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Structural basis of human kinesin-8 function and inhibition.

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Locke J, Joseph AP, Peña A, Möckel MM, Mayer TU, Topf M, Moores CA
OpenAccess logo Proc Natl Acad Sci U S A 114 E9539-E9548 (2017)
Related entries: 5oam, 5ocu

Cited: 29 times
EuropePMC logo PMID: 29078367

Abstract

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.

Articles - 5ogc mentioned but not cited (1)

  1. Structural basis of human kinesin-8 function and inhibition. Locke J, Joseph AP, Peña A, Möckel MM, Mayer TU, Topf M, Moores CA. Proc Natl Acad Sci U S A 114 E9539-E9548 (2017)


Reviews citing this publication (5)

  1. The Mechanism of Tubulin Assembly into Microtubules: Insights from Structural Studies. Knossow M, Campanacci V, Khodja LA, Gigant B. iScience 23 101511 (2020)
  2. These motors were made for walking. Hunter B, Allingham JS. Protein Sci 29 1707-1723 (2020)
  3. Synthetic biology approaches to dissecting linear motor protein function: towards the design and synthesis of artificial autonomous protein walkers. Linke H, Höcker B, Furuta K, Forde NR, Curmi PMG. Biophys Rev 12 1041-1054 (2020)
  4. Emerging Insights into the Function of Kinesin-8 Proteins in Microtubule Length Regulation. Shrestha S, Hazelbaker M, Yount AL, Walczak CE. Biomolecules 9 E1 (2018)
  5. Automated Modeling and Validation of Protein Complexes in Cryo-EM Maps. Cragnolini T, Sweeney A, Topf M. Methods Mol Biol 2215 189-223 (2021)

Articles citing this publication (23)

  1. Microtubule end tethering of a processive kinesin-8 motor Kif18b is required for spindle positioning. McHugh T, Gluszek AA, Welburn JPI. J Cell Biol 217 2403-2416 (2018)
  2. TEMPy2: a Python library with improved 3D electron microscopy density-fitting and validation workflows. Cragnolini T, Sahota H, Joseph AP, Sweeney A, Malhotra S, Vasishtan D, Topf M. Acta Crystallogr D Struct Biol 77 41-47 (2021)
  3. Comparing Cryo-EM Reconstructions and Validating Atomic Model Fit Using Difference Maps. Joseph AP, Lagerstedt I, Jakobi A, Burnley T, Patwardhan A, Topf M, Winn M. J Chem Inf Model 60 2552-2560 (2020)
  4. Plasmodium kinesin-8X associates with mitotic spindles and is essential for oocyst development during parasite proliferation and transmission. Zeeshan M, Shilliday F, Liu T, Abel S, Mourier T, Ferguson DJP, Rea E, Stanway RR, Roques M, Williams D, Daniel E, Brady D, Roberts AJ, Holder AA, Pain A, Le Roch KG, Moores CA, Tewari R. PLoS Pathog 15 e1008048 (2019)
  5. Structure of Microtubule-Trapped Human Kinesin-5 and Its Mechanism of Inhibition Revealed Using Cryoelectron Microscopy. Peña A, Sweeney A, Cook AD, Locke J, Topf M, Moores CA. Structure 28 450-457.e5 (2020)
  6. Drosophila kinesin-8 stabilizes the kinetochore-microtubule interaction. Edzuka T, Goshima G. J Cell Biol 218 474-488 (2019)
  7. Interplay between the Kinesin and Tubulin Mechanochemical Cycles Underlies Microtubule Tip Tracking by the Non-motile Ciliary Kinesin Kif7. Jiang S, Mani N, Wilson-Kubalek EM, Ku PI, Milligan RA, Subramanian R. Dev Cell 49 711-730.e8 (2019)
  8. Cryo-EM structure of the Ustilago maydis kinesin-5 motor domain bound to microtubules. von Loeffelholz O, Moores CA. J Struct Biol 207 312-316 (2019)
  9. Kinesin-8-specific loop-2 controls the dual activities of the motor domain according to tubulin protofilament shape. Hunter B, Benoit MPMH, Asenjo AB, Doubleday C, Trofimova D, Frazer C, Shoukat I, Sosa H, Allingham JS. Nat Commun 13 4198 (2022)
  10. Three-Dimensional Optical Tweezers Tracking Resolves Random Sideward Steps of the Kinesin-8 Kip3. Bugiel M, Schäffer E. Biophys J 115 1993-2002 (2018)
  11. Identification of biomarkers in colon cancer based on bioinformatic analysis. Zhu Y, Sun L, Yu J, Xiang Y, Shen M, Wasan HS, Ruan S, Qiu S. Transl Cancer Res 9 4879-4895 (2020)
  12. Kinesin-8 and Dis1/TOG collaborate to limit spindle elongation from prophase to anaphase A for proper chromosome segregation in fission yeast. Pinder C, Matsuo Y, Maurer SP, Toda T. J Cell Sci 132 jcs232306 (2019)
  13. Small molecule allosteric uncoupling of microtubule depolymerase activity from motility in human Kinesin-5 during mitotic spindle assembly. Kim CD, Kim ED, Liu L, Buckley RS, Parameswaran S, Kim S, Wojcik EJ. Sci Rep 9 19900 (2019)
  14. Discrete regions of the kinesin-8 Kip3 tail differentially mediate astral microtubule stability and spindle disassembly. Dave S, Anderson SJ, Sinha Roy P, Nsamba ET, Bunning AR, Fukuda Y, Gupta ML. Mol Biol Cell 29 1866-1877 (2018)
  15. Selective and ATP-competitive kinesin KIF18A inhibitor suppresses the replication of influenza A virus. Cho YB, Hong S, Kang KW, Kang JH, Lee SM, Seo YJ. J Cell Mol Med 24 5463-5475 (2020)
  16. Bioenergetics of the Dictyostelium Kinesin-8 Motor Isoform. Koonce MP, Tikhonenko I. Biomolecules 10 E563 (2020)
  17. Integrated bioinformatics analysis to identify key genes related to the prognosis of esophageal squamous cell carcinoma. Yang Y, Sun Z, Shi Y, Sun J, Zhang X. Transl Cancer Res 10 1679-1691 (2021)
  18. Mechanochemical tuning of a kinesin motor essential for malaria parasite transmission. Liu T, Shilliday F, Cook AD, Zeeshan M, Brady D, Tewari R, Sutherland CJ, Roberts AJ, Moores CA. Nat Commun 13 6988 (2022)
  19. Structural snapshots of the kinesin-2 OSM-3 along its nucleotide cycle: implications for the ATP hydrolysis mechanism. Varela PF, Chenon M, Velours C, Verhey KJ, Ménétrey J, Gigant B. FEBS Open Bio 11 564-577 (2021)
  20. Weakened APC/C activity at mitotic exit drives cancer vulnerability to KIF18A inhibition. Gliech CR, Yeow ZY, Tapias-Gomez D, Yang Y, Yang Y, Huang Z, Tijhuis AE, Spierings DC, Foijer F, Chung G, Tamayo N, Bahrami-Nejad Z, Collins P, Nguyen TT, Plata Stapper A, Hughes PE, Payton M, Holland AJ. EMBO J 43 666-694 (2024)
  21. ChemEM: Flexible Docking of Small Molecules in Cryo-EM Structures. Sweeney A, Mulvaney T, Maiorca M, Topf M. J Med Chem 67 199-212 (2024)
  22. Importin α/β promote Kif18B microtubule association and enhance microtubule destabilization activity. Shrestha S, Ems-McClung SC, Hazelbaker MA, Yount AL, Shaw SL, Walczak CE. Mol Biol Cell 34 ar30 (2023)
  23. Microtubule depolymerization contributes to spontaneous neurotransmitter release in vitro. Velasco CD, Santarella-Mellwig R, Schorb M, Gao L, Thorn-Seshold O, Llobet A. Commun Biol 6 488 (2023)


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