Journal
STRUCTURE
Volume 16, Issue 4, Pages 607-620Publisher
CELL PRESS
DOI: 10.1016/j.str.2008.01.011
Keywords
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Funding
- NIMH NIH HHS [R01 MH065531-04, R01 MH065531, R01 MH065531-03, R01MH065531, R01 MH065531-06, R01 MH065531-05, R01 MH065531-02] Funding Source: Medline
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Calmodulin (CaM) regulation of Ca2+ channels is central to Ca2+ signaling. Ca(V)1 versus Ca(V)2 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 Ca(V)2.1 and Ca(V)2.3 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 Ca(V)2.1 regulation, whereas downstream perturbations had limited effects. Furthermore, our Ca(V)2 structures closely resemble published Ca2+/CaM-Ca(V)1.2 IQ structures, arguing against Ca(V)1/2 regulatory differences based solely on contrasting CaM/IQ conformations. Instead, alanine scanning of the Ca(V)2.1 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.
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