title: Structure of human cytoplasmic dynein-2 primed for its power stroke.
abstract: Members of the dynein family, consisting of cytoplasmic and axonemal isoforms, are motors that move towards the minus ends of microtubules. Cytoplasmic dynein-1 (dynein-1) plays roles in mitosis and cellular cargo transport, and is implicated in viral infections and neurodegenerative diseases. Cytoplasmic dynein-2 (dynein-2) performs intraflagellar transport and is associated with human skeletal ciliopathies. Dyneins share a conserved motor domain that couples cycles of ATP hydrolysis with conformational changes to produce movement. Here we present the crystal structure of the human cytoplasmic dynein-2 motor bound to the ATP-hydrolysis transition state analogue ADP.vanadate. The structure reveals a closure of the motor's ring of six AAA+ domains (ATPases associated with various cellular activites: AAA1-AAA6). This induces a steric clash with the linker, the key element for the generation of movement, driving it into a conformation that is primed to produce force. Ring closure also changes the interface between the stalk and buttress coiled-coil extensions of the motor domain. This drives helix sliding in the stalk which causes the microtubule binding domain at its tip to release from the microtubule. Our structure answers the key questions of how ATP hydrolysis leads to linker remodelling and microtubule affinity regulation.
authors.affiliation: Medical Research Council Laboratory of Molecular Biology, Division of Structural Studies, Francis Crick Avenue, Cambridge, CB2 0QH, United Kingdom.
authors.forename: Helgo
authors.initials: H
authors.lastname: Schmidt
authors.affiliation: Medical Research Council Laboratory of Molecular Biology, Division of Structural Studies, Francis Crick Avenue, Cambridge, CB2 0QH, United Kingdom.
authors.forename: Ruta
authors.initials: R
authors.lastname: Zalyte
authors.affiliation: Medical Research Council Laboratory of Molecular Biology, Division of Structural Studies, Francis Crick Avenue, Cambridge, CB2 0QH, United Kingdom.
authors.forename: Linas
authors.initials: L
authors.lastname: Urnavicius
authors.affiliation: Medical Research Council Laboratory of Molecular Biology, Division of Structural Studies, Francis Crick Avenue, Cambridge, CB2 0QH, United Kingdom.
authors.forename: Andrew P
authors.initials: AP
authors.lastname: Carter
mesh_terms: D000244:Adenosine Diphosphate / Q000031:analogs & derivatives / Q000378:metabolism; D001665:Binding Sites; D018360:Crystallography, X-Ray; D003593:Cytoplasm; D056445:Cytoplasmic Dyneins / Q000737:chemistry* / Q000378:metabolism*; D006801:Humans; D006868:Hydrolysis; D008958:Models, Molecular; D009068:Movement; D011487:Protein Conformation
chemical_list: D000244:Adenosine Diphosphate; D056445:Cytoplasmic Dyneins