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

High-voltage-activated Ca 2+ channels are essential for diverse biological processes. They are composed of four or five subunits, including α 1 , α 2 -δ, β and γ (ref. 1 ). Their expression and function are critically dependent on the β-subunit, which transports α 1 to the surface membrane and regulates diverse channel properties 2 , 3 , 4 . It is believed 3 , 4 , 5 , 6 that the β-subunit interacts with α 1 primarily through the β-interaction domain (BID), which binds directly to the α-interaction domain (AID) of α 1 7 ; however, the molecular mechanism of the α 1 –β interaction is largely unclear. Here we report the crystal structures of the conserved core region of β 3 , alone and in complex with AID, and of β 4 alone. The structures show that the β-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 α 1 and β-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 α 1 . The presence of multiple protein-interacting modules in the β-subunit opens a new dimension to its function as a multi-functional protein.