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Comprehensive structural model of the mechanochemical cycle of a mitotic motor highlights molecular adaptations in the kinesin family.

Goulet A, Major J, Jun Y, Gross SP, Rosenfeld SS, Moores CA
Proc Natl Acad Sci U S A 111 1837-42 (2014)
Related entries: 4ck6, 4ck7

Cited: 45 times
EuropePMC logo PMID: 24449904

Abstract

Kinesins are responsible for a wide variety of microtubule-based, ATP-dependent functions. Their motor domain drives these activities, but the molecular adaptations that specify these diverse and essential cellular activities are poorly understood. It has been assumed that the first identified kinesin--the transport motor kinesin-1--is the mechanistic paradigm for the entire superfamily, but accumulating evidence suggests otherwise. To address the deficits in our understanding of the molecular basis of functional divergence within the kinesin superfamily, we studied kinesin-5s, which are essential mitotic motors whose inhibition blocks cell division. Using cryo-electron microscopy and determination of structure at subnanometer resolution, we have visualized conformations of microtubule-bound human kinesin-5 motor domain at successive steps in its ATPase cycle. After ATP hydrolysis, nucleotide-dependent conformational changes in the active site are allosterically propagated into rotations of the motor domain and uncurling of the drug-binding loop L5. In addition, the mechanical neck-linker element that is crucial for motor stepping undergoes discrete, ordered displacements. We also observed large reorientations of the motor N terminus that indicate its importance for kinesin-5 function through control of neck-linker conformation. A kinesin-5 mutant lacking this N terminus is enzymatically active, and ATP-dependent neck-linker movement and motility are defective, although not ablated. All these aspects of kinesin-5 mechanochemistry are distinct from kinesin-1. Our findings directly demonstrate the regulatory role of the kinesin-5 N terminus in collaboration with the motor's structured neck-linker and highlight the multiple adaptations within kinesin motor domains that tune their mechanochemistries according to distinct functional requirements.

Articles - 4ck5 mentioned but not cited (2)

  1. Comprehensive structural model of the mechanochemical cycle of a mitotic motor highlights molecular adaptations in the kinesin family. Goulet A, Major J, Jun Y, Gross SP, Rosenfeld SS, Moores CA. Proc Natl Acad Sci U S A 111 1837-1842 (2014)
  2. Near-atomic cryo-EM structure of PRC1 bound to the microtubule. Kellogg EH, Howes S, Ti SC, Ramírez-Aportela E, Kapoor TM, Chacón P, Nogales E. Proc Natl Acad Sci U S A 113 9430-9439 (2016)


Reviews citing this publication (7)

  1. Cryo-EM: A Unique Tool for the Visualization of Macromolecular Complexity. Nogales E, Scheres SH. Mol Cell 58 677-689 (2015)
  2. The Kinesin-1 Chemomechanical Cycle: Stepping Toward a Consensus. Hancock WO. Biophys J 110 1216-1225 (2016)
  3. Review: Mechanochemistry of the kinesin-1 ATPase. Cross RA. Biopolymers 105 476-482 (2016)
  4. Visualizing microtubule structural transitions and interactions with associated proteins. Nogales E, Zhang R. Curr Opin Struct Biol 37 90-96 (2016)
  5. Emerging microtubule targets in glioma therapy. Katsetos CD, Reginato MJ, Baas PW, D'Agostino L, Legido A, Tuszyn Ski JA, Dráberová E, Dráber P. Semin Pediatr Neurol 22 49-72 (2015)
  6. Mechanisms by Which Kinesin-5 Motors Perform Their Multiple Intracellular Functions. Pandey H, Popov M, Goldstein-Levitin A, Gheber L. Int J Mol Sci 22 6420 (2021)
  7. New insights into the mechanochemical coupling mechanism of kinesin-microtubule complexes from their high-resolution structures. Benoit MPMH, Hunter B, Allingham JS, Sosa H. Biochem Soc Trans 51 1505-1520 (2023)

Articles citing this publication (36)

  1. High-resolution structures of kinesin on microtubules provide a basis for nucleotide-gated force-generation. Shang Z, Zhou K, Xu C, Csencsits R, Cochran JC, Sindelar CV. Elife 3 e04686 (2014)
  2. Conserved mechanisms of microtubule-stimulated ADP release, ATP binding, and force generation in transport kinesins. Atherton J, Farabella I, Yu IM, Rosenfeld SS, Houdusse A, Topf M, Moores CA. Elife 3 e03680 (2014)
  3. Kinesin processivity is gated by phosphate release. Milic B, Andreasson JO, Hancock WO, Block SM. Proc Natl Acad Sci U S A 111 14136-14140 (2014)
  4. Kinesin-5 is a microtubule polymerase. Chen Y, Hancock WO. Nat Commun 6 8160 (2015)
  5. TEMPy: a Python library for assessment of three-dimensional electron microscopy density fits. Farabella I, Vasishtan D, Joseph AP, Pandurangan AP, Sahota H, Topf M. J Appl Crystallogr 48 1314-1323 (2015)
  6. KIF15 promotes pancreatic cancer proliferation via the MEK-ERK signalling pathway. Wang J, Guo X, Xie C, Jiang J. Br J Cancer 117 245-255 (2017)
  7. Structural insight into TPX2-stimulated microtubule assembly. Zhang R, Roostalu J, Surrey T, Nogales E. Elife 6 e30959 (2017)
  8. Structural basis for power stroke vs. Brownian ratchet mechanisms of motor proteins. Hwang W, Karplus M. Proc Natl Acad Sci U S A 116 19777-19785 (2019)
  9. Kinesin-5 allosteric inhibitors uncouple the dynamics of nucleotide, microtubule, and neck-linker binding sites. Scarabelli G, Grant BJ. Biophys J 107 2204-2213 (2014)
  10. Pathogenic mutations in the kinesin-3 motor KIF1A diminish force generation and movement through allosteric mechanisms. Budaitis BG, Jariwala S, Rao L, Yue Y, Sept D, Verhey KJ, Gennerich A. J Cell Biol 220 e202004227 (2021)
  11. The structural kinetics of switch-1 and the neck linker explain the functions of kinesin-1 and Eg5. Muretta JM, Jun Y, Gross SP, Major J, Thomas DD, Rosenfeld SS. Proc Natl Acad Sci U S A 112 E6606-13 (2015)
  12. 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)
  13. The divergent mitotic kinesin MKLP2 exhibits atypical structure and mechanochemistry. Atherton J, Yu IM, Cook A, Muretta JM, Joseph A, Major J, Sourigues Y, Clause J, Topf M, Rosenfeld SS, Houdusse A, Moores CA. Elife 6 e27793 (2017)
  14. Kinesin motility is driven by subdomain dynamics. Hwang W, Lang MJ, Karplus M. Elife 6 e28948 (2017)
  15. The Kinesin-5 Chemomechanical Cycle Is Dominated by a Two-heads-bound State. Chen GY, Mickolajczyk KJ, Hancock WO. J Biol Chem 291 20283-20294 (2016)
  16. Eg5 Inhibitors Have Contrasting Effects on Microtubule Stability and Metaphase Spindle Integrity. Chen GY, Kang YJ, Gayek AS, Youyen W, Tüzel E, Ohi R, Hancock WO. ACS Chem Biol 12 1038-1046 (2017)
  17. Microtubule C-Terminal Tails Can Change Characteristics of Motor Force Production. Shojania Feizabadi M, Janakaloti Narayanareddy BR, Vadpey O, Jun Y, Chapman D, Rosenfeld S, Gross SP. Traffic 16 1075-1087 (2015)
  18. A posttranslational modification of the mitotic kinesin Eg5 that enhances its mechanochemical coupling and alters its mitotic function. Muretta JM, Reddy BJN, Scarabelli G, Thompson AF, Jariwala S, Major J, Venere M, Rich JN, Willard B, Thomas DD, Stumpff J, Grant BJ, Gross SP, Rosenfeld SS. Proc Natl Acad Sci U S A 115 E1779-E1788 (2018)
  19. Kinesin-2 KIF3AB exhibits novel ATPase characteristics. Albracht CD, Rank KC, Obrzut S, Rayment I, Gilbert SP. J Biol Chem 289 27836-27848 (2014)
  20. A kinesin-1 variant reveals motor-induced microtubule damage in cells. Budaitis BG, Badieyan S, Yue Y, Blasius TL, Reinemann DN, Lang MJ, Cianfrocco MA, Verhey KJ. Curr Biol 32 2416-2429.e6 (2022)
  21. Bioinformatics Analysis of KIF1A Expression and Gene Regulation Network in Ovarian Carcinoma. Lu X, Li G, Liu S, Wang H, Zhang Z, Chen B. Int J Gen Med 14 3707-3717 (2021)
  22. KIF15 contributes to cell proliferation and migration in breast cancer. Gao X, Zhu L, Lu X, Wang Y, Li R, Jiang G. Hum Cell 33 1218-1228 (2020)
  23. 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)
  24. Investigating role of conformational changes of microtubule in regulating its binding affinity to kinesin by all-atom molecular dynamics simulation. Shi XX, Fu YB, Guo SK, Wang PY, Chen H, Xie P. Proteins 86 1127-1139 (2018)
  25. The yeast kinesin-5 Cin8 interacts with the microtubule in a noncanonical manner. Bell KM, Cha HK, Sindelar CV, Cochran JC. J Biol Chem 292 14680-14694 (2017)
  26. KIF5A Promotes Bladder Cancer Proliferation In Vitro and In Vivo. Tian DW, Wu ZL, Jiang LM, Gao J, Wu CL, Hu HL. Dis Markers 2019 4824902 (2019)
  27. Cryo-EM structure of a microtubule-bound parasite kinesin motor and implications for its mechanism and inhibition. Cook AD, Roberts AJ, Atherton J, Tewari R, Topf M, Moores CA. J Biol Chem 297 101063 (2021)
  28. Downregulation of KIF15 inhibits the tumorigenesis of non-small-cell lung cancer via inactivating Raf/MEK/ERK signaling. Luo Y, Zhang B, Xu L, Li M, Wu J, Zhou Y, Li Y. Histol Histopathol 37 269-285 (2022)
  29. KIF11 As a Potential Pan-Cancer Immunological Biomarker Encompassing the Disease Staging, Prognoses, Tumor Microenvironment, and Therapeutic Responses. Guo X, Zhou L, Wu Y, Li J. Oxid Med Cell Longev 2022 2764940 (2022)
  30. snRPN controls the ability of neurons to regenerate axons. Mertsch S, Schlicht K, Melkonyan H, Schlatt S, Thanos S. Restor Neurol Neurosci 36 31-43 (2018)
  31. Mitotic kinesins in action: diffusive searching, directional switching, and ensemble coordination. Gicking AM, Qiu W, Hancock WO. Mol Biol Cell 29 1153-1156 (2018)
  32. Intracellular functions and motile properties of bi-directional kinesin-5 Cin8 are regulated by neck linker docking. Goldstein-Levitin A, Pandey H, Allhuzaeel K, Kass I, Gheber L. Elife 10 e71036 (2021)
  33. Nucleotide-free structures of KIF20A illuminate atypical mechanochemistry in this kinesin-6. Ranaivoson FM, Crozet V, Benoit MPMH, Abdalla Mohammed Khalid A, Kikuti C, Sirkia H, El Marjou A, Miserey-Lenkei S, Asenjo AB, Sosa H, Schmidt CF, Rosenfeld SS, Houdusse A. Open Biol 13 230122 (2023)
  34. The effects of osmolytes on in vitro kinesin-microtubule motility assays. VanDelinder V, Sickafoose I, Imam ZI, Ko R, Bachand GD. RSC Adv 10 42810-42815 (2020)
  35. KIF5A upregulation in hepatocellular carcinoma: A novel prognostic biomarker associated with unique tumor microenvironment status. Liu Q, Liu YY, Chen XM, Tao BY, Chen K, Li WM, Xu CT, Shi Y, Li H, Liu HR. Front Oncol 12 1071722 (2022)
  36. Noncanonical interaction with microtubules via the N-terminal nonmotor domain is critical for the functions of a bidirectional kinesin. Singh SK, Siegler N, Pandey H, Yanir N, Popov M, Goldstein-Levitin A, Sadan M, Debs G, Zarivach R, Frank GA, Kass I, Sindelar CV, Zalk R, Gheber L. Sci Adv 10 eadi1367 (2024)


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