Journal
CELL RESEARCH
Volume 29, Issue 7, Pages 562-578Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/s41422-019-0178-z
Keywords
-
Categories
Funding
- ProteoGenomics Research Laboratory
- 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, B1661138004]
- 'Strategic Priority Research Program' of the Chinese Academy of Sciences [XDB19000000, XDB08030102]
- MOE Innovative team [IRT_17R102]
Ask authors/readers for more resources
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 alpha N1 helix of N-terminal extension and alpha C 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.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available