An intramolecular interaction between the FHA domain and a coiled coil negatively regulates the kinesin motor KIF1A

EMBO J. 2004 Apr 7;23(7):1506-15. doi: 10.1038/sj.emboj.7600164. Epub 2004 Mar 11.

Abstract

Motor proteins not actively involved in transporting cargoes should remain inactive at sites of cargo loading to save energy and remain available for loading. KIF1A/Unc104 is a monomeric kinesin known to dimerize into a processive motor at high protein concentrations. However, the molecular mechanisms underlying monomer stabilization and monomer-to-dimer transition are not well understood. Here, we report an intramolecular interaction in KIF1A between the forkhead-associated (FHA) domain and a coiled-coil domain (CC2) immediately following the FHA domain. Disrupting this interaction by point mutations in the FHA or CC2 domains leads to a dramatic accumulation of KIF1A in the periphery of living cultured neurons and an enhancement of the microtubule (MT) binding and self-multimerization of KIF1A. In addition, point mutations causing rigidity in the predicted flexible hinge disrupt the intramolecular FHA-CC2 interaction and increase MT binding and peripheral accumulation of KIF1A. These results suggest that the intramolecular FHA-CC2 interaction negatively regulates KIF1A activity by inhibiting MT binding and dimerization of KIF1A, and point to a novel role of the FHA domain in the regulation of kinesin motors.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cells, Cultured
  • Humans
  • Kinesins / chemistry*
  • Kinesins / genetics
  • Kinesins / metabolism*
  • Models, Molecular
  • Molecular Motor Proteins / chemistry
  • Molecular Motor Proteins / genetics
  • Molecular Motor Proteins / metabolism
  • Nerve Tissue Proteins / chemistry*
  • Nerve Tissue Proteins / genetics
  • Nerve Tissue Proteins / metabolism*
  • Neurons / cytology
  • Neurons / metabolism
  • Point Mutation
  • Protein Binding
  • Protein Structure, Secondary*
  • Protein Structure, Tertiary
  • Recombinant Fusion Proteins / chemistry
  • Recombinant Fusion Proteins / genetics
  • Recombinant Fusion Proteins / metabolism

Substances

  • KIF1A protein, human
  • Molecular Motor Proteins
  • Nerve Tissue Proteins
  • Recombinant Fusion Proteins
  • Kinesins