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Amino-terminus oligomerization regulates cardiac ryanodine receptor function

Zissimopoulos, Spyros, Viero, Cedric, Seidel, Monika, Cumbes, Bevan ORCID:, White, Judith, Cheung, Iris, Stewart, Richard, Jeyakumar, Lois, Fleischer, Sidney, Mukherjee, Saptarshi, Thomas, Nia Lowri ORCID:, Williams, Alan John and Lai, Francis Anthony ORCID: 2013. Amino-terminus oligomerization regulates cardiac ryanodine receptor function. Journal of Cell Science n/a 10.1242/​jcs.133538

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The ryanodine receptor (RyR) is an ion channel composed of four identical subunits mediating calcium efflux from the endo/sarcoplasmic reticulum of excitable and non-excitable cells. We present several lines of evidence indicating that the RyR2 amino-terminus is capable of self-association. A combination of yeast two-hybrid screens, co-immunoprecipitation analysis, chemical cross-linking and gel filtration assays collectively demonstrate that an RyR2 N-terminal fragment possesses the intrinsic ability to oligomerize, enabling apparent tetramer formation. Interestingly, N-terminus tetramerization mediated by endogenous disulfide bond formation occurs in native RyR2, but notably not in RyR1. Disruption of N-terminal inter-subunit interactions within RyR2 results in dysregulation of channel activation at diastolic Ca2+ 12 concentrations from ryanodine binding and single channel measurements. Our findings suggest that the N-terminus interactions mediating tetramer assembly are involved in RyR channel closure, identifying a critical role for this structural association in the dynamic regulation of intracellular Ca2+ 15 release.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Medicine
Subjects: R Medicine > R Medicine (General)
Uncontrolled Keywords: cardiac ryanodine receptor; amino-terminus; calcium release channel; oligomerization
Additional Information: Online publication date: 13 August 2013.
Publisher: The Company of Biologists Ltd
ISSN: 0021-9533
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Last Modified: 25 Oct 2022 08:14

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