Structure of the CaV2 IQ domain in complex with Ca²⁺/calmodulin

Abstract

Calmodulin (CaM) regulation of Ca²⁺ channels is a core paradigm for neurobiological Ca²⁺ signaling. CaV1 versus CaV2 classes of these channels exhibit divergent forms of regulation, despite suggestions that all such modulation involves Ca²⁺/CaM binding to an IQ domain on channels. Understanding this diversity thus promises valuable mechanistic insight. Based on the structure of the Ca²⁺/CaM-CaV1.2 (L-type)IQ domain, it has been suggested that CaV1/2 regulatory diversity might reflect isoform-dependent differences in Ca²⁺/CaM IQ conformation. Here, we report the high-resolution structures for the Ca²⁺/CaM-IQ domains of both CaV2.1(P/Q-type) and CaV2.3(R-type) channels. In these highly similar structures, CaM embraces a helical IQ domain with a parallel orientation. Only minor differences from the CaV1.2 structure are present, insufficient to predict regulatory differences. To explore alternate explanations, we combined alanine scanning of the IQ domain in CaV2.1, with CaV2 structure-based molecular simulation of CaM/IQ binding energetics. These approaches raise the possibility that the C-lobe of CaM partially dislodges from the IQ element during functional regulation, allowing exposed residues to trigger regulation via isoform-specific interactions with other regions. [J Physiol Sci. 2008;58 Suppl:S72]