TY - JOUR T1 - The mechanism of selective kinesin inhibition by kinesin binding protein JF - bioRxiv DO - 10.1101/2020.07.17.208736 SP - 2020.07.17.208736 AU - Joseph Atherton AU - Jessica J. A. Hummel AU - Natacha Olieric AU - Julia Locke AU - Alejandro Peña AU - Steven S. Rosenfeld AU - Michel O. Steinmetz AU - Casper C. Hoogenraad AU - Carolyn A. Moores Y1 - 2020/01/01 UR - http://biorxiv.org/content/early/2020/07/17/2020.07.17.208736.abstract N2 - 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, crescent-shaped right-handed α-solenoid that sequesters the tubulin-binding surface of the kinesin motor domain, structurally distorting the motor domain and sterically blocking MT attachment. KBP uses its α-solenoid concave face and edge loops to bind the kinesin motor domain and selective mutation of this extended binding surface disrupts KBP inhibition of kinesin transport in cells. The KBP-interacting surface of the motor domain contains motifs exclusively conserved in KBP-interacting kinesins, providing a basis for kinesin selectivity.Competing Interest StatementThe authors have declared no competing interest. ER -