Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 106, Issue 13, Pages 5135-5140Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.0807487106
Keywords
structure; function; voltage-gated calcium channel
Categories
Funding
- National Institutes of Health [AR44864, AR44657, GM68826, HL087099]
- National Institutes of Health Dental and Craniofacial Training
- Welch Foundation [Q-581]
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Voltage-dependent calcium channels (Ca-v) open in response to changes in membrane potential, but their activity is modulated by Ca2+ binding to calmodulin (CaM). Structural studies of this family of channels have focused on CaM bound to the IQ motif; however, the minimal differences between structures cannot adequately describe CaM's role in the regulation of these channels. We report a unique crystal structure of a 77-residue fragment of the Ca(v)1.2 alpha(1) subunit carboxyl terminus, which includes a tandem of the pre-IQ and IQ domains, in complex with Ca2+center dot CaM in 2 distinct binding modes. The structure of the Cav1.2 fragment is an unusual dimer of 2 coiled-coiled pre-IQ regions bridged by 2Ca(2+)center dot CaMs interacting with the pre-IQ regions and a canonical Ca(v)1-IQ-Ca2+center dot CaM complex. Native Ca(v)1.2 channels are shown to be a mixture of monomers/dimers and a point mutation in the pre-IQ region predicted to abolish the coiled-coil structure significantly reduces Ca2+-dependent inactivation of heterologously expressed Ca(v)1.2 channels.
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