Arrhythmia mutations in calmodulin cause conformational changes that affect interactions with the cardiac voltage-gated calcium channel

Wang, Kaiqian; Holt, Christian; Lu, Jocelyn; Brohus, Malene; Larsen, Kamilla Taunsig; Overgaard, Michael Toft; Wimmer, Reinhard; Van Petegem, Filip

doi:10.1073/pnas.1808733115

Title: Arrhythmia mutations in calmodulin cause conformational changes that affect interactions with the cardiac voltage-gated calcium channel

Journal Article · 21 October 2018 · Proceedings of the National Academy of Sciences of the United States of America

DOI: https://doi.org/10.1073/pnas.1808733115 · OSTI ID:1483880

Wang, Kaiqian ^[1]; Holt, Christian ^[2]; Lu, Jocelyn ^[1]; Brohus, Malene ^[2]; Larsen, Kamilla Taunsig ^[2];

^[2];

^[2]; Van Petegem, Filip ^[1]

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 (Ca_V1.2). 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 Ca_V1.2 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.

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Research Organization:: Argonne National Laboratory (ANL), Argonne, IL (United States). Advanced Photon Source (APS)

Sponsoring Organization:: Canadian Institutes of Health Research (CIHR); Carlsberg Foundations; Danish Council for Independent Research (DFF); Danish Ministry of Higher Education and Science; Lundbeck Foundation; National Research Council Canada (NRC); Natural Sciences and Engineering Research Council of Canada (NSERC); Novo Nordisk Foundation; Obel Family Foundation; Province of Saskatchewan; SparNord; University of Saskatchewan; Western Economic Diversification Canada

OSTI ID:: 1483880

Journal Information:: Proceedings of the National Academy of Sciences of the United States of America, Journal Name: Proceedings of the National Academy of Sciences of the United States of America Journal Issue: 45 Vol. 115; ISSN 0027-8424

Publisher:: National Academy of SciencesCopyright Statement

Country of Publication:: United States

Language:: ENGLISH

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Arrhythmogenic calmodulin E105A mutation alters cardiac RyR2 regulation leading to cardiac dysfunction in zebrafish Da'as, Sahar I.; Thanassoulas, Angelos; Calver, Brian L. Annals of the New York Academy of Sciences, Vol. 1448, Issue 1 https://doi.org/10.1111/nyas.14033	journal	March 2019
The Crossroad of Ion Channels and Calmodulin in Disease Urrutia, Janire; Aguado, Alejandra; Muguruza-Montero, Arantza International Journal of Molecular Sciences, Vol. 20, Issue 2 https://doi.org/10.3390/ijms20020400	journal	January 2019

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Title: Arrhythmia mutations in calmodulin cause conformational changes that affect interactions with the cardiac voltage-gated calcium channel

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