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

Manu Ben Johny, Philemon S. Yang, Hojjat Bazzazi and David T. Yue ()
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Manu Ben Johny: Calcium Signals Laboratory, The Johns Hopkins University School of Medicine
Philemon S. Yang: Calcium Signals Laboratory, The Johns Hopkins University School of Medicine
Hojjat Bazzazi: Calcium Signals Laboratory, The Johns Hopkins University School of Medicine
David T. Yue: Calcium Signals Laboratory, The Johns Hopkins University School of Medicine

Nature Communications, 2013, vol. 4, issue 1, 1-13

Abstract: Abstract Calmodulin regulation of CaV channels is a prominent Ca2+ feedback mechanism orchestrating vital adjustments of Ca2+ entry. The long-held structural correlation of this regulation has been Ca2+-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 Ca2+–calmodulin to interfaces beyond the IQ domain, initiating substantial rearrangements of the calmodulin/channel complex. The N-lobe of Ca2+–calmodulin binds an N-terminal spatial Ca2+ 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.

Date: 2013
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DOI: 10.1038/ncomms2727

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