8vk4
Structure of mouse RyR1 in complex with S100A1 (high-Ca2+/CFF/ATP dataset)
Structural highlights
FunctionFKB1A_MOUSE Keeps in an inactive conformation TGFBR1, the TGF-beta type I serine/threonine kinase receptor, preventing TGF-beta receptor activation in absence of ligand. Recruits SMAD7 to ACVR1B which prevents the association of SMAD2 and SMAD3 with the activin receptor complex, thereby blocking the activin signal. May modulate the RYR1 calcium channel activity. PPIases accelerate the folding of proteins. It catalyzes the cis-trans isomerization of proline imidic peptide bonds in oligopeptides (By similarity). 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[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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