Format

Send to:

Choose Destination
See comment in PubMed Commons below
Mol Cell. 2012 Sep 14;47(5):707-21. doi: 10.1016/j.molcel.2012.06.025. Epub 2012 Aug 1.

Molecular basis for specific regulation of neuronal kinesin-3 motors by doublecortin family proteins.

Author information

  • 1Center for Neuroscience Research, Children's National Medical Center, Washington, DC 20010, USA. jliu@cnmcresearch.org

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.

Copyright © 2012 Elsevier Inc. All rights reserved.

PMID:
22857951
[PubMed - indexed for MEDLINE]
PMCID:
PMC3549492
Free PMC Article
PubMed Commons home

PubMed Commons

0 comments
How to join PubMed Commons

    Supplemental Content

    Full text links

    Icon for Elsevier Science Icon for PubMed Central
    Loading ...
    Write to the Help Desk