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Dynamic switching of calmodulin interactions underlies Ca2+ regulation of CaV1.3 channels.

ABSTRACT: Calmodulin regulation of CaV channels is a prominent Ca(2+) feedback mechanism orchestrating vital adjustments of Ca(2+) entry. The long-held structural correlation of this regulation has been Ca(2+)-bound calmodulin, complexed alone with an IQ domain on the channel carboxy terminus. Here, however, systematic alanine mutagenesis of the entire carboxyl tail of an L-type CaV1.3 channel casts doubt on this paradigm. To identify the actual molecular states underlying channel regulation, we develop a structure-function approach relating the strength of regulation to the affinity of underlying calmodulin/channel interactions, by a Langmuir relation (individually transformed Langmuir analysis). Accordingly, we uncover frank exchange of Ca(2+)-calmodulin to interfaces beyond the IQ domain, initiating substantial rearrangements of the calmodulin/channel complex. The N-lobe of Ca(2+)-calmodulin binds an N-terminal spatial Ca(2+) transforming element module on the channel amino terminus, whereas the C-lobe binds an EF-hand region upstream of the IQ domain. This system of structural plasticity furnishes a next-generation blueprint for CaV channel modulation.

SUBMITTER: Ben Johny M

PROVIDER: S-EPMC3856249 | biostudies-literature | 2013

REPOSITORIES: biostudies-literature

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Dynamic switching of calmodulin interactions underlies Ca2+ regulation of CaV1.3 channels.

Ben Johny Manu M Yang Philemon S PS Bazzazi Hojjat H Yue David T DT

Nature communications 20130101

Calmodulin regulation of CaV channels is a prominent Ca(2+) feedback mechanism orchestrating vital adjustments of Ca(2+) entry. The long-held structural correlation of this regulation has been Ca(2+)-bound calmodulin, complexed alone with an IQ domain on the channel carboxy terminus. Here, however, systematic alanine mutagenesis of the entire carboxyl tail of an L-type CaV1.3 channel casts doubt on this paradigm. To identify the actual molecular states underlying channel regulation, we develop a ...[more]

PMID: 23591884

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Dynamic switching of calmodulin interactions underlies Ca2+ regulation of CaV1.3 channels.

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Dynamic switching of calmodulin interactions underlies Ca2+ regulation of CaV1.3 channels.

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