CHANNELS MAGUKal Regulation of Calcium Channels?

Voltage-dependent calcium channels, which facilitate calcium influx into excitable cells and thereby influence myriad calcium-sensitive processes, contain four functionally distinct subunits: α1, α2, β, and . The calcium-selective pore is formed by the α1 subunit, whereas the β subunit modulates channel opening and plays a critical role in α1 trafficking. Sequence analysis has suggested that β subunits interact with the α1 interaction domain (AID); however, the detailed mechanisms whereby the relatively soluble intracellular β subunit affects α1 trafficking and function are poorly understood. Opatowsky et al. performed high-resolution crystallographic analyses of the β_2a functional core, alone and in complex with an AID peptide, and defined β as a membrane-associated guanylate kinase (MAGUK, a family of proteins that often function as molecular scaffolds), thereby confirming previous speculation based on homology modeling (see Preview by Yue). Although lacking the PDZ domain characteristic of previously defined MAGUKs, β retained SH3- and GK-like domains, interacting with the AID through its GK domain. A comparison of crystallographic data with circular dichroism spectroscopy of the AID peptide in solution indicated that association with β imposed a helical structure on the AID. The authors proposed that this imposition of helical structure propagates through this region of the α subunit so that interaction with β is critical for proper α1 folding. They further suggest that β has evolved so as to maximize interactions with other proteins, and they discuss the implications of their structural data for β-subunit regulation of calcium channel gating and for β as a potential site for colocalization of intracellular regulators of calcium channel function.

Y. Opatowsky, C.-C. Chen, K. P. Campbell, J. A. Hirsch, Structural analysis of the voltage-dependent calcium channel β subunit functional core and its complex with the α1 interaction domain. Neuron 42, 387-399 (2004). [Online Journal]

D. T. Yue, The dawn of high-resolution structure for the queen of ion channels. Neuron 42, 357-359 (2004). [Online Journal]

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EDITORS' CHOICE
STRUCTURAL BIOLOGY
Unexpected Interaction Between Calcium Channel Subunits

(15 June 2004)
Sci. STKE 2004 (237), tw212. [DOI: 10.1126/stke.2372004TW212]
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