Abstract
Voltage-gated calcium channels are key players in a number of fundamental physiological functions including contraction, secretion, transmitter release or gene activation. They allow a flux of calcium into the cell that constitutes a switch-on signal for most of these functions. The structures responsible for the shaping of these fluxes by the membrane voltage belong to the channel itself, but a number of associated proteins are known to more precisely tune this calcium entry and adapt it to the cellular demand. The calcium channel regulatory beta subunit is undoubtedly the most important one, being influent on the expression, the kinetics, the voltage-dependence of channel opening and closing and on the pharmacology of the channel. Heterologous expression, combined to mutagenesis and electrophysiological and biochemical experiments have revealed the roles of short sequences of the beta subunit, including the BID (beta-interaction domain), in the physical and functional interactions with the channel pore. The resolved crystal structure of the beta subunit now sheds new light on these sequences and their interactions with the rest of the protein. The presence of a type 3 src-homology (SH3) domain and a guanylate kinase (GK) domain confirms that the subunit belongs to the MAGUK protein family. Consistently, the polyproline binding site and the kinase function of the SH3 and the GK domains, respectively, are non functional, and the BID appears to be buried in the structure, preserving the SH3-GK interaction but not directly available for interactions with the channel pore subunit. Anchoring of the beta subunit to the channel occurs via a hydrophobic grove in the GK domain, leaving a large surface of the subunit open to other protein-protein interactions. To what extent the intramolecular SH3-GK interaction is necessary for the stabilisation of this grove in a functional unit remains to be understood. The beta subunit may thus play a key role in scaffolding multiple proteins around the channel and organizing diverse calcium-dependent signalling pathways directly linked to voltage-gated calcium entry. These findings will undoubtedly vitalize the search for new beta-specific partners and functions.