1. Structural Biology and Molecular Biophysics

The mechanism of kinesin inhibition by kinesin binding protein

  1. Joseph Atherton  Is a corresponding author
  2. Jessica JA Hummel
  3. Natacha Olieric
  4. Julia Locke
  5. Alejandro Peña
  6. Steven S Rosenfeld
  7. Michel O Steinmetz
  8. Casper C Hoogenraad
  9. Carolyn A Moores
  1. King's College London, United Kingdom
  2. Utrecht University, Netherlands
  3. Paul Scherrer Institute, Switzerland
  4. The Francis Crick Institute, United Kingdom
  5. Pharmidex 19 Pharmaceuticals, United Kingdom
  6. Mayo Clinic, United States
  7. Institute of Structural and Molecular Biology, Birkbeck College, United Kingdom
https://doi.org/10.7554/eLife.61481
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Cite this article
  1. Joseph Atherton
  2. Jessica JA Hummel
  3. Natacha Olieric
  4. Julia Locke
  5. Alejandro Peña
  6. Steven S Rosenfeld
  7. Michel O Steinmetz
  8. Casper C Hoogenraad
  9. Carolyn A Moores
(2020)
The mechanism of kinesin inhibition by kinesin binding protein
eLife 9:e61481.
https://doi.org/10.7554/eLife.61481
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Abstract

Subcellular compartmentalisation is necessary for eukaryotic cell function. Spatial and temporal regulation of kinesin activity is essential for building these local environments via control of intracellular cargo distribution. Kinesin binding protein (KBP) interacts with a subset of kinesins via their motor domains, inhibits their microtubule (MT) attachment and blocks their cellular function. However, its mechanisms of inhibition and selectivity have been unclear. Here we use cryo-electron microscopy to reveal the structure of KBP and of a KBP-kinesin motor domain complex. KBP is a TPR-containing, right-handed α-solenoid that sequesters the kinesin motor domain’s tubulin-binding surface, structurally distorting the motor domain and sterically blocking its MT attachment. KBP uses its α-solenoid concave face and edge loops to bind the kinesin motor domain, and selected structure-guided mutations disrupt KBP inhibition of kinesin transport in cells. The KBP-interacting motor domain surface contains motifs exclusively conserved in KBP-interacting kinesins, suggesting a basis for kinesin selectivity.

Data availability

Cryo-EM electron density maps and models have been deposited in the electron microscopy data bank (EMDB) and protein data bank (PDB) respectively. The relevant deposition codes are provided in Table 1.

The following data sets were generated

Article and author information

Author details

  1. Joseph Atherton

    Randall Centre for Cell & Molecular Biophysics, King's College London, London, United Kingdom
    For correspondence
    joseph.atherton@kcl.ac.uk
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-6362-2347

  2. Jessica JA Hummel

    Cell Biology, Neurobiology and Biophysics, Department of Biology, Utrecht University, Utrecht, Netherlands
    Competing interests
    The authors declare that no competing interests exist.

  3. Natacha Olieric

    Laboratory of Biomolecular Research, Division of Biology and Chemistry, Paul Scherrer Institute, Villigen, Switzerland
    Competing interests
    The authors declare that no competing interests exist.

  4. Julia Locke

    Macromolecular Machines Laboratory, The Francis Crick Institute, London, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.

  5. Alejandro Peña

    Department of In Silico Drug Discovery, Pharmidex 19 Pharmaceuticals, Hatfield, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.

  6. Steven S Rosenfeld

    Department of Cancer Biology, Mayo Clinic, Jacksonville, United States
    Competing interests
    The authors declare that no competing interests exist.

  7. Michel O Steinmetz

    Laboratory of Biomolecular Research, Division of Biology and Chemistry, Paul Scherrer Institute, Villigen, Switzerland
    Competing interests
    The authors declare that no competing interests exist.

  8. Casper C Hoogenraad

    Cell Biology, Neurobiology and Biophysics, Utrecht University, Utrecht, Netherlands
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-2666-0758

  9. Carolyn A Moores

    Biological Sciences, Institute of Structural and Molecular Biology, Birkbeck College, London, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-5686-6290

Funding

Medical Research Council (MR/R000352/1)

  • Joseph Atherton

Worldwide Cancer Research (16-0037)

  • Julia Locke
  • Alejandro Peña

Wellcome Trust (202679/Z/16/Z,206166/Z/17/Z and 079605/Z/06/Z)

  • Joseph Atherton
  • Julia Locke
  • Alejandro Peña

Biotechnology and Biological Sciences Research Council (BB/L014211/1)

  • Joseph Atherton
  • Julia Locke
  • Alejandro Peña

National Institute of General Medical Sciences (R01GM130556)

  • Steven S Rosenfeld

Swiss National Science Foundation (31003A_166608)

  • Natacha Olieric
  • Michel O Steinmetz

Netherlands Organization for Scientific Research (NWO-ALW-VICI,CCH)

  • Jessica JA Hummel
  • Casper C Hoogenraad

European Research Council (ERC-consolidator,CCH)

  • Jessica JA Hummel
  • Casper C Hoogenraad

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Reviewing Editor

  1. Andrew P Carter, MRC Laboratory of Molecular Biology, United Kingdom

Version history

  1. Received: July 27, 2020
  2. Accepted: November 28, 2020
  3. Accepted Manuscript published: November 30, 2020 (version 1)
  4. Version of Record published: December 17, 2020 (version 2)

Copyright

© 2020, Atherton et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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  1. Joseph Atherton
  2. Jessica JA Hummel
  3. Natacha Olieric
  4. Julia Locke
  5. Alejandro Peña
  6. Steven S Rosenfeld
  7. Michel O Steinmetz
  8. Casper C Hoogenraad
  9. Carolyn A Moores
(2020)
The mechanism of kinesin inhibition by kinesin binding protein
eLife 9:e61481.
https://doi.org/10.7554/eLife.61481

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