title: STAC3 stably interacts through its C1 domain with CaV1.1 in skeletal muscle triads.
abstract: The adaptor protein STAC3 is essential for skeletal muscle excitation-contraction (EC) coupling and a mutation in the STAC3 gene has been linked to a severe muscle disease, Native American myopathy (NAM). However the function of STAC3, its interaction partner, and the mode of interaction within the EC-coupling complex remained elusive. Here we demonstrate that STAC3 forms a stable interaction with the voltage-sensor of EC-coupling, CaV1.1, and that this interaction depends on a hitherto unidentified protein-protein binding pocket in the C1 domain of STAC3. While the NAM mutation does not affect the stability of the STAC3-CaV1.1 interaction, mutation of two crucial residues in the C1 binding pocket increases the turnover of STAC3 in skeletal muscle triads. Thus, the C1 domain of STAC3 is responsible for its stable incorporation into the CaV1.1 complex, whereas the SH3 domain containing the NAM mutation site may be involved in low-affinity functional interactions in EC-coupling.
authors.affiliation: Department of Physiology and Medical Physics, Medical University of Innsbruck, 6020 Innsbruck, Austria.
authors.forename: Marta
authors.initials: M
authors.lastname: Campiglio
authors.affiliation: Department of Physiology and Medical Physics, Medical University of Innsbruck, 6020 Innsbruck, Austria.
authors.forename: Bernhard E
authors.initials: BE
authors.lastname: Flucher
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D004252:DNA Mutational Analysis; D051037:Large-Conductance Calcium-Activated Potassium Channel alpha Subunits / Q000378:metabolism*; D051379:Mice; D018482:Muscle, Skeletal / Q000502:physiology*; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D011485:Protein Binding; D025941:Protein Interaction Mapping; D011817:Rabbits
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D051037:Large-Conductance Calcium-Activated Potassium Channel alpha Subunits; D009419:Nerve Tissue Proteins; C583601:STAC3 protein, mouse