Structural basis of the alpha sub(1)- beta subunit interaction of voltage-gated Ca sub(2+) channels

High-voltage-activated Ca sub(2+) channels are essential for diverse biological processes. They are composed of four or five subunits, including alpha sub(1), alpha sub(2)- delta , beta and gamma (ref. 1). Their expression and function are critically dependent on the beta -subunit, which transports alpha sub(1) to the surface membrane and regulates diverse channel properties. It is believed that the beta -subunit interacts with alpha sub(1) primarily through the beta -interaction domain (BID), which binds directly to the alpha -interaction domain (AID) of alpha sub(1); however, the molecular mechanism of the alpha sub(1)- beta interaction is largely unclear. Here we report the crystal structures of the conserved core region of beta sub(3), alone and in complex with AID, and of beta sub(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 sub(1) and beta -subunits. 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 sub(1). The presence of multiple protein-interacting modules in the beta -subunit opens a new dimension to its function as a multi-functional protein.