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 integration1. An essential CaV intracellular protein, the β-subunit (CaVβ)1,2, binds a conserved domain (the α-interaction domain, AID) between transmembrane domains I and II of the pore-forming α1 subunit3 and profoundly affects multiple channel properties such as voltage-dependent activation2, inactivation rates2, G-protein modulation4, drug sensitivity5 and cell surface expression6,7. Here, we report the high-resolution crystal structures of the CaVβ2a conserved core, alone and in complex with the AID. Previous work suggested that a conserved region, the β-interaction domain (BID), formed the AID-binding site3,8; however, this region is largely buried in the CaVβ core and is unavailable for protein–protein interactions. The structure of the AID–CaVβ2a complex shows instead that CaVβ2a engages the AID through an extensive, conserved hydrophobic cleft (named the α-binding pocket, ABP). The ABP–AID interaction positions one end of the CaVβ near the intracellular end of a pore-lining segment, called IS6, that has a critical role in CaV inactivation9,10. Together, these data suggest that CaVβs influence CaV gating by direct modulation of IS6 movement within the channel pore.