RT Journal Article
SR Electronic
T1 Role of coiled-coil registry shifts in activation of human Bicaudal D2 for dynein recruitment upon cargo-binding
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 638536
DO 10.1101/638536
A1 Crystal R. Noell
A1 Jia Ying Loh
A1 Erik W. Debler
A1 Kyle M. Loftus
A1 Heying Cui
A1 Blaine B. Russ
A1 Puja Goyal
A1 Sozanne R. Solmaz
YR 2019
UL http://biorxiv.org/content/early/2019/05/15/638536.abstract
AB Dynein adaptors such as Bicaudal D2 (BicD2) recognize cargo for dynein-dependent transport. BicD2-dependent transport pathways are important for brain and muscle development. Cargo-bound adaptors are required to activate dynein for processive transport, but the mechanism of action is elusive. Here, we report the structure of the cargo-binding domain of human BicD2 that forms a dimeric coiled-coil with homotypic registry, in which both helices are aligned. To investigate if BicD2 can switch to an asymmetric registry, where a portion of one helix is vertically shifted, we performed molecular dynamics simulations. Both registry types are stabilized by distinct conformations of F743. For the F743I variant, which increases dynein recruitment in the Drosophila homolog, and for the human R747C variant, which causes spinal muscular atrophy, spontaneous coiled-coil registry shifts are observed, which may cause the BicD2-hyperactivation phenotype and disease. We propose that a registry shift upon cargo-binding activates auto-inhibited BicD2 for dynein recruitment.HighlightsStable, bona fide BicD2 coiled-coils with distinct registries can be formed.We provide evidence that a human disease mutation causes a coiled-coil registry shift.A coiled-coil registry shift could relieve BicD2-autoinhibition upon cargo-binding.The ability to undergo registry shifts may be an inherent property of coiled-coils.In Brief Our results support that stable coiled-coils of BicD2 with distinct registries can be formed, and suggest a molecular mechanism for such registry switches. We provide evidence that disease-causing mutations in coiled-coils may alter the equilibrium between registry-shifted conformers, which we propose as a general mechanism of pathogenesis for coiled-coils.