Crystal Structure of the CaV2 IQ Domain in Complex with Ca2+/Calmodulin: High-Resolution Mechanistic Implications for Channel Regulation by Ca2+

Masayuki X. Mori, Craig W. Vander Kooi, Daniel J. Leahy, David T. Yue

Research output: Contribution to journalArticlepeer-review

81 Scopus citations

Abstract

Calmodulin (CaM) regulation of Ca2+ channels is central to Ca2+ signaling. CaV1 versus CaV2 classes of these channels exhibit divergent forms of regulation, potentially relating to customized CaM/IQ interactions among different channels. Here we report the crystal structures for the Ca2+/CaM IQ domains of both CaV2.1 and CaV2.3 channels. These highly similar structures emphasize that major CaM contacts with the IQ domain extend well upstream of traditional consensus residues. Surprisingly, upstream mutations strongly diminished CaV2.1 regulation, whereas downstream perturbations had limited effects. Furthermore, our CaV2 structures closely resemble published Ca2+/CaM-CaV1.2 IQ structures, arguing against CaV1/2 regulatory differences based solely on contrasting CaM/IQ conformations. Instead, alanine scanning of the CaV2.1 IQ domain, combined with structure-based molecular simulation of corresponding CaM/IQ binding energy perturbations, suggests that the C lobe of CaM partially dislodges from the IQ element during channel regulation, allowing exposed IQ residues to trigger regulation via isoform-specific interactions with alternative channel regions.

Original languageEnglish
Pages (from-to)607-620
Number of pages14
JournalStructure
Volume16
Issue number4
DOIs
StatePublished - Apr 8 2008

Bibliographical note

Funding Information:
We thank Wanjun Yang for dedicated technical support; Mark Mayer and Samuel Bouyain for advice on crystallization; Lai Hock Tay for introducing the potential use of Robetta; David Masica, Jeffrey Gray, and Tanja Kortemme for advice on the use of Robetta; and Michael Tadross and Henry Colecraft for insightful comments and discussion. This work was supported by RO1MH065531 from the NIMH (to D.T.Y.).

Keywords

  • PROTEINS

ASJC Scopus subject areas

  • Structural Biology
  • Molecular Biology

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