title: 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.
authors.affiliation: Department of Biomedical Engineering, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA.
authors.forename: Manu
authors.initials: M
authors.lastname: Ben Johny
authors.forename: Philemon S
authors.initials: PS
authors.lastname: Yang
authors.forename: Hojjat
authors.initials: H
authors.lastname: Bazzazi
authors.forename: David T
authors.initials: DT
authors.lastname: Yue
mesh_terms: D002118:Calcium / Q000378:metabolism*; D020746:Calcium Channels, L-Type / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D002147:Calmodulin / Q000378:metabolism*; D057809:HEK293 Cells; D006801:Humans; D013329:Structure-Activity Relationship
chemical_list: C472073:CACNA1D protein, human; D020746:Calcium Channels, L-Type; D002147:Calmodulin; D002118:Calcium