The role of a voltage-dependent Ca ²⁺ channel intracellular linker: A structure-function analysis

Voltage-dependent calcium channels (VDCCs) allow the passage of Ca ²⁺ ions through cellular membranes in response to membrane depolarization. The channel pore-forming supunit,α1, and a regulatory supunit (Ca _Vβ) form a high affinity complex where Ca _Vβ binds to a α1 interacting domain in the intracellular linker between α1 membrane domains I and II (I-II linker). We determined crystal structures of Ca _Vβ2 functional core in complex with the Ca _V1.2 and Ca _V2.2 I-II linkers to a resolution of 1.95 and 2.0 Å, respectively. Structural differences between the highly conserved linkers, important for coupling Ca _Vβ to the channel pore, guided mechanistic functional studies. Electrophysiological measurements point to the importance of differing linker structure in both Ca _V1 and 2 suptypes with mutations affecting both voltage- and calcium-dependent inactivation and voltage dependence of activation. These linker effects persist in the absence of Ca _Vβ, pointing to the intrinsic role of the linker in VDCC function and suggesting that I-II linker structure can serve as a brake during inactivation.