Essential CaVβ modulatory properties are AID-independent

Voltage-gated Ca2+ channel beta (Ca-v beta) subunits have a highly conserved core consisting of interacting Src homology 3 and guanylate kinase domains, and are postulated to exert their effects through AID, the major interaction site in the pore-forming alpha(1) subunit. This stereotypical interaction does not explain how individual Ca-v beta subunits modulate alpha(1) subunits differentially. Here we show that AID is neither necessary nor sufficient for critical Ca-v beta regulatory properties. Complete modulation depends on additional contacts that are exclusive of AID and not revealed in recent crystal structures. These data offer a new context for understanding Ca-v beta modulation, suggesting that the AID interaction orients the Ca-v beta core so as to permit additional isoform-specific Ca-v alpha(1)-Ca-v beta interactions that underlie the particular regulation seen with each Ca-v alpha(1)-Ca-v beta pair, rather than as the main site of regulation.