Zissimopoulos, Spyros, Viero, C., Seidel, Monika, Cumbes, Bevan ORCID: https://orcid.org/0000-0001-8529-0040, White, Judith, Cheung, I., Stewart, R., Jeyakumar, L., Fleischer, S., Mukherjee, Saptarshi, Thomas, Nia Lowri ORCID: https://orcid.org/0000-0001-8822-8576, Williams, Alan John and Lai, Francis ORCID: https://orcid.org/0000-0003-2852-8547 2013. N-terminus oligomerization regulates the function of cardiac ryanodine receptors. Journal of Cell Science 126 (21) , pp. 5042-5051. 10.1242/jcs.133538 |
Abstract
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 N-terminus is capable of self-association. A combination of yeast two-hybrid screens, co-immunoprecipitation analysis, chemical crosslinking and gel filtration assays collectively demonstrate that a 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+ 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 crucial role for this structural association in the dynamic regulation of intracellular Ca2+ release.
Item Type: | Article |
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Status: | Published |
Schools: | Medicine |
Subjects: | R Medicine > R Medicine (General) |
Publisher: | Company of Biologists |
ISSN: | 0021-9533 |
Date of Acceptance: | 30 July 2013 |
Last Modified: | 22 Nov 2022 09:43 |
URI: | https://orca.cardiff.ac.uk/id/eprint/110484 |
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