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Letters to Nature
Nature 429, 671-675 (10 June 2004) | doi:10.1038/nature02588; Received 1 March 2004; Accepted 23 April 2004; Published online 12 May 2004
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Structure of a complex between a voltage-gated calcium channel
-subunit and an
-subunit domain
Filip Van Petegem, Kimberly A. Clark, Franck C. Chatelain & Daniel L. Minor, Jr
- Cardiovascular Research Institute, Departments of Biochemistry and Biophysics, and Cellular and Molecular Pharmacology, University of California San Francisco, 513 Parnassus Avenue, Box 0130, San Francisco, California 94143, USA
Correspondence to: Daniel L. Minor, Jr Email: minor@itsa.ucsf.edu
Coordinates and structure factors have been deposited in the Protein Data Bank under accession codes 1T0H and 1T0J.
Abstract
Voltage-gated calcium channels (CaVs) govern muscle contraction, hormone and neurotransmitter release, neuronal migration, activation of calcium-dependent signalling cascades, and synaptic input integration1. An essential CaV intracellular protein, the
-subunit (CaV
)1, 2, binds a conserved domain (the
-interaction domain, AID) between transmembrane domains I and II of the pore-forming
1 subunit3 and profoundly affects multiple channel properties such as voltage-dependent activation2, inactivation rates2, G-protein modulation4, drug sensitivity5 and cell surface expression6, 7. Here, we report the high-resolution crystal structures of the CaV
2a conserved core, alone and in complex with the AID. Previous work suggested that a conserved region, the
-interaction domain (BID), formed the AID-binding site3, 8; however, this region is largely buried in the CaV
core and is unavailable for protein–protein interactions. The structure of the AID–CaV
2a complex shows instead that CaV
2a engages the AID through an extensive, conserved hydrophobic cleft (named the
-binding pocket, ABP). The ABP–AID interaction positions one end of the CaV
near the intracellular end of a pore-lining segment, called IS6, that has a critical role in CaV inactivation9, 10. Together, these data suggest that CaV
s influence CaV gating by direct modulation of IS6 movement within the channel pore.
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