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

Abstract

Voltage-gated calcium channels (Ca_Vs) govern muscle contraction, hormone and neurotransmitter release, neuronal migration, activation of calcium-dependent signalling cascades, and synaptic input integration¹. An essential Ca_V intracellular protein, the β-subunit (Ca_Vβ)^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 expression^6,7. Here, we report the high-resolution crystal structures of the Ca_Vβ_2a 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 site^3,8; however, this region is largely buried in the Ca_Vβ core and is unavailable for protein–protein interactions. The structure of the AID–Ca_Vβ_2a complex shows instead that Ca_Vβ_2a engages the AID through an extensive, conserved hydrophobic cleft (named the α-binding pocket, ABP). The ABP–AID interaction positions one end of the Ca_Vβ 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_Vβs influence Ca_V gating by direct modulation of IS6 movement within the channel pore.