Activation and Regulation of Cytoplasmic Dynein

Cytoplasmic dynein is an AAA+ motor that drives the transport of many intracellular cargoes towards the minus end of microtubules (MTs). Previous in vitro studies characterized isolated dynein as an exceptionally weak motor that moves slowly and diffuses on an MT. Recent studies altered this view by demonstrating that dynein remains in an autoinhibited conformation on its own, and processive motility is activated when it forms a ternary complex with dynactin and a cargo adaptor. This complex assembles more efficiently in the presence of Lis1, providing an explanation for why Lis1 is a required cofactor for most cytoplasmic dynein-driven processes in cells. This review describes how dynein motility is activated and regulated by cargo adaptors and accessory proteins. Dynein remains in an inactive conformation on its own, and motility is activated when it forms a complex with dynactin and a cargo adaptor.Previous studies identified isolated mammalian dynein as an exceptionally weak motor that diffuses on an MT and produces low forces.In vitro reconstitution of the mammalian dynein–dynactin complex recently altered this view, and revealed that dynein is a robust motor that walks rapidly and produces forces comparable to plus-end-directed kinesin.CryoEM and single-molecule studies showed that cargo adaptors recruit two dynein motors to dynactin for faster movement and higher force production.Lis1, the only accessory factor that binds directly to the motor domain of dynein, promotes the formation of fully activated dynein–dynactin complexes containing two dynein dimers, and then dissociates from dynein leading to rapid motility.A subset of cargo adaptors that simultaneously recruit kinesin and dynein to the cargo, may coordinate kinesin–dynein activity to determine which direction the cargo moves.