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

Mol Cell. 2012 Sep 14;47(5):707-21. doi: 10.1016/j.molcel.2012.06.025. Epub 2012 Aug 1.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Female
  • Kinesin / metabolism*
  • Male
  • Mice
  • Mice, Knockout
  • Microtubule-Associated Proteins / deficiency
  • Microtubule-Associated Proteins / metabolism*
  • Microtubules / metabolism
  • Neurons / cytology
  • Neurons / metabolism*
  • Neuropeptides / deficiency
  • Neuropeptides / metabolism*
  • Protein-Serine-Threonine Kinases / deficiency
  • Protein-Serine-Threonine Kinases / metabolism*

Substances

  • Kif1a protein, mouse
  • Microtubule-Associated Proteins
  • Neuropeptides
  • doublecortin protein
  • Dcamkl1 protein, mouse
  • Protein-Serine-Threonine Kinases
  • Kinesin