Structural analysis of the voltage-dependent calcium channel β subunit functional core and its complex with the α1 interaction domain

Yarden Opatowsky, Chien Chang Chen, Kevin P. Campbell, Joel A. Hirsch

Research output: Contribution to journalArticlepeer-review

237 Scopus citations

Abstract

Voltage-dependent calcium channels (VDCC) are multiprotein assemblies that regulate the entry of extracellular calcium into electrically excitable cells and serve as signal transduction centers. The α1 subunit forms the membrane pore while the intracellular β subunit is responsible for trafficking of the channel to the plasma membrane and modulation of its electrophysiological properties. Crystallographic analyses of a β subunit functional core alone and in complex with a α1 interaction domain (AID) peptide, the primary binding site of β to the α1 subunit, reveal that β represents a novel member of the MAGUK protein family. The findings illustrate how the guanylate kinase fold has been fashioned into a protein-protein interaction module by alteration of one of its substrate sites. Combined results indicate that the AID peptide undergoes a helical transition in binding to β. We outline the mechanistic implications for understanding the β subunit's broad regulatory role of the VDCC, particularly via the AID.

Original languageEnglish
Pages (from-to)387-399
Number of pages13
JournalNeuron
Volume42
Issue number3
DOIs
StatePublished - 13 May 2004
Externally publishedYes

Bibliographical note

Funding Information:
We thank the beamline staffs at the ESRF (ID-14, ID-29, BM-14). Special thanks go to Dr. Gavin Fox for assistance during our MAD experiment data collection at BM-14. Also, we acknowledge the support of the bioinformatics unit in the Faculty of Life Sciences at TAU for our computational needs and the proteomics unit for mass spectrometry. We are grateful to Orna Chomsky-Hecht for mutagenesis and to Drs. N. Ben-Tal, N. Dascal, and N. Nelson for a critical reading of the manuscript. This research has been supported by a grant (507/00) to J.A.H. from the Israel Science Foundation and the Charles H. Revson Foundation.

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