Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 114, Issue 45, Pages E9520-E9528Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1708852114
Keywords
STAC adaptor proteins; voltage-gated calcium channel; muscle excitation-contraction coupling; disease mutation; X-ray crystallography
Categories
Funding
- Natural Sciences and Engineering Research Council of Canada
- National Research Council Canada
- Canadian Institutes of Health Research (CIHR)
- Province of Saskatchewan
- University of Saskatchewan
- Western Economic Diversification Canada
- CIHR Operating Grant [MOP-119608]
- Austrian Science Fund (FWF) [T855, P27031]
- Austrian Science Fund (FWF) [P27031, T855] Funding Source: Austrian Science Fund (FWF)
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Excitation-contraction (EC) coupling in skeletal muscle requires functional and mechanical coupling between L-type voltage-gated calcium channels (Ca(V)1.1) and the ryanodine receptor (RyR1). Recently, STAC3 was identified as an essential protein for EC coupling and is part of a group of three proteins that can bind and modulate L-type voltage-gated calcium channels. Here, we report crystal structures of tandem-SH3 domains of different STAC isoforms up to 1.2-angstrom resolution. These form a rigid interaction through a conserved interdomain interface. We identify the linker connecting transmembrane repeats II and III in two different Ca-V isoforms as a binding site for the SH3 domains and report a crystal structure of the complex with the STAC2 isoform. The interaction site includes the location for a disease variant in STAC3 that has been linked to Native American myopathy (NAM). Introducing the mutation does not cause misfolding of the SH3 domains, but abolishes the interaction. Disruption of the interaction via mutations in the II-III loop perturbs skeletal muscle EC coupling, but preserves the ability of STAC3 to slow down inactivation of Ca(V)1.2.
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