8owi
From Proteopedia
Crystal structure of the corona-targeting domain of CENP-E
Structural highlights
FunctionCENPE_HUMAN Essential for the maintenance of chromosomal stability through efficient stabilization of microtubule capture at kinetochores. Plays a key role in the movement of chromosomes toward the metaphase plate during mitosis. Is a slow plus end-directed motor whose activity is essential for metaphase chromosome alignment. Couples chromosome position to microtubule depolymerizing activity. The highly processive microtubule-dependent motor activity of CENPE serves to power chromosome congression and provides a flexible, motile tether linking kinetochores to dynamic spindle microtubules. Necessary for the mitotic checkpoint signal at individual kinetochores to prevent aneuploidy due to single chromosome loss. Required for the efficient recruitment of BUBR1, MAD1 and MAD2 to attached and newly unattached kinetochores. Stimulates mammalian BUBR1 kinase activity. Accumulates just before mitosis at the G2 phase of the cell cycle.[1] [2] Publication Abstract from PubMedThe outer corona plays an essential role at the onset of mitosis by expanding to maximize microtubule attachment to kinetochores.(1)(,)(2) The low-density structure of the corona forms through the expansion of unattached kinetochores. It comprises the RZZ complex, the dynein adaptor Spindly, the plus-end directed microtubule motor centromere protein E (CENP-E), and the Mad1/Mad2 spindle-assembly checkpoint proteins.(3)(,)(4)(,)(5)(,)(6)(,)(7)(,)(8)(,)(9)(,)(10) CENP-E specifically associates with unattached kinetochores to facilitate chromosome congression,(11)(,)(12)(,)(13)(,)(14)(,)(15)(,)(16) interacting with BubR1 at the kinetochore through its C-terminal region (2091-2358).(17)(,)(18)(,)(19)(,)(20)(,)(21) We recently showed that CENP-E recruitment to BubR1 at the kinetochores is both rapid and essential for correct chromosome alignment. However, CENP-E is also recruited to the outer corona by a second, slower pathway that is currently undefined.(19) Here, we show that BubR1-independent localization of CENP-E is mediated by a conserved loop that is essential for outer-corona targeting. We provide a structural model of the entire CENP-E kinetochore-targeting domain combining X-ray crystallography and Alphafold2. We reveal that maximal recruitment of CENP-E to unattached kinetochores critically depends on BubR1 and the outer corona, including dynein. Ectopic expression of the CENP-E C-terminal domain recruits the RZZ complex, Mad1, and Spindly, and prevents kinetochore biorientation in cells. We propose that BubR1-recruited CENP-E, in addition to its essential role in chromosome alignment to the metaphase plate, contributes to the recruitment of outer corona proteins through interactions with the CENP-E corona-targeting domain to facilitate the rapid capture of microtubules for efficient chromosome alignment and mitotic progression. A conserved CENP-E region mediates BubR1-independent recruitment to the outer corona at mitotic onset.,Weber J, Legal T, Lezcano AP, Gluszek-Kustusz A, Paterson C, Eibes S, Barisic M, Davies OR, Welburn JPI Curr Biol. 2024 Mar 11;34(5):1133-1141.e4. doi: 10.1016/j.cub.2024.01.042. Epub , 2024 Feb 13. PMID:38354735[3] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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