Exp Mol Med.  2007 Oct;39(5):594-602.

Homo-dimerization of RyR1 C-terminus via charged residues in random coils or in an alpha-helix

Affiliations
  • 1Department of Physiology, College of Medicine, The Catholic University of Korea, Seoul 137-701, Korea. EHUI@catholic.ac.kr
  • 2Department of Anesthesiology, Perioperative and Pain Medicine, Brigham and Women's Hospital, Harvard Medical SchoolBoston, MA 02115, USA.

Abstract

To investigate the mechanism by which the C-terminus (4,938-5,037) of the ryanodine receptor 1 (RyR1) homo-tetramerizes, forming a functional Ca2+ -release channel, the structural requirements for the tetramerization were studied using site-directed mutagenesis. Alanine-substitutions at five charged residues, E4976, H5003, D5026, E5033 and D5034, significantly decreased the formation of homo-dimers (reduced by > 50%). Interaction between the C-terminus and cytoplasmic loop I (4,821-4,835) required two positively charged residues, H4832 and K4835. Based on the predicted protein secondary structures, all seven charged residues are located in random coils. Paired alanine-substitutions at six negatively charged residues (E4942A/D4953A, D4945A/E4952A and E4948A/ E4955A) of the alpha-helix (4,940-4,956) in the C-terminus increased homo-dimerization. Therefore, the homo-tetramerization of RyR1 may be mediated by intra- and/or inter-monomer electrostatic interactions among the C-terminal charged residues in random coils or in an alpha-helix.

Keyword

mutagenesis, site-directed; ryanodine receptor calcium release channel; structure-activity relationship
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