title: Molecular basis for specific regulation of neuronal kinesin-3 motors by doublecortin family proteins.
abstract: 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.
authors.affiliation: Center for Neuroscience Research, Children's National Medical Center, Washington, DC 20010, USA. jliu@cnmcresearch.org
authors.forename: Judy S
authors.initials: JS
authors.lastname: Liu
authors.forename: Christian R
authors.initials: CR
authors.lastname: Schubert
authors.forename: Xiaoqin
authors.initials: X
authors.lastname: Fu
authors.forename: Franck J
authors.initials: FJ
authors.lastname: Fourniol
authors.forename: Jyoti K
authors.initials: JK
authors.lastname: Jaiswal
authors.forename: Anne
authors.initials: A
authors.lastname: Houdusse
authors.forename: Collin M
authors.initials: CM
authors.lastname: Stultz
authors.forename: Carolyn A
authors.initials: CA
authors.lastname: Moores
authors.forename: Christopher A
authors.initials: CA
authors.lastname: Walsh
mesh_terms: D000818:Animals; D000089622:Doublecortin Domain Proteins; D000089662:Doublecortin Protein; D000089742:Doublecortin-Like Kinases; D005260:Female; D016547:Kinesins / Q000378:metabolism*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008869:Microtubule-Associated Proteins / Q000172:deficiency / Q000378:metabolism*; D008870:Microtubules / Q000378:metabolism; D009474:Neurons / Q000166:cytology / Q000378:metabolism*; D009479:Neuropeptides / Q000172:deficiency / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000172:deficiency / Q000378:metabolism*
chemical_list: C000714328:DCX protein, human; C000714847:Dcx protein, mouse; D000089622:Doublecortin Domain Proteins; D000089662:Doublecortin Protein; C490576:Kif1a protein, mouse; D008869:Microtubule-Associated Proteins; D009479:Neuropeptides; D000089742:Doublecortin-Like Kinases; C485525:Dclk1 protein, mouse; D017346:Protein Serine-Threonine Kinases; D016547:Kinesins