The mechanism of kinesin inhibition by kinesin binding protein
- King's College London, United Kingdom
- Utrecht University, Netherlands
- Paul Scherrer Institute, Switzerland
- The Francis Crick Institute, United Kingdom
- Pharmidex 19 Pharmaceuticals, United Kingdom
- Mayo Clinic, United States
- Institute of Structural and Molecular Biology, Birkbeck College, United Kingdom
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.
Article and author information
Author details
Casper C Hoogenraad
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
- Andrew P Carter, MRC Laboratory of Molecular Biology, United Kingdom
Version history
- Received: July 27, 2020
- Accepted: November 28, 2020
- Accepted Manuscript published: November 30, 2020 (version 1)
- 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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The mechanism of kinesin inhibition by kinesin binding protein
eLife 9:e61481.
https://doi.org/10.7554/eLife.61481
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