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Title | Molecular basis for specific regulation of neuronal kinesin-3 motors by doublecortin family proteins. |
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Journal, issue, pages | Mol Cell, Vol. 47, Issue 5, Page 707-721, Year 2012 |
Publish date | Sep 14, 2012 |
Authors | Judy S Liu / Christian R Schubert / Xiaoqin Fu / Franck J Fourniol / Jyoti K Jaiswal / Anne Houdusse / Collin M Stultz / Carolyn A Moores / Christopher A Walsh / |
PubMed 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 ...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. |
External links | Mol Cell / PubMed:22857951 / PubMed Central |
Methods | EM (helical sym.) / EM (single particle) |
Resolution | 8.2 - 8.3 Å |
Structure data | EMDB-2095: Cryo-electron microscopy reconstruction of doublecortin-stabilised microtubules in absence of kinesin EMDB-2098: Cryo-electron microscopy reconstruction of doublecortin-stabilised microtubules in presence of kinesin |
Chemicals | ChemComp-GDP: ChemComp-GTP: |
Source |
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Keywords | HYDROLASE / MICROTUBULE-ASSOCIATED PROTEIN / MICROTUBULE / NECK-LINKER |