Abstract
The type 2 ryanodine receptor (RyR2) is responsible for releasing Ca2+ from the sarcoplasmic reticulum of cardiomyocytes, subsequently leading to muscle contraction. Here, we report 4 cryo-electron microscopy (cryo-EM) structures of porcine RyR2 bound to distinct modulators that, together with our published structures, provide mechanistic insight into RyR2 regulation. Ca2+ alone induces a contraction of the central domain that facilitates the dilation of the S6 bundle but is insufficient to open the pore. The small-molecule agonist PCB95 helps Ca2+ to overcome the barrier for opening. FKBP12.6 induces a relaxation of the central domain that decouples it from the S6 bundle, stabilizing RyR2 in a closed state even in the presence of Ca2+ and PCB95. Although the channel is open when PCB95 is replaced by caffeine and adenosine 5′-triphosphate (ATP), neither of the modulators alone can sufficiently counter the antagonistic effect to open the channel. Our study marks an important step toward mechanistic understanding of the sophisticated regulation of this key channel whose aberrant activity engenders life-threatening cardiac disorders.
Original language | English (US) |
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Pages (from-to) | 25575-25582 |
Number of pages | 8 |
Journal | Proceedings of the National Academy of Sciences of the United States of America |
Volume | 116 |
Issue number | 51 |
DOIs | |
State | Published - Dec 17 2019 |
All Science Journal Classification (ASJC) codes
- General
Keywords
- Allosteric regulation
- Cryo-EM structures
- Modulators
- Type 2 ryanodine receptor