Abstract
Ryanodine receptor 1 (RyR1) mediates excitation–contraction coupling by releasing Ca2+ from sarcoplasmic reticulum (SR) to the cytoplasm of skeletal muscle cells. RyR1 activation is regulated by several proteins from both the cytoplasm and lumen of the SR. Here, we report the structure of RyR1 from native SR membranes in closed and open states. Compared to the previously reported structures of purified RyR1, our structure reveals helix‐like densities traversing the bilayer approximately 5 nm from the RyR1 transmembrane domain and sarcoplasmic extensions linking RyR1 to a putative calsequestrin network. We document the primary conformation of RyR1 in situ and its structural variations. The activation of RyR1 is associated with changes in membrane curvature and movement in the sarcoplasmic extensions. Our results provide structural insight into the mechanism of RyR1 in its native environment.
Highlights
Ryanodine receptors (RyRs) are large ion channels performing Ca2+ release from the sarcoplasmic reticulum (SR) into the cytosol of skeletal and cardiac muscle, triggering muscle fibre contraction [1,2]
CSQ has two isoforms: CSQ1, which interacts with Ryanodine receptor 1 (RyR1) in skeletal muscle, and CSQ2, which interacts with RyR2, a form primarily expressed in cardiac muscle [10]
We purified the SR-containing fractions from rabbit muscle as previously described [32] and imaged them by cryo-electron tomography
Summary
Ryanodine receptors (RyRs) are large ion channels performing Ca2+ release from the sarcoplasmic reticulum (SR) into the cytosol of skeletal and cardiac muscle, triggering muscle fibre contraction [1,2]. We report a structure of RyR1 in native membranes purified from rabbit skeletal muscle, determined by cryo-electron tomography and subtomogram averaging (StA). The structure includes the native membrane, shows observable curvature, as well as several interacting protein densities that were not observed in the reported high-resolution cryo-EM structures of purified RyR1.
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