The inhibitory glutathione transferase M2-2 binding site is located in divergent region 3 of the cardiac ryanodine receptor
Copyright policy )The inhibitory glutathione transferase M2-2 binding site is located in divergent region 3 of the cardiac ryanodine receptor
The muscle-specific glutathione transferase GSTM2-2 modulates the activity of ryanodine receptor (RyR) calcium release channels: it inhibits the activity of cardiac RyR (RyR2) channels with high affinity and activates skeletal RyR (RyR1) channels with low affinity. The C terminal domain of GSTM2-2 (GSTM2C) alone physically binds to RyR2 and inhibits its activity, but it does not bind to RyR1. We have now used yeast two-hybrid analysis, chemical cross-linking, intrinsic tryptophan fluorescence and Ca(2+) release studies to determine that the binding site for GSTM2C is in divergent region 3 (D3) of RyR2. The D3 region encompasses residues 1855-1890 in RyR2. Specific mutagenesis shows the binding primarily involves electrostatic interactions with residues K1875, K1886, R1887 and K1889, all residues that are present in RyR2, but not in RyR1. The significant sequence differences between the D3 regions of RyR2 and RyR1 explain why GSTM2-2 specifically inhibits RyR2. This specific inhibition of RyR2 could modulate Ca cycling and be useful for the treatment of heart failure. RyR2 inhibition during diastole may improve filling of the SR with Ca(2+) and improve contractility.
- Australian National University Australia
cross linking, 572, Molecular Sequence Data, heart failure, Yeast two hybrid analysis, Glutathione transferase GSTM2-2, ryanodine receptor 2, Two-Hybrid System Techniques, binding affinity, calcium transport, tryptophan, Keywords: glutathione transferase M2, Amino Acid Sequence, Calcium Signaling, Cloning, Molecular, Divergent region 3 of RyRs, Glutathione Transferase, carboxy terminal sequence, Binding Sites, binding site, Inhibition of RyR2 channels, article, Tryptophan, Ryanodine Receptor Calcium Release Channel, heart muscle contractil Cardiac RyR2 channels, ryanodine receptor 1, Skeletal RyR1 channels, enzyme activity, Sarcoplasmic Reticulum, Mutagenesis, Site-Directed, fluorescence, Protein Binding
cross linking, 572, Molecular Sequence Data, heart failure, Yeast two hybrid analysis, Glutathione transferase GSTM2-2, ryanodine receptor 2, Two-Hybrid System Techniques, binding affinity, calcium transport, tryptophan, Keywords: glutathione transferase M2, Amino Acid Sequence, Calcium Signaling, Cloning, Molecular, Divergent region 3 of RyRs, Glutathione Transferase, carboxy terminal sequence, Binding Sites, binding site, Inhibition of RyR2 channels, article, Tryptophan, Ryanodine Receptor Calcium Release Channel, heart muscle contractil Cardiac RyR2 channels, ryanodine receptor 1, Skeletal RyR1 channels, enzyme activity, Sarcoplasmic Reticulum, Mutagenesis, Site-Directed, fluorescence, Protein Binding
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