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

Voltage-gated calcium channels (Ca V s) 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 β-subunit (Ca V β) 1 , 2 , binds a conserved domain (the α-interaction domain, AID) between transmembrane domains I and II of the pore-forming α 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 β 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 V β core and is unavailable for protein–protein interactions. The structure of the AID–Ca V β 2a complex shows instead that Ca V β 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 V β 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 βs influence Ca V gating by direct modulation of IS6 movement within the channel pore.