Kinesin-1/Hsc70-dependent mechanism of slow axonal transport and its relation to fast axonal transport.
Cytoplasmic protein transport in axons ('slow axonal transport') is essential for neuronal homeostasis, and involves Kinesin-1, the same motor for membranous organelle transport ('fast axonal transport'). However, both molecular mechanisms of slow axonal transport and difference in usage of Kinesin-1 between slow and fast axonal transport have been elusive. Here, we show that slow axonal transport depends on the interaction between the DnaJ-like domain of the kinesin light chain in the Kinesin-1 motor complex and Hsc70, scaffolding between cytoplasmic proteins and Kinesin-1. The domain is within the tetratricopeptide repeat, which can bind to membranous organelles, and competitive perturbation of the domain in squid giant axons disrupted cytoplasmic protein transport and reinforced membranous organelle transport, indicating that this domain might have a function as a switchover system between slow and fast transport by Hsc70. Transgenic mice overexpressing a dominant-negative form of the domain showed delayed slow transport, accelerated fast transport and optic axonopathy. These findings provide a basis for the regulatory mechanism of intracellular transport and its intriguing implication in neuronal dysfunction.
Terada
Sumio
S
Department of Cell Biology and Anatomy, University of Tokyo Graduate School of Medicine, Bunkyo-ku, Tokyo, Japan.
Kinjo
Masataka
M
Aihara
Makoto
M
Takei
Yosuke
Y
Hirokawa
Nobutaka
N
D000595:Amino Acid Sequence; D000818:Animals; D001370:Axonal Transport / Q000502:physiology*; D001369:Axons / Q000378:metabolism; D003402:Creatine Kinase / Q000737:chemistry / Q000378:metabolism; D049832:Decapodiformes; D050883:HSC70 Heat-Shock Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D050956:HSP40 Heat-Shock Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D066298:In Vitro Techniques; D016547:Kinesins; D007700:Kinetics; D051379:Mice; D008822:Mice, Transgenic; D008869:Microtubule-Associated Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D020409:Molecular Motor Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D008969:Molecular Sequence Data; D046912:Multiprotein Complexes; D009900:Optic Nerve / Q000473:pathology; D054730:Protein Interaction Domains and Motifs; D021381:Protein Transport; D011994:Recombinant Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism
D050883:HSC70 Heat-Shock Proteins; D050956:HSP40 Heat-Shock Proteins; C494372:Hspa8 protein, mouse; D008869:Microtubule-Associated Proteins; D020409:Molecular Motor Proteins; D046912:Multiprotein Complexes; D011994:Recombinant Proteins; D003402:Creatine Kinase; D016547:Kinesins