTICLES
BubR1 phosphorylates CENP-E as a switch enabling the transition from lateral association to end-on capture of spindle microtubules
Yuejia Huang1, Lin Lin 2,3, Xing Liu 1,4, Sheng Ye 2, Phil Y. Yao4, Wenwen Wang 1,4, Fengrui Yang 1,4, Xinjiao Gao1, Junying Li1,Yin Zhang 1,5, Jiancun Zhang1, Zhihong Yang1, Xu Liu 1,4, Zhenye Yang1, Jianye Zang1, Maikun Teng1, Zhiyong Wang1, Ke Ruan1,Xia Ding 4,5, Lin Li 1,3, Don W. Cleveland 6, Rongguang Zhang 2,3 and Xuebiao Yao1
1Anhui 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; 2National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China; 3National Center for Protein Science Shanghai, Institute for Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China; 4Department of Physiology, Morehouse School of Medicine, Atlanta, GA 30310, USA; 5School of Basic Medical Sciences, Beijing University of Chinese Medicine, Beijing 100029, China and 6Ludwig Institute for Cancer Research, University of California, La Jolla, CA 92093, USA
Correspondence: Rongguang Zhang (rzhang@ibp.ac.cn) or Xuebiao Yao (yaoxb@ustc.edu.cn)These authors contributed equally: Yuejia Huang, Lin Lin, Xing Liu, Sheng Ye
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.
https://doi.org/10.1038/s41422-019-0178-z
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