Arrhythmia mutations in calmodulin cause conformational changes that affect interactions with the cardiac voltage-gated calcium channel
- Univ. of British Columbia, Vancouver, BC (Canada)
- Aalborg Univ. (Denmark)
Calmodulin (CaM) represents one of the most conserved proteins among eukaryotes and is known to bind and modulate more than a 100 targets. Recently, several disease-associated mutations have been identified in theCALMgenes that are causative of severe cardiac arrhythmia syndromes. Although several mutations have been shown to affect the function of various cardiac ion channels, direct structural insights into any CaM disease mutation have been lacking. Here we report a crystallographic and NMR investigation of several disease mutant CaMs, linked to long-QT syndrome, in complex with the IQ domain of the cardiac voltage-gated calcium channel (CaV1.2). Surprisingly, two mutants (D95V, N97I) cause a major distortion of the C-terminal lobe, resulting in a pathological conformation not reported before. Furthermore, these structural changes result in altered interactions with the CaV1.2 IQ domain. Another mutation (N97S) reduces the affinity for Ca2+by introducing strain in EF hand 3. A fourth mutant (F141L) shows structural changes in the Ca2+-free state that increase the affinity for the IQ domain. These results thus show that different mechanisms underlie the ability of CaM disease mutations to affect Ca2+-dependent inactivation of the voltage-gated calcium channel.
- Research Organization:
- Argonne National Laboratory (ANL), Argonne, IL (United States). Advanced Photon Source (APS)
- Sponsoring Organization:
- Danish Ministry of Higher Education and Science; Natural Sciences and Engineering Research Council of Canada (NSERC); National Research Council Canada (NRC); Canadian Institutes of Health Research (CIHR); Province of Saskatchewan; Western Economic Diversification Canada; University of Saskatchewan; Obel Family Foundation; Novo Nordisk Foundation; Lundbeck Foundation; Danish Council for Independent Research (DFF); SparNord; Carlsberg Foundations
- Grant/Contract Number:
- AU-2010-612-181; PJT-148632; NNF15OC0012345; NNF16OC0023344; R151-2013-14432; DFF-4181-00447; DFF-1323-00344; NNF15OC0016186
- OSTI ID:
- 1483880
- Journal Information:
- Proceedings of the National Academy of Sciences of the United States of America, Vol. 115, Issue 45; ISSN 0027-8424
- Publisher:
- National Academy of SciencesCopyright Statement
- Country of Publication:
- United States
- Language:
- ENGLISH
Web of Science
Chemical shift assignments of a calmodulin intermediate with two Ca2+ bound in complex with the IQ-motif of voltage-gated Ca2+ channels (CaV1.2)
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journal | February 2019 |
Crystal structures of Ca 2+ –calmodulin bound to Na V C-terminal regions suggest role for EF-hand domain in binding and inactivation
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journal | May 2019 |
Arrhythmogenic calmodulin E105A mutation alters cardiac RyR2 regulation leading to cardiac dysfunction in zebrafish
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journal | March 2019 |
The Crossroad of Ion Channels and Calmodulin in Disease
|
journal | January 2019 |
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