Structural insights into binding of STAC proteins to voltage-gated calcium channels

• Published in: Proceedings of the National Academy of Sciences - PNAS 2017-11, Vol.114 (45), p.E9520-E9528
• Main Authors: Yuen, Siobhan M. Wong King, Campiglio, Marta, Tung, Ching-Chieh, Flucher, Bernhard E., Van Petegem, Filip
• Format: Article
• Language: English
• Subjects: Adaptor Proteins, Signal Transducing - metabolism; Animals; BASIC BIOLOGICAL SCIENCES; Binding sites; Binding Sites - physiology; Biological Sciences; Calcium; Calcium - metabolism; Calcium channels; Calcium channels (L-type); Calcium channels (voltage-gated); Calcium Channels, L-Type - metabolism; Calcium Signaling - physiology; Channels; Cleft Palate - metabolism; Contraction; Coupling; Crystal structure; Crystallography, X-Ray - methods; Deactivation; disease mutation; Excitation Contraction Coupling - physiology; Humans; Inactivation; Isoforms; Malignant Hyperthermia - metabolism; Mechanical properties; Membrane Proteins - metabolism; Minority & ethnic groups; Muscle contraction; muscle excitation–contraction coupling; Muscle, Skeletal - metabolism; Muscles; Musculoskeletal system; Mutation; Mutation - genetics; Myopathy; Myotonia Congenita - metabolism; PNAS Plus; Protein Isoforms - metabolism; Proteins; Rabbits; Ryanodine Receptor Calcium Release Channel - metabolism; Ryanodine receptors; Skeletal muscle; STAC adaptor proteins; voltage-gated calcium channel; X-ray crystallography; Xenopus laevis - metabolism
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.1708852114

Excitation–contraction (EC) coupling in skeletal muscle requires functional and mechanical coupling between L-type voltage-gated calcium channels (CaV1.1) 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-Å resolution. These form a rigid interaction through a conserved interdomain interface. We identify the linker connecting transmembrane repeats II and III in two different CaV 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 CaV1.2.