The kinesin-5 tail domain directly modulates the mechanochemical cycle of the motor domain for anti-parallel microtubule sliding

Tatyana Bodrug, Elizabeth Wilson-Kubalek, Stanley Nithianantham, Alex F. Thompson, April Alfieri, Ignas Gaska, Jennifer Major, Garret Debs, Sayaka Inagaki, Pedro Gutierrez, Larisa Gheber, Richard McKenney, Charles Sindelar, Ronald Milligan, Jason Stumpff, Steven Rosenfeld, Scott T. Forth, Jawdat Al-Bassam

Research output: Contribution to journalArticle

Abstract

Kinesin-5 motors organize mitotic spindles by sliding apart microtubules. They are homotetramers with dimeric motor and tail domains at both ends of a bipolar minifilament. Here, we describe a regulatory mechanism involving direct binding between tail and motor domains and its fundamental role in microtubule sliding. Kinesin-5 tails decrease microtubule-stimulated ATP-hydrolysis by specifically engaging motor domains in the nucleotide-free or ADP states. Cryo-EM reveals that tail binding stabilizes an open motor domain ATP-active site. Full-length motors undergo slow motility and cluster together along microtubules, while tail-deleted motors exhibit rapid motility without clustering. The tail is critical for motors to zipper together two microtubules by generating substantial sliding forces. The tail is essential for mitotic spindle localization, which becomes severely reduced in tail-deleted motors. Our studies suggest a revised microtubule-sliding model, in which kinesin-5 tails stabilize motor domains microtubule-bound states by slowing ATP-binding resulting in high-force production at both homotetramer ends.

Original languageEnglish (US)
Article numbere51131
JournaleLife
Volume9
DOIs
StatePublished - Jan 2020

ASJC Scopus subject areas

  • Neuroscience(all)
  • Immunology and Microbiology(all)
  • Biochemistry, Genetics and Molecular Biology(all)

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    Bodrug, T., Wilson-Kubalek, E., Nithianantham, S., Thompson, A. F., Alfieri, A., Gaska, I., Major, J., Debs, G., Inagaki, S., Gutierrez, P., Gheber, L., McKenney, R., Sindelar, C., Milligan, R., Stumpff, J., Rosenfeld, S., Forth, S. T., & Al-Bassam, J. (2020). The kinesin-5 tail domain directly modulates the mechanochemical cycle of the motor domain for anti-parallel microtubule sliding. eLife, 9, [e51131]. https://doi.org/10.7554/eLife.51131