Role of Coiled-coil Registry Shifts in Activation of Human Bicaudal D2 for Dynein Recruitment Upon Cargo-Binding

Dynein adaptors such as Bicaudal D2 (BicD2) recognize cargo for dynein-dependent transport and cargo-bound adaptors are required to activate dynein for processive transport, but the mechanism of action is unknown. Here, we report the X-ray structure of the cargo-binding domain of human BicD2 and investigate structural dynamics of the coiled-coil. Our molecular dynamics simulations support that BicD2 can switch from a homotypic coiled-coil registry, in which both helices of the homo-dimer are aligned, to an asymmetric registry, where a portion of one helix is vertically shifted, as both states are similarly stable and defined by distinct conformations of F743. The F743I variant increases dynein recruitment in the Drosophila homolog whereas the human R747C variant causes spinal muscular atrophy. We report spontaneous registry shifts for both variants, which may be the cause for BicD2-hyperactivation and disease. We propose that a registry shift upon cargo-binding may activate auto-inhibited BicD2 for dynein...