| Structural highlights
Function
[KI18A_HUMAN] Microtubule-depolymerizing kinesin which plays a role in chromosome congression by reducing the amplitude of preanaphase oscillations and slowing poleward movement during anaphase, thus suppressing chromosome movements. May stabilize the CENPE-BUB1B complex at the kinetochores during early mitosis and maintains CENPE levels at kinetochores during chromosome congression.[1] [2] [3] [4] [TBB_PIG] Tubulin is the major constituent of microtubules. It binds two moles of GTP, one at an exchangeable site on the beta chain and one at a non-exchangeable site on the alpha chain. [F2Z4C1_BOVIN] Tubulin is the major constituent of microtubules. It binds two moles of GTP, one at an exchangeable site on the beta chain and one at a non-exchangeable site on the alpha chain.[RuleBase:RU000352][SAAS:SAAS00824325]
Publication Abstract from PubMed
Kinesin motors play diverse roles in mitosis and are targets for antimitotic drugs. The clinical significance of these motors emphasizes the importance of understanding the molecular basis of their function. Equally important, investigations into the modes of inhibition of these motors provide crucial information about their molecular mechanisms. Kif18A regulates spindle microtubules through its dual functionality, with microtubule-based stepping and regulation of microtubule dynamics. We investigated the mechanism of Kif18A and its inhibition by the small molecule BTB-1. The Kif18A motor domain drives ATP-dependent plus-end microtubule gliding, and undergoes conformational changes consistent with canonical mechanisms of plus-end-directed motility. The Kif18A motor domain also depolymerizes microtubule plus and minus ends. BTB-1 inhibits both of these microtubule-based Kif18A activities. A reconstruction of BTB-1-bound, microtubule-bound Kif18A, in combination with computational modeling, identified an allosteric BTB-1-binding site near loop5, where it blocks the ATP-dependent conformational changes that we characterized. Strikingly, BTB-1 binding is close to that of well-characterized Kif11 inhibitors that block tight microtubule binding, whereas BTB-1 traps Kif18A on the microtubule. Our work highlights a general mechanism of kinesin inhibition in which small-molecule binding near loop5 prevents a range of conformational changes, blocking motor function.
Structural basis of human kinesin-8 function and inhibition.,Locke J, Joseph AP, Pena A, Mockel MM, Mayer TU, Topf M, Moores CA Proc Natl Acad Sci U S A. 2017 Oct 23. pii: 201712169. doi:, 10.1073/pnas.1712169114. PMID:29078367[5]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Mayr MI, Hummer S, Bormann J, Gruner T, Adio S, Woehlke G, Mayer TU. The human kinesin Kif18A is a motile microtubule depolymerase essential for chromosome congression. Curr Biol. 2007 Mar 20;17(6):488-98. Epub 2007 Mar 8. PMID:17346968 doi:10.1016/j.cub.2007.02.036
- ↑ Stumpff J, von Dassow G, Wagenbach M, Asbury C, Wordeman L. The kinesin-8 motor Kif18A suppresses kinetochore movements to control mitotic chromosome alignment. Dev Cell. 2008 Feb;14(2):252-62. doi: 10.1016/j.devcel.2007.11.014. PMID:18267093 doi:10.1016/j.devcel.2007.11.014
- ↑ Gardner MK, Odde DJ, Bloom K. Kinesin-8 molecular motors: putting the brakes on chromosome oscillations. Trends Cell Biol. 2008 Jul;18(7):307-10. doi: 10.1016/j.tcb.2008.05.003. Epub, 2008 May 29. PMID:18513970 doi:10.1016/j.tcb.2008.05.003
- ↑ Huang Y, Yao Y, Xu HZ, Wang ZG, Lu L, Dai W. Defects in chromosome congression and mitotic progression in KIF18A-deficient cells are partly mediated through impaired functions of CENP-E. Cell Cycle. 2009 Aug 15;8(16):2643-9. Epub 2009 Aug 29. PMID:19625775
- ↑ Locke J, Joseph AP, Pena A, Mockel MM, Mayer TU, Topf M, Moores CA. Structural basis of human kinesin-8 function and inhibition. Proc Natl Acad Sci U S A. 2017 Oct 23. pii: 201712169. doi:, 10.1073/pnas.1712169114. PMID:29078367 doi:http://dx.doi.org/10.1073/pnas.1712169114
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