Asymmetric effect of SF mutations on Ca _V 1.3 VDI and CDI. (A) Schematic shows asymmetric effect of the SF W[+2]A mutations in evoking VDI of Ca_V1.3. The interdomain interface between DIII and DIV is stabilized primarily by the conserved W[+2] residue which may serve as a wedge. Disruption of this interaction destabilizes the local conformation. By contrast, the interdomain interface between DI–DII, DII–DII, and DI–DIV is stabilized by both the W[+2] residue and through additional interdomain contacts. Consequently, SF conformation is maintained even with the W[+2]A mutation in DI through DIII. (B) For CDI, the W[+2] residue likely plays a role in transducing SF conformational rearrangements. The N- versus C-lobe of CaM appears to be asymmetrically coupled to distinct SF domains, likely evoking distinct SF conformational changes.