1. Cardiovascular Research Institute, Departments of Biochemistry and Biophysics, and Cellular and Molecular Pharmacology, University of California San Francisco, 513 Parnassus Avenue, Box 0130, San Francisco, California 94143, USA

Correspondence to: Daniel L. Minor, Jr Email: minor@itsa.ucsf.edu
Coordinates and structure factors have been deposited in the Protein Data Bank under accession codes 1T0H and 1T0J.

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 -subunit (Ca_V)^{1, 2}, binds a conserved domain (the -interaction domain, AID) between transmembrane domains I and II of the pore-forming ₁ 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_V2a conserved core, alone and in complex with the AID. Previous work suggested that a conserved region, the -interaction domain (BID), formed the AID-binding site^{3, 8}; however, this region is largely buried in the Ca_V core and is unavailable for protein–protein interactions. The structure of the AID–Ca_V2a complex shows instead that Ca_V2a engages the AID through an extensive, conserved hydrophobic cleft (named the -binding pocket, ABP). The ABP–AID interaction positions one end of the Ca_V 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_Vs influence Ca_V gating by direct modulation of IS6 movement within the channel pore.

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