Activation of cytoplasmic dynein motility by dynactin-cargo adapter complexes

How dynein makes the right moves The molecular motor cytoplasmic dynein moves a wide range of different intracellular cargoes. Dynein's activity in vivo requires another protein, dynactin, but exactly why that should be has been very unclear. Although in vitro experiments have provided some evidence that dynactin increases dynein's processivity, the resulting dynein motility has never come close to matching dynein's cargo-transporting activity in living cells. Now, McKenney et al. show that tripartite complexes of dynein, dynactin, and an adaptor molecule are highly processive in vitro, moving the sort of distances that dynein transports cargo in vivo (see the Perspective by Allan). Science, this issue p. 337; see also p. 271 Single-molecule studies reveal a mechanism to activate the molecular motor cytoplasmic dynein in a cargo-specific manner. [Also see Perspective by Allan] Cytoplasmic dynein is a molecular motor that transports a large variety of cargoes (e.g., organelles, messenger RNAs, and viruses) along microtubules over long intracellular distances. The dynactin protein complex is important for dynein activity in vivo, but its precise role has been unclear. Here, we found that purified mammalian dynein did not move processively on microtubules in vitro. However, when dynein formed a complex with dynactin and one of four different cargo-specific adapter proteins, the motor became ultraprocessive, moving for distances similar to those of native cargoes in living cells. Thus, we propose that dynein is largely inactive in the cytoplasm and that a variety of adapter proteins activate processive motility by linking dynactin to dynein only when the motor is bound to its proper cargo.