Voltage-dependent calcium channels (VDCC) are multiprotein assemblies that regulate the entry of extracellular calcium into electrically excitable cells and serve as signal transduction centers. The α1 subunit forms the membrane pore while the intracellular β subunit is responsible for trafficking of the channel to the plasma membrane and modulation of its electrophysiological properties. Crystallographic analyses of a β subunit functional core alone and in complex with a α1 interaction domain (AID) peptide, the primary binding site of β to the α1 subunit, reveal that β represents a novel member of the MAGUK protein family. The findings illustrate how the guanylate kinase fold has been fashioned into a protein-protein interaction module by alteration of one of its substrate sites. Combined results indicate that the AID peptide undergoes a helical transition in binding to β. We outline the mechanistic implications for understanding the β subunit's broad regulatory role of the VDCC, particularly via the AID.