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Amino-terminus oligomerization regulates cardiac ryanodine receptor function

Zissimopoulos, Spyros, Viero, Cedric, Seidel, Monika, Cumbes, Bevan, White, Judith, Cheung, Iris, Stewart, Richard, Jeyakumar, Lois, Fleischer, Sidney, Mukherjee, Saptarshi, Thomas, Nia Lowri, Williams, Alan John and Lai, Francis Anthony 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: 27 Mar 2020 02:38

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