Structure of a complex between a voltage-gated calcium channel β-subunit and an α-subunit domain

Voltage-gated calcium channels (CaVs) govern muscle contraction, hormone and neurotransmitter release, neuronal migration, activation of calcium-dependent signalling cascades, and synaptic input integration(1). An essential Ca-V intracellular protein, the beta-subunit (Ca(V)beta)(1,2), binds a conserved domain ( the alpha-interaction domain, AID) between transmembrane domains I and II of the pore-forming alpha(1) subunit(3) and profoundly affects multiple channel properties such as voltage-dependent activation(2), inactivation rates(2), G-protein modulation(4), drug sensitivity(5) and cell surface expression(6,7). Here, we report the high-resolution crystal structures of the Ca(V)beta(2a) conserved core, alone and in complex with the AID. Previous work suggested that a conserved region, the beta-interaction domain (BID), formed the AID-binding site(3,8); however, this region is largely buried in the Ca(V)beta core and is unavailable for protein - protein interactions. The structure of the AID - Ca(V)beta(2a) complex shows instead that Ca(V)beta(2a) engages the AID through an extensive, conserved hydrophobic cleft ( named the alpha-binding pocket, ABP). The ABP - AID interaction positions one end of the Ca(V)beta near the intracellular end of a pore-lining segment, called IS6, that has a critical role in Ca-V inactivation(9,10). Together, these data suggest that Ca(V)betas influence Ca-V gating by direct modulation of IS6 movement within the channel pore.