期刊
JOURNAL OF CELL SCIENCE
卷 126, 期 21, 页码 5042-5051出版社
COMPANY BIOLOGISTS LTD
DOI: 10.1242/jcs.133538
关键词
Cardiac ryanodine receptor; N-terminus; Calcium release channel; Oligomerization
类别
资金
- British Heart Foundation Fellowship [FS/08/063]
- Wales Heart Research Institute Training Placement Scholarships
- British Heart Foundation [FS/08/063/25812, RG/09/009/28069] Funding Source: researchfish
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.
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