Multiple Sequence Variants in STAC3 Affect Interactions with CaV1.1 and Excitation-Contraction Coupling

Structure. 2020 Aug 4;28(8):922-932.e5. doi: 10.1016/j.str.2020.05.005. Epub 2020 Jun 2.

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 CaV1.1 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 CaV1.1. Our results suggest that multiple STAC3 variants may cause myopathy.

Keywords: Ryanodine Receptor; X-ray crystallography; calcium channel; calcium signaling; calorimetry; genetic disorder; molecular dynamics; muscle excitation-contraction coupling; myopathy.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Action Potentials
  • Adaptor Proteins, Signal Transducing / chemistry*
  • Adaptor Proteins, Signal Transducing / genetics
  • Adaptor Proteins, Signal Transducing / metabolism
  • Binding Sites
  • Calcium Channels, L-Type / chemistry
  • Calcium Channels, L-Type / metabolism*
  • Cell Line
  • Cleft Palate / genetics*
  • Excitation Contraction Coupling*
  • Humans
  • Malignant Hyperthermia / genetics*
  • Molecular Dynamics Simulation
  • Mutation, Missense
  • Myotonia Congenita / genetics*
  • Protein Binding
  • Protein Conformation, beta-Strand
  • src Homology Domains

Substances

  • Adaptor Proteins, Signal Transducing
  • Calcium Channels, L-Type
  • Stac3 protein, human

Supplementary concepts

  • Native American myopathy