1. Multiple Sequence Variants in STAC3 Affect Interactions with Ca V 1.1 and Excitation-Contraction Coupling.
- Author
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Rufenach B, Christy D, Flucher BE, Bui JM, Gsponer J, Campiglio M, and Van Petegem F
- Subjects
- Action Potentials, Adaptor Proteins, Signal Transducing genetics, Adaptor Proteins, Signal Transducing metabolism, Binding Sites, Calcium Channels, L-Type chemistry, Cell Line, Humans, Molecular Dynamics Simulation, Mutation, Missense, Protein Binding, Protein Conformation, beta-Strand, src Homology Domains, Adaptor Proteins, Signal Transducing chemistry, Calcium Channels, L-Type metabolism, Cleft Palate genetics, Excitation Contraction Coupling, Malignant Hyperthermia genetics, Myotonia Congenita genetics
- Abstract
STAC3 is a soluble protein essential for skeletal muscle excitation-contraction (EC) coupling. Through its tandem SH3 domains, it interacts with the cytosolic II-III loop of the skeletal muscle voltage-gated calcium channel. STAC3 is the target for a mutation (W284S) that causes Native American myopathy, but multiple other sequence variants have been reported. Here, we report a crystal structure of the human STAC3 tandem SH3 domains. We analyzed the effect of five disease-associated variants, spread over both SH3 domains, on their ability to bind to the Ca
V 1.1 II-III loop and on muscle EC coupling. In addition to W284S, we find the F295L and K329N variants to affect both binding and EC coupling. The ability of the K329N variant, located in the second SH3 domain, to affect the interaction highlights the importance of both SH3 domains in association with CaV 1.1. Our results suggest that multiple STAC3 variants may cause myopathy., Competing Interests: Declaration of Interests The authors declare no competing interests., (Copyright © 2020 Elsevier Ltd. All rights reserved.)- Published
- 2020
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