title: Hook Adaptors Induce Unidirectional Processive Motility by Enhancing the Dynein-Dynactin Interaction.
abstract: Cytoplasmic dynein drives the majority of minus end-directed vesicular and organelle motility in the cell. However, it remains unclear how dynein is spatially and temporally regulated given the variety of cargo that must be properly localized to maintain cellular function. Recent work has suggested that adaptor proteins provide a mechanism for cargo-specific regulation of motors. Of particular interest, studies in fungal systems have implicated Hook proteins in the regulation of microtubule motors. Here we investigate the role of mammalian Hook proteins, Hook1 and Hook3, as potential motor adaptors. We used optogenetic approaches to specifically recruit Hook proteins to organelles and observed rapid transport of peroxisomes to the perinuclear region of the cell. This rapid and efficient translocation of peroxisomes to microtubule minus ends indicates that mammalian Hook proteins activate dynein rather than kinesin motors. Biochemical studies indicate that Hook proteins interact with both dynein and dynactin, stabilizing the formation of a supramolecular complex. Complex formation requires the N-terminal domain of Hook proteins, which resembles the calponin-homology domain of end-binding (EB) proteins but cannot bind directly to microtubules. Single-molecule motility assays using total internal reflection fluorescence microscopy indicate that both Hook1 and Hook3 effectively activate cytoplasmic dynein, inducing longer run lengths and higher velocities than the previously characterized dynein activator bicaudal D2 (BICD2). Together, these results suggest that dynein adaptors can differentially regulate dynein to allow for organelle-specific tuning of the motor for precise intracellular trafficking.
authors.affiliation: From the Department of Physiology and Pennsylvania Muscle Institute and Biochemistry and Molecular Biophysics Graduate Group, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania 19104.
authors.forename: Mara A
authors.initials: MA
authors.lastname: Olenick
authors.affiliation: From the Department of Physiology and Pennsylvania Muscle Institute and.
authors.forename: Mariko
authors.initials: M
authors.lastname: Tokito
authors.affiliation: From the Department of Physiology and Pennsylvania Muscle Institute and.
authors.forename: Malgorzata
authors.initials: M
authors.lastname: Boczkowska
authors.affiliation: From the Department of Physiology and Pennsylvania Muscle Institute and Biochemistry and Molecular Biophysics Graduate Group, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania 19104.
authors.forename: Roberto
authors.initials: R
authors.lastname: Dominguez
authors.affiliation: From the Department of Physiology and Pennsylvania Muscle Institute and Biochemistry and Molecular Biophysics Graduate Group, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania 19104 holzbaur@mail.med.upenn.edu.
authors.forename: Erika L F
authors.initials: EL
authors.lastname: Holzbaur
mesh_terms: D000818:Animals; D019556:COS Cells; D002522:Chlorocebus aethiops; D000072159:Dynactin Complex / Q000235:genetics / Q000378:metabolism*; D004398:Dyneins / Q000235:genetics / Q000378:metabolism*; D006367:HeLa Cells; D006801:Humans; D051379:Mice; D008869:Microtubule-Associated Proteins / Q000235:genetics / Q000378:metabolism*; D008870:Microtubules / Q000235:genetics / Q000378:metabolism; D020675:Peroxisomes / Q000235:genetics / Q000378:metabolism
chemical_list: C561542:BICD2 protein, human; C435206:Bicd2 protein, mouse; D000072159:Dynactin Complex; C471056:Hook1 protein, mouse; D008869:Microtubule-Associated Proteins; C471055:hook1 protein, human; C425466:hook3 protein, human; C479499:hook3 protein, mouse; D004398:Dyneins
keywords: cytoskeleton; dynein; intracellular trafficking; kinesin; microtubule