Molecular basis for allosteric regulation of the type 2 ryanodine receptor channel gating by key modulators
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 p...
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Published in | Proceedings of the National Academy of Sciences - PNAS Vol. 116; no. 51; pp. 25575 - 25582 |
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Main Authors | , , , , , , , |
Format | Journal Article |
Language | English |
Published |
United States
National Academy of Sciences
17.12.2019
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Subjects | |
Online Access | Get full text |
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Summary: | 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. |
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Bibliography: | ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 Reviewers: L.F., Stanford University; and F.L.A.V.P., University of British Columbia. Author contributions: D.G. and N.Y. designed research; X.C., D.G., K.R., G.Z., G.H., J.L., and Q.Z. performed research; X.C., D.G., K.R., G.Z., G.H., J.L., Q.Z., and N.Y. analyzed data; and D.G. and N.Y. wrote the paper. Contributed by Nieng Yan, October 28, 2019 (sent for review August 20, 2019; reviewed by Liang Feng and Filip L. A. Van Petegem) 1X.C. and D.G. contributed equally to this work. |
ISSN: | 0027-8424 1091-6490 |
DOI: | 10.1073/pnas.1914451116 |