Ca 2+ inactivation of the mammalian ryanodine receptor type 1 in a lipidic environment revealed by cryo-EM

Activation of the intracellular Ca channel ryanodine receptor (RyR) triggers a cytosolic Ca surge, while elevated cytosolic Ca inhibits the channel in a negative feedback mechanism. Cryogenic electron microscopy of rabbit RyR1 embedded in nanodiscs under partially inactivating Ca conditions revealed...

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Bibliographic Details
Published in:eLife 2022-03, Vol.11
Main Authors: Nayak, Ashok R, Samsó, Montserrat
Format: Article
Language:English
Subjects:
Animals
Calcium - metabolism
Cryoelectron Microscopy
Cytosol - metabolism
EF Hand Motifs
Mammals - metabolism
Rabbits
Ryanodine Receptor Calcium Release Channel - metabolism
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Summary:Activation of the intracellular Ca channel ryanodine receptor (RyR) triggers a cytosolic Ca surge, while elevated cytosolic Ca inhibits the channel in a negative feedback mechanism. Cryogenic electron microscopy of rabbit RyR1 embedded in nanodiscs under partially inactivating Ca conditions revealed an open and a closed-inactivated conformation. Ca binding to the high-affinity site engages the central and C-terminal domains into a block, which pries the S6 four-helix bundle open. Further rotation of this block pushes S6 toward the central axis, closing (inactivating) the channel. Main characteristics of the Ca -inactivated conformation are downward conformation of the cytoplasmic assembly and tightly knit subunit interface contributed by a fully occupied Ca activation site, two inter-subunit resolved lipids, and two salt bridges between the EF hand domain and the S2-S3 loop validated by disease-causing mutations. The structural insight illustrates the prior Ca activation prerequisite for Ca inactivation and provides for a seamless transition from inactivated to closed conformations.
ISSN:2050-084X