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Structure of mouse RyR1 (high-Ca2+/CFF/ATP dataset)
Structural highlights
FunctionRYR1_MOUSE Cytosolic calcium-activated calcium channel that mediates the release of Ca(2+) from the sarcoplasmic reticulum into the cytosol and thereby plays a key role in triggering muscle contraction following depolarization of T-tubules (PubMed:18003898, PubMed:21156754, PubMed:7515481, PubMed:7621815). Repeated very high-level exercise increases the open probability of the channel and leads to Ca(2+) leaking into the cytoplasm (PubMed:18268335). Can also mediate the release of Ca(2+) from intracellular stores in neurons, and may thereby promote prolonged Ca(2+) signaling in the brain (PubMed:22036948). Required for normal embryonic development of muscle fibers and skeletal muscle (PubMed:7515481). Required for normal heart morphogenesis, skin development and ossification during embryogenesis (PubMed:18003898, PubMed:7515481).[1] [2] [3] [4] [5] [6] Publication Abstract from PubMedS100A1, a small homodimeric EF-hand Ca(2+)-binding protein (~21 kDa), plays an important regulatory role in Ca(2+) signaling pathways involved in various biological functions including Ca(2+) cycling and contractile performance in skeletal and cardiac myocytes. One key target of the S100A1 interactome is the ryanodine receptor (RyR), a huge homotetrameric Ca(2+) release channel (~2.3 MDa) of the sarcoplasmic reticulum. Here, we report cryoelectron microscopy structures of S100A1 bound to RyR1, the skeletal muscle isoform, in absence and presence of Ca(2+). Ca(2+)-free apo-S100A1 binds beneath the bridging solenoid (BSol) and forms contacts with the junctional solenoid and the shell-core linker of RyR1. Upon Ca(2+)-binding, S100A1 undergoes a conformational change resulting in the exposure of the hydrophobic pocket known to serve as a major interaction site of S100A1. Through interactions of the hydrophobic pocket with RyR1, Ca(2+)-bound S100A1 intrudes deeper into the RyR1 structure beneath BSol than the apo-form and induces sideways motions of the C-terminal BSol region toward the adjacent RyR1 protomer resulting in tighter interprotomer contacts. Interestingly, the second hydrophobic pocket of the S100A1-dimer is largely exposed at the hydrophilic surface making it prone to interactions with the local environment, suggesting that S100A1 could be involved in forming larger heterocomplexes of RyRs with other protein partners. Since S100A1 interactions stabilizing BSol are implicated in the regulation of RyR-mediated Ca(2+) release, the characterization of the S100A1 binding site conserved between RyR isoforms may provide the structural basis for the development of therapeutic strategies regarding treatments of RyR-related disorders. Structural insights into the regulation of RyR1 by S100A1.,Weninger G, Miotto MC, Tchagou C, Reiken S, Dridi H, Brandenburg S, Riedemann GC, Yuan Q, Liu Y, Chang A, Wronska A, Lehnart SE, Marks AR Proc Natl Acad Sci U S A. 2024 Jul 2;121(27):e2400497121. doi: , 10.1073/pnas.2400497121. Epub 2024 Jun 25. PMID:38917010[7] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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