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Near-atomic cryo-EM structure of yeast kinesin-5-microtubule complex reveals a distinct binding footprint

Ottilie von Loeffelholz, Alejandro Peña, Douglas Robert Drummond, Robert Cross, Carolyn Ann Moores
doi: https://doi.org/10.1101/302455
Ottilie von Loeffelholz
1Institute of Structural and Molecular Biology, Birkbeck College, London WC1E 7HX, U.K.
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Alejandro Peña
1Institute of Structural and Molecular Biology, Birkbeck College, London WC1E 7HX, U.K.
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Douglas Robert Drummond
2Division of Biomedical Cell Biology, Warwick Medical School, Coventry, CV4 7AL, U.K.
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Robert Cross
2Division of Biomedical Cell Biology, Warwick Medical School, Coventry, CV4 7AL, U.K.
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Carolyn Ann Moores
1Institute of Structural and Molecular Biology, Birkbeck College, London WC1E 7HX, U.K.
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  • For correspondence: c.moores@mail.cryst.bbk.ac.uk
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Summary

Kinesin-5s are essential members of the superfamily of microtubule-dependent motors that undertake conserved roles in cell division. We investigated coevolution of the motor-microtubule interface using cryo-electron microscopy to determine the near-atomic structure of the motor domain of Cut7, the fission yeast kinesin-5, bound to fission yeast microtubules. AMPPNP-bound Cut7 adopts a kinesin-conserved ATP-like conformation, with a closed nucleotide binding pocket and docked neck linker that supports cover neck bundle formation. Compared to mammalian tubulin microtubules, Cut7’s footprint on S. pombe microtubule surface is subtly different because of their different architecture. However, the core motor-microtubule interaction that stimulates motor ATPase is tightly conserved, reflected in similar Cut7 ATPase activities on each microtubule type. The S. pombe microtubules were bound by the drug epothilone, which is visible in the taxane binding pocket. Stabilization of S. pombe microtubules is mediated by drug binding at this conserved site despite their noncanonical architecture and mechanochemistry.

Highlights

  • S. pombe Cut7 has a distinct binding footprint on S. pombe microtubules

  • The core interface driving microtubule activation of motor ATPase is conserved

  • The neck linker is docked in AMPPNP-bound Cut7 and the cover neck bundle is formed

  • Epothilone binds at the taxane binding site to stabilize S. pombe microtubules

eTOC text To investigate coevolution of the motor-microtubule interface, we used cryo-electron microscopy to determine the near-atomic structure of the motor domain of Cut7, the fission yeast kinesin-5, bound to microtubules polymerized from natively purified fission yeast tubulin and stabilised by the drug epothilone.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
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Posted April 16, 2018.
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Near-atomic cryo-EM structure of yeast kinesin-5-microtubule complex reveals a distinct binding footprint
Ottilie von Loeffelholz, Alejandro Peña, Douglas Robert Drummond, Robert Cross, Carolyn Ann Moores
bioRxiv 302455; doi: https://doi.org/10.1101/302455
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Near-atomic cryo-EM structure of yeast kinesin-5-microtubule complex reveals a distinct binding footprint
Ottilie von Loeffelholz, Alejandro Peña, Douglas Robert Drummond, Robert Cross, Carolyn Ann Moores
bioRxiv 302455; doi: https://doi.org/10.1101/302455

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