Molecular Basis for Specific Regulation of Neuronal Kinesin-3 Motors by Doublecortin Family Proteins

• Published in: Molecular cell Vol. 47; no. 5; pp. 707 - 721
• Main Authors: Liu, Judy S., Schubert, Christian R., Fu, Xiaoqin, Fourniol, Franck J., Jaiswal, Jyoti K., Houdusse, Anne, Stultz, Collin M., Moores, Carolyn A., Walsh, Christopher A.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 14.09.2012; Cell Press
• Subjects: ADP; Animals; cryo-electron microscopy; Doublecortin Domain Proteins; Doublecortin Protein; Doublecortin-Like Kinases; electron microscopy; Female; humans; kinesin; Kinesins - metabolism; Male; Mice; Mice, Knockout; Microtubule-Associated Proteins - deficiency; Microtubule-Associated Proteins - metabolism; microtubules; Microtubules - metabolism; molecular motor proteins; motors; mutation; neurons; Neurons - cytology; Neurons - metabolism; Neuropeptides - deficiency; Neuropeptides - metabolism; Protein Serine-Threonine Kinases - deficiency; Protein Serine-Threonine Kinases - metabolism; proteins; synaptic vesicles
• ISSN: 1097-2765; 1097-4164; 1097-4164
• DOI: 10.1016/j.molcel.2012.06.025

Doublecortin (Dcx) defines a growing family of microtubule (MT)-associated proteins (MAPs) involved in neuronal migration and process outgrowth. We show that Dcx is essential for the function of Kif1a, a kinesin-3 motor protein that traffics synaptic vesicles. Neurons lacking Dcx and/or its structurally conserved paralogue, doublecortin-like kinase 1 (Dclk1), show impaired Kif1a-mediated transport of Vamp2, a cargo of Kif1a, with decreased run length. Human disease-associated mutations in Dcx's linker sequence (e.g., W146C, K174E) alter Kif1a/Vamp2 transport by disrupting Dcx/Kif1a interactions without affecting Dcx MT binding. Dcx specifically enhances binding of the ADP-bound Kif1a motor domain to MTs. Cryo-electron microscopy and subnanometer-resolution image reconstruction reveal the kinesin-dependent conformational variability of MT-bound Dcx and suggest a model for MAP-motor crosstalk on MTs. Alteration of kinesin run length by MAPs represents a previously undiscovered mode of control of kinesin transport and provides a mechanism for regulation of MT-based transport by local signals. ► Dcx is required for neuronal transport mediated by the kinesin-3 motor Kif1a ► Dcx increases Kif1a/Vamp2 run length without affecting conventional kinesin ► Dcx enhances the affinity of the ADP-bound Kif1a motor domain for microtubules ► Kif1a microtubule binding requires displacement of the flexible Dcx domain linker