6OFP

Structure of the C-terminal cargo binding domain of human Bicaudal D2

Summary for 6OFP

• Entry DOI: 10.2210/pdb6ofp/pdb
• Descriptor: Protein bicaudal D homolog 2 (2 entities in total)
• Functional Keywords: bicaudal d2, dynein, dynein adaptor, coiled-coil, registry shift, spinal muscular atrophy, cytoskeletal motor, motor protein
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 2
• Total formula weight: 21875.16

Authors

Noell, C.R.,Debler, E.W.,Cui, H.,Solmaz, S.R. (deposition date: 2019-03-31, release date: 2019-07-24, Last modification date: 2023-10-11)

Primary citation

Noell, C.R.,Loh, J.Y.,Debler, E.W.,Loftus, K.M.,Cui, H.,Russ, B.B.,Zhang, K.,Goyal, P.,Solmaz, S.R.
Role of Coiled-Coil Registry Shifts in the Activation of Human Bicaudal D2 for Dynein Recruitment upon Cargo Binding.
J Phys Chem Lett, 10:4362-4367, 2019

PubMed Abstract: 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 the structural dynamics of the coiled-coil. Our molecular dynamics simulations support the fact that BicD2 can switch from a homotypic coiled-coil registry, in which both helices of the homodimer 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 homologue, 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 autoinhibited BicD2 for dynein recruitment.

PubMed: 31306018
DOI: 10.1021/acs.jpclett.9b01865

Experimental method

X-RAY DIFFRACTION (2.006 Å)