1. Department of Biological Sciences, Columbia University, New York, New York 10027, USA

Correspondence to: Jian Yang Email: jy160@columbia.edu
Coordinates have been deposited in the Protein Data Bank under accession codes 1VYU, 1VYT and 1VYV.

Abstract

High-voltage-activated Ca²⁺ channels are essential for diverse biological processes. They are composed of four or five subunits, including ₁, ₂-, and (ref. 1). Their expression and function are critically dependent on the -subunit, which transports ₁ to the surface membrane and regulates diverse channel properties^{2, 3, 4}. It is believed^{3, 4, 5, 6} that the -subunit interacts with ₁ primarily through the -interaction domain (BID), which binds directly to the -interaction domain (AID) of ₁⁷; however, the molecular mechanism of the ₁– interaction is largely unclear. Here we report the crystal structures of the conserved core region of ₃, alone and in complex with AID, and of ₄ alone. The structures show that the -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 ₁ and -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 ₁. The presence of multiple protein-interacting modules in the -subunit opens a new dimension to its function as a multi-functional protein.

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