title: Autoinhibition of a Neuronal Kinesin UNC-104/KIF1A Regulates the Size and Density of Synapses.
abstract: Kinesin motor proteins transport intracellular cargoes throughout cells by hydrolyzing ATP and moving along microtubule tracks. Intramolecular autoinhibitory interactions have been shown for several kinesins in vitro; however, the physiological significance of autoinhibition remains poorly understood. Here, we identified four mutations in the stalk region and motor domain of the synaptic vesicle (SV) kinesin UNC-104/KIF1A that specifically disrupt autoinhibition. These mutations augment both microtubule and cargo vesicle binding in vitro. In vivo, these mutations cause excessive activation of UNC-104, leading to decreased synaptic density, smaller synapses, and ectopic localization of SVs in the dendrite. We also show that the SV-bound small GTPase ARL-8 activates UNC-104 by unlocking the autoinhibition. These results demonstrate that the autoinhibitory mechanism is used to regulate the distribution of transport cargoes and is important for synaptogenesis in vivo.
authors.affiliation: Howard Hughes Medical Institute, Department of Biology, Stanford University, 385 Serra Mall, Stanford, CA 94305, USA; Frontier Research Institute for Interdisciplinary Sciences and Graduate School of Life Sciences, Tohoku University, Aramaki Aza Aoba 6-3, Aoba-ku, Sendai, Miyagi 980-8578, Japan.
authors.forename: Shinsuke
authors.initials: S
authors.lastname: Niwa
authors.affiliation: Howard Hughes Medical Institute, Department of Biology, Stanford University, 385 Serra Mall, Stanford, CA 94305, USA.
authors.forename: David M
authors.initials: DM
authors.lastname: Lipton
authors.affiliation: Department of Cell Biology and Anatomy, Graduate School of Medicine, The University of Tokyo, Hongo 7-3-1, Tokyo 113-0033, Japan.
authors.forename: Manatsu
authors.initials: M
authors.lastname: Morikawa
authors.affiliation: School of Chemical & Biomolecular Engineering, Georgia Institute of Technology, 311 Ferst Drive NW, Atlanta, GA 30332-0100, USA.
authors.forename: Charles
authors.initials: C
authors.lastname: Zhao
authors.affiliation: Department of Cell Biology and Anatomy, Graduate School of Medicine, The University of Tokyo, Hongo 7-3-1, Tokyo 113-0033, Japan.
authors.forename: Nobutaka
authors.initials: N
authors.lastname: Hirokawa
authors.affiliation: School of Chemical & Biomolecular Engineering, Georgia Institute of Technology, 311 Ferst Drive NW, Atlanta, GA 30332-0100, USA.
authors.forename: Hang
authors.initials: H
authors.lastname: Lu
authors.affiliation: Howard Hughes Medical Institute, Department of Biology, Stanford University, 385 Serra Mall, Stanford, CA 94305, USA. Electronic address: kangshen@stanford.edu.
authors.forename: Kang
authors.initials: K
authors.lastname: Shen
mesh_terms: D000818:Animals; D001692:Biological Transport; D017173:Caenorhabditis elegans / Q000235:genetics / Q000378:metabolism* / Q000648:ultrastructure; D029742:Caenorhabditis elegans Proteins / Q000235:genetics / Q000378:metabolism*; D003712:Dendrites / Q000378:metabolism / Q000648:ultrastructure; D020558:GTP Phosphohydrolases / Q000235:genetics / Q000378:metabolism*; D015870:Gene Expression; D008870:Microtubules / Q000378:metabolism* / Q000648:ultrastructure; D009154:Mutation; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D011485:Protein Binding; D000072417:Protein Domains; D009435:Synaptic Transmission; D013572:Synaptic Vesicles / Q000378:metabolism* / Q000648:ultrastructure
chemical_list: D029742:Caenorhabditis elegans Proteins; D009419:Nerve Tissue Proteins; C423186:UNC-104 protein, C elegans; D020558:GTP Phosphohydrolases; C552949:arl-8 protein, C elegans