title: Intraflagellar transport dynein is autoinhibited by trapping of its mechanical and track-binding elements.
abstract: Cilia are multifunctional organelles that are constructed using intraflagellar transport (IFT) of cargo to and from their tip. It is widely held that the retrograde IFT motor, dynein-2, must be controlled in order to reach the ciliary tip and then unleashed to power the return journey. However, the mechanism is unknown. Here, we systematically define the mechanochemistry of human dynein-2 motors as monomers, dimers, and multimotor assemblies with kinesin-II. Combining these data with insights from single-particle EM, we discover that dynein-2 dimers are intrinsically autoinhibited. Inhibition is mediated by trapping dynein-2's mechanical 'linker' and 'stalk' domains within a novel motor-motor interface. We find that linker-mediated inhibition enables efficient transport of dynein-2 by kinesin-II in vitro. These results suggest a conserved mechanism for autoregulation among dimeric dyneins, which is exploited as a switch for dynein-2's recycling activity during IFT.
authors.affiliation: Institute of Structural and Molecular Biology, Birkbeck, London, UK.
authors.forename: Katerina
authors.initials: K
authors.lastname: Toropova
authors.affiliation: Institute of Structural and Molecular Biology, Birkbeck, London, UK.
authors.forename: Miroslav
authors.initials: M
authors.lastname: Mladenov
authors.affiliation: Institute of Structural and Molecular Biology, Birkbeck, London, UK.
authors.forename: Anthony J
authors.initials: AJ
authors.lastname: Roberts
mesh_terms: D004398:Dyneins / Q000737:chemistry* / Q000378:metabolism* / Q000648:ultrastructure; D006801:Humans; D016547:Kinesins / Q000737:chemistry / Q000378:metabolism / Q000648:ultrastructure; D008854:Microscopy, Electron; D008954:Models, Biological; D008958:Models, Molecular; D011487:Protein Conformation; D055503:Protein Multimerization
chemical_list: C074152:kinesin-II; D004398:Dyneins; D016547:Kinesins