Key result
Cryo-EM of the mammalian ryanodine receptor type 1 revealed distinct open (4.0 Å) and closed-inactivated (3.3 Å) states, showing that inactivation is not a simple reverse of activation.
This cryo-EM study reveals the structural basis for Ca2+-dependent inactivation of the mammalian ryanodine receptor type 1, showing that the closed-inactivated state is structurally distinct from the closed-activable state.
Structural distinction of RyR1 inactivation states leaves open new targets; requires validation before any clinical translation.
Activation of the intracellular Ca 2+ channel ryanodine receptor (RyR) triggers a cytosolic Ca 2+ surge, while elevated cytosolic Ca 2+ inhibits the channel in a negative feedback mechanism. Cryo-EM carried out under partially inactivating Ca 2+ conditions revealed two conformations of RyR1, an open state and an inactivated state, resolved at 4.0 and 3.3 Å resolution, respectively. RyR1s were embedded in nanodiscs with two lipids resolved at each inter-subunit crevice. Ca 2+ binding to the high affinity site engages the central (CD) and C-terminal domains (CTD) into a quasi-rigid unit, which separates the S6 four-helix bundle and opens the channel. Further out-of-plane rotation of the quasi-rigid unit pushes S6 towards the central axis, closing (inactivating) the channel. The inactivated conformation is characterized by a downward conformation of the cytoplasmic assembly, a tightly-knit subunit interface contributed by a fully occupied and partially remodeled Ca 2+ activation site, and two salt bridges between the EF hand domain and the S2-S3 loop of the neighboring subunit validated by naturally-occurring diseasecausing mutations. Ca 2+ also bound to ATP, mediating a tighter interaction between S6 and CTD. Our study suggests that the closed-inactivated is a distinctive state of the RyR1 and its transition to the closed-activable state is not a simple reverse of the Ca 2+ mediated activation pathway.
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Nayak et al. (2021) studied this question. Cryo-EM structural analysis was evaluated on Structural conformation of RyR1 under partially inactivating Ca2+ conditions. Cryo-EM of the mammalian ryanodine receptor type 1 revealed distinct open (4.0 Å) and closed-inactivated (3.3 Å) states, showing that inactivation is not a simple reverse of activation.
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