A model of LIS1 function in cargo-adapter-mediated dynein activation. Based on our result that the dynein–dynactin–ΔC-HookA complex is still formed without LIS1, we propose that between the fully closed (phi) and open states of dynein, there is an intermediate state in which the dynein tails are partially separated to allow the interactions with dynactin and cargo adapters. However, this complex is not functional in vivo without LIS1. Based on our result that the phi-opening mutations mimic LIS1 function to a significant extent, we propose that LIS1 shifts the equilibria toward the open state and then the fully functional state where the two HCs within the dimer are parallel to each other (Zhang et al., 2017a). This functional state may have a relatively weak affinity for LIS1 to allow its dissociation from the complex at some point during the minus-end–directed movement.