Voltage-gated Ca2+ channel (Cav) 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 1 subunit. This stereotypical interaction does not explain how individual Cav subunits modulate 1 subunits differentially. Here we show that AID is neither necessary nor sufficient for critical Cav 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 Cav modulation, suggesting that the AID interaction orients the Cav core so as to permit additional isoform-specific Cav1-Cav interactions that underlie the particular regulation seen with each Cav1-Cav pair, rather than as the main site of regulation.
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modulatory properties are AID-independent
(Cav
1 subunit. This stereotypical interaction does not explain how individual Cav
