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The mechanism of kinesin inhibition by kinesin binding protein

  • Atherton, Joseph ORCID Randall Centre for Cell & Molecular Biophysics, King's College London, London, United Kingdom
  • Hummel, Jessica JA Cell Biology, Neurobiology and Biophysics, Department of Biology, Utrecht University, Utrecht, Netherlands
  • Olieric, Natacha Laboratory of Biomolecular Research, Division of Biology and Chemistry, Paul Scherrer Institute, Villigen, Switzerland
  • Locke, Julia Macromolecular Machines Laboratory, The Francis Crick Institute, London, United Kingdom
  • Peña, Alejandro Department of In Silico Drug Discovery, Pharmidex 19 Pharmaceuticals, Hatfield, United Kingdom
  • Rosenfeld, Steven S Department of Cancer Biology, Mayo Clinic, Jacksonville, United States
  • Steinmetz, Michel O Laboratory of Biomolecular Research, Division of Biology and Chemistry, Paul Scherrer Institute, Villigen, Switzerland
  • Hoogenraad, Casper C ORCID Cell Biology, Neurobiology and Biophysics, Utrecht University, Utrecht, Netherlands
  • Moores, Carolyn A ORCID Biological Sciences, Institute of Structural and Molecular Biology, Birkbeck College, London, United Kingdom
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  • 2020-11-30
Published in:
  • eLife. - eLife Sciences Publications, Ltd. - 2020, vol. 9
General Biochemistry, Genetics and Molecular Biology
General Immunology and Microbiology
General Neuroscience
General Medicine
English 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.
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  • English
Open access status
gold
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https://sonar.ch/global/documents/86725
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