N-terminus oligomerization regulates the function of cardiac ryanodine receptors

作者：Zissimopoulos Spyros^*; Viero Cedric; Seidel Monika; Cumbes Bevan; White Judith; Cheung Iris; Stewart Richard; Jeyakumar Loice H; Fleischer Sidney; Mukherjee Saptarshi; Thomas N Lowri; Williams Alan J; Lai F Anthony

来源：Journal of Cell Science, 2013, 126(21): 5042-5051.

DOI：10.1242/jcs.133538

• Cardiac ryanodine receptor
• N-terminus
• Calcium release channel
• Oligomerization

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.

• 出版日期2013-11-1