Regulation of ryanodine receptor RyR2 by protein-protein interactions: prediction of a PKA binding site on the N-terminal domain of RyR2 and its relation to disease causing mutations

• Published in: F1000 research Vol. 4; p. 29
• Main Authors: Walpoth, Belinda Nazan, Erman, Burak
• Format: Journal Article
• Language: English
• Published: England F1000Research 2015; F1000 Research Ltd
• Subjects: Biomacromolecule-Ligand Interactions; Protein Chemistry & Proteomics; Protein Folding; protein-protein interactions; protein signaling; protein function; ryanodine receptor RyR2; Protein Kinase A; ligand docking; elastic net model; evolutionarily conserved residues; disease causing mutations
• ISSN: 2046-1402; 2046-1402
• DOI: 10.12688/f1000research.5858.1

Protein-protein interactions are the key processes responsible for signaling and function in complex networks. Determining the correct binding partners and predicting the ligand binding sites in the absence of experimental data require predictive models. Hybrid models that combine quantitative atomistic calculations with statistical thermodynamics formulations are valuable tools for bioinformatics predictions. We present a hybrid prediction and analysis model for determining putative binding partners and interpreting the resulting correlations in the yet functionally uncharacterized interactions of the ryanodine RyR2 N-terminal domain. Using extensive docking calculations and libraries of hexameric peptides generated from regulator proteins of the RyR2 channel, we show that the residues 318-323 of protein kinase A, PKA, have a very high affinity for the N-terminal of RyR2. Using a coarse grained Elastic Net Model, we show that the binding site lies at the end of a pathway of evolutionarily conserved residues in RyR2. The two disease causing mutations are also on this path. The program for the prediction of the energetically responsive residues by the Elastic Net Model is freely available on request from the corresponding author.