6JKM

Crystal structure of BubR1 kinase domain

Summary for 6JKM

• Entry DOI: 10.2210/pdb6jkm/pdb
• Descriptor: Mitotic checkpoint control protein kinase BUB1, ADENOSINE-5'-DIPHOSPHATE, MAGNESIUM ION, ... (5 entities in total)
• Functional Keywords: kinase, mitotic checkpoint, transferase
• Biological source: Drosophila melanogaster (Fruit fly)
• Total number of polymer chains: 1
• Total formula weight: 40171.76

Authors

Lin, L.,Ye, S.,Huang, Y.,Liu, X.,Zhang, R.,Yao, X. (deposition date: 2019-03-01, release date: 2019-06-26, Last modification date: 2023-11-22)

Primary citation

Huang, Y.,Lin, L.,Liu, X.,Ye, S.,Yao, P.Y.,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, D.W.,Zhang, R.,Yao, X.
BubR1 phosphorylates CENP-E as a switch enabling the transition from lateral association to end-on capture of spindle microtubules.
Cell Res., 29:562-578, 2019

PubMed Abstract: 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.

PubMed: 31201382
DOI: 10.1038/s41422-019-0178-z

Experimental method

X-RAY DIFFRACTION (1.95 Å)