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TitleMolecular basis for specific regulation of neuronal kinesin-3 motors by doublecortin family proteins.
Journal, issue, pagesMol Cell, Vol. 47, Issue 5, Page 707-721, Year 2012
Publish dateSep 14, 2012
AuthorsJudy 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 AbstractDoublecortin (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 linksMol Cell / PubMed:22857951 / PubMed Central
MethodsEM (helical sym.) / EM (single particle)
Resolution8.2 - 8.3 Å
Structure data

2095

4atu

EMDB-2095: Cryo-electron microscopy reconstruction of doublecortin-stabilised microtubules in absence of kinesin
PDB-4atu: Human doublecortin N-DC repeat plus linker, and tubulin (2XRP) docked into an 8A cryo-EM map of doublecortin-stabilised microtubules reconstructed in absence of kinesin
Method: EM (helical sym.) / Resolution: 8.3 Å

2098

4atx

EMDB-2098: Cryo-electron microscopy reconstruction of doublecortin-stabilised microtubules in presence of kinesin
PDB-4atx: Rigor kinesin motor domain with an ordered neck-linker, docked on tubulin dimer, modelled into the 8A cryo-EM map of doublecortin- microtubules decorated with kinesin
Method: EM (helical sym.) / Resolution: 8.2 Å

Chemicals

ChemComp-GDP:
GUANOSINE-5'-DIPHOSPHATE / GDP, energy-carrying molecule*YM / Guanosine diphosphate

ChemComp-GTP:
GUANOSINE-5'-TRIPHOSPHATE / GTP, energy-carrying molecule*YM / Guanosine triphosphate

Source
  • bos taurus (cattle)
  • homo sapiens (human)
  • rattus norvegicus (Norway rat)
KeywordsHYDROLASE / MICROTUBULE-ASSOCIATED PROTEIN / MICROTUBULE / NECK-LINKER

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