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Publication Abstract from PubMed

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 alphaN1 helix of N-terminal extension and alphaC 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.

BubR1 phosphorylates CENP-E as a switch enabling the transition from lateral association to end-on capture of spindle microtubules.,Huang Y, Lin L, Liu X, Ye S, Yao PY, Wang W, Yang F, Gao X, Li J, Zhang Y, Zhang J, Yang Z, Liu X, Yang Z, Zang J, Teng M, Wang Z, Ruan K, Ding X, Li L, Cleveland DW, Zhang R, Yao X Cell Res. 2019 Jun 14. pii: 10.1038/s41422-019-0178-z. doi:, 10.1038/s41422-019-0178-z. PMID:31201382^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.