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Molecular basis for specific regulation of neuronal Kinesin-3 motors by Doublecortin family proteins

Liu, J.S. and Schubert, C.R. and Fu, X. and Fourniol, Franck J. and Jaiswal, J.K. and Houdusse, A. and Stultz, C.M. and Moores, Carolyn A. and Walsh, C.A. (2012) Molecular basis for specific regulation of neuronal Kinesin-3 motors by Doublecortin family proteins. Molecular Cell 47 (5), pp. 707-721. ISSN 1097-2765.

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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.

Item Type: Article
School or Research Centre: Birkbeck Schools and Research Centres > School of Science > Biological Sciences
Depositing User: Administrator
Date Deposited: 10 Sep 2012 10:52
Last Modified: 17 Apr 2013 12:24

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