Skip to main content

Molecular basis for allosteric regulation of the type 2 ryanodine receptor channel gating by key modulators

Author(s): Chi, Ximin; Gong, Deshun; Ren, Kang; Zhou, Gewei; Huang, Gaoxingyu; et al

Download
To refer to this page use: http://arks.princeton.edu/ark:/88435/pr1kp7tq83
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.
Publication Date: 2-Dec-2019
Citation: Chi, Ximin, Gong, Deshun, Ren, Kang, Zhou, Gewei, Huang, Gaoxingyu, Lei, Jianlin, Zhou, Qiang, Yan, Nieng. (2019). Molecular basis for allosteric regulation of the type 2 ryanodine receptor channel gating by key modulators.. Proceedings of the National Academy of Sciences of the United States of America, 116 (51), 25575 - 25582. doi:10.1073/pnas.1914451116
DOI: doi:10.1073/pnas.1914451116
ISSN: 0027-8424
EISSN: 1091-6490
Pages: 25575 - 25582
Language: eng
Type of Material: Journal Article
Journal/Proceeding Title: Proceedings of the National Academy of Sciences of the United States of America
Version: Final published version. This is an open access article.



Items in OAR@Princeton are protected by copyright, with all rights reserved, unless otherwise indicated.