Determinants in CaV1 Channels That Regulate the Ca2+ Sensitivity of Bound Calmodulin

Calmodulin binds to IQ motifs in the α1 subunit of CaV1.1 and CaV1.2, but the affinities of calmodulin for the motif and for Ca2+ are higher when bound to CaV1.2 IQ. The CaV1.1 IQ and CaV1.2 IQ sequences differ by four amino acids. We determined the structure of calmodulin bound to CaV1.1 IQ and com...

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Published inThe Journal of biological chemistry Vol. 284; no. 30; pp. 20041 - 20051
Main Authors Halling, D. Brent, Georgiou, Dimitra K., Black, D.J., Yang, Guojun, Fallon, Jennifer L., Quiocho, Florante A., Pedersen, Steen E., Hamilton, Susan L.
Format Journal Article
LanguageEnglish
Published United States Elsevier Inc 24.07.2009
American Society for Biochemistry and Molecular Biology
Subjects
Amino Acid Motifs
Amino Acid Sequence
Animals
Calcium - chemistry
Calcium - metabolism
Calcium Channels, L-Type - chemistry
Calcium Channels, L-Type - metabolism
Calmodulin - chemistry
Calmodulin - genetics
Calmodulin - metabolism
Crystallography, X-Ray
Humans
Mammals
Models, Molecular
Molecular Sequence Data
Mutagenesis, Site-Directed
Peptides - chemistry
Peptides - metabolism
Protein Binding
Protein Conformation
Protein Structure and Folding
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Summary:Calmodulin binds to IQ motifs in the α1 subunit of CaV1.1 and CaV1.2, but the affinities of calmodulin for the motif and for Ca2+ are higher when bound to CaV1.2 IQ. The CaV1.1 IQ and CaV1.2 IQ sequences differ by four amino acids. We determined the structure of calmodulin bound to CaV1.1 IQ and compared it with that of calmodulin bound to CaV1.2 IQ. Four methionines in Ca2+-calmodulin form a hydrophobic binding pocket for the peptide, but only one of the four nonconserved amino acids (His-1532 of CaV1.1 and Tyr-1675 of CaV1.2) contacts this calmodulin pocket. However, Tyr-1675 in CaV1.2 contributes only modestly to the higher affinity of this peptide for calmodulin; the other three amino acids in CaV1.2 contribute significantly to the difference in the Ca2+ affinity of the bound calmodulin despite having no direct contact with calmodulin. Those residues appear to allow an interaction with calmodulin with one lobe Ca2+-bound and one lobe Ca2+-free. Our data also provide evidence for lobe-lobe interactions in calmodulin bound to CaV1.2.
ISSN:0021-9258
1083-351X
DOI:10.1074/jbc.M109.013326