title: TRAK/Milton motor-adaptor proteins steer mitochondrial trafficking to axons and dendrites.
abstract: In neurons, the distinct molecular composition of axons and dendrites is established through polarized targeting mechanisms, but it is currently unclear how nonpolarized cargoes, such as mitochondria, become uniformly distributed over these specialized neuronal compartments. Here, we show that TRAK family adaptor proteins, TRAK1 and TRAK2, which link mitochondria to microtubule-based motors, are required for axonal and dendritic mitochondrial motility and utilize different transport machineries to steer mitochondria into axons and dendrites. TRAK1 binds to both kinesin-1 and dynein/dynactin, is prominently localized in axons, and is needed for normal axon outgrowth, whereas TRAK2 predominantly interacts with dynein/dynactin, is more abundantly present in dendrites, and is required for dendritic development. These functional differences follow from their distinct conformations: TRAK2 preferentially adopts a head-to-tail interaction, which interferes with kinesin-1 binding and axonal transport. Our study demonstrates how the molecular interplay between bidirectional adaptor proteins and distinct microtubule-based motors drives polarized mitochondrial transport.
authors: Cell Biology, Department of Biology, Faculty of Science, Utrecht University, 3584 CH Utrecht, The Netherlands.
authors: Myrrhe
authors: M
authors: van Spronsen
authors: Marina
authors: M
authors: Mikhaylova
authors: Joanna
authors: J
authors: Lipka
authors: Max A
authors: MA
authors: Schlager
authors: Dave J
authors: DJ
authors: van den Heuvel
authors: Marijn
authors: M
authors: Kuijpers
authors: Phebe S
authors: PS
authors: Wulf
authors: Nanda
authors: N
authors: Keijzer
authors: Jeroen
authors: J
authors: Demmers
authors: Lukas C
authors: LC
authors: Kapitein
authors: Dick
authors: D
authors: Jaarsma
authors: Hans C
authors: HC
authors: Gerritsen
authors: Anna
authors: A
authors: Akhmanova
authors: Casper C
authors: CC
authors: Hoogenraad
mesh_terms: D033942:Adaptor Proteins, Vesicular Transport / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001369:Axons / Q000378:metabolism*; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D016764:Cell Polarity / Q000235:genetics; D002478:Cells, Cultured; D003712:Dendrites / Q000378:metabolism*; D004622:Embryo, Mammalian; D049452:Green Fluorescent Proteins / Q000378:metabolism; D006624:Hippocampus / Q000166:cytology; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D016547:Kinesins / Q000378:metabolism / Q000502:physiology; D008928:Mitochondria / Q000378:metabolism*; D008954:Models, Biological; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D009474:Neurons / Q000648:ultrastructure*; D011485:Protein Binding / Q000235:genetics; D011487:Protein Conformation; D011494:Protein Kinases / Q000378:metabolism; D021381:Protein Transport / Q000235:genetics; D034741:RNA, Small Interfering / Q000378:metabolism; D051381:Rats; D013997:Time Factors; D014162:Transfection
chemical_list: D033942:Adaptor Proteins, Vesicular Transport; D002352:Carrier Proteins; D047908:Intracellular Signaling Peptides and Proteins; C500506:KIF5A protein, human; C488101:KIF5B protein, human; D009419:Nerve Tissue Proteins; D034741:RNA, Small Interfering; C531552:TRAK1 protein, human; C465341:TRAK2 protein, human; D049452:Green Fluorescent Proteins; D011494:Protein Kinases; C094981:p150 protein kinase; D016547:Kinesins