title: An intramolecular interaction between the FHA domain and a coiled coil negatively regulates the kinesin motor KIF1A.
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.
authors.affiliation: National Creative Research Initiative Center for Synaptogenesis and Department of Biological Sciences, Korea Advanced Institute of Science and Technology, Daejeon, Korea.
authors.forename: Jae-Ran
authors.initials: JR
authors.lastname: Lee
authors.forename: Hyewon
authors.initials: H
authors.lastname: Shin
authors.forename: Jeonghoon
authors.initials: J
authors.lastname: Choi
authors.forename: Jaewon
authors.initials: J
authors.lastname: Ko
authors.forename: Seho
authors.initials: S
authors.lastname: Kim
authors.forename: Hyun Woo
authors.initials: HW
authors.lastname: Lee
authors.forename: Karam
authors.initials: K
authors.lastname: Kim
authors.forename: Seong-Hwan
authors.initials: SH
authors.lastname: Rho
authors.forename: Jun Hyuck
authors.initials: JH
authors.lastname: Lee
authors.forename: Hye-Eun
authors.initials: HE
authors.lastname: Song
authors.forename: Soo Hyun
authors.initials: SH
authors.lastname: Eom
authors.forename: Eunjoon
authors.initials: E
authors.lastname: Kim
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D006801:Humans; D016547:Kinesins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D008958:Models, Molecular; D020409:Molecular Motor Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D009474:Neurons / Q000166:cytology / Q000378:metabolism; D017354:Point Mutation; D011485:Protein Binding; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D011993:Recombinant Fusion Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism
chemical_list: C094065:KIF1A protein, human; D020409:Molecular Motor Proteins; D009419:Nerve Tissue Proteins; D011993:Recombinant Fusion Proteins; D016547:Kinesins