Structural basis of the α1-β subunit interaction of voltage-gated Ca2+ channels

High-voltage-activated Ca2+ channels are essential for diverse biological processes. They are composed of four or five subunits, including alpha(1), alpha(2)-delta, beta and gamma ( ref. 1). Their expression and function are critically dependent on the beta-subunit, which transports alpha(1) to the surfacemembrane and regulates diverse channel properties(2-4). It is believed(3-6) that the beta-subunit interacts with alpha(1) primarily through the beta-interaction domain (BID), which binds directly to the alpha-interaction domain (AID) of alpha(1)(7); however, the molecular mechanism of the alpha(1)-beta interaction is largely unclear. Here we report the crystal structures of the conserved core region of b 3, alone and in complex with AID, and of b 4 alone. The structures show that the beta-subunit core contains two interacting domains: a Src homology 3 (SH3) domain and a guanylate kinase (GK) domain. The AID binds to a hydrophobic groove in the GK domain through extensive interactions, conferring extremely high affinity between alpha(1) and beta-subunits(4,8). The BID is essential both for the structural integrity of and for bridging the SH3 and GK domains, but it does not participate directly in binding alpha(1). The presence of multiple protein-interactingmodules in the beta-subunit opens a new dimension to its function as a multi-functional protein.