Background Familial Mediterranean fever (FMF), the most common hereditary autoinflammatory disorder, is associated with variations in the MEFV gene, which encodes the pyrin protein. The majority of the amino acid substitutions in pyrin are located at the C-terminal SPRY domain, but functional consequences of these variations have yet to be identified.
Objectives This study aimed to analyze the SPRY domain structure by using a bioinformatics and thermodynamics approach for the prediction of ligand binding sites, energy pathways and their relationship with known FMF-related variations.
Methods We used the elastic net model for the structural analysis of SPRY, which assumes that fluctuations of the energy are related to fluctuations of residue positions and the connectivity matrix of the protein. This model establishes a connection between energy fluctuation pathways and protein architecture. This model helps to predict the locations of hotspots for ligand binding and identifies the pathways of energy conduction within the protein. We also assessed the possible binding sites of caspase 1 to SPRY domain of pyrin, as one of the few known interacting proteins, using the elastic net model together with molecular docking software GOLD.
Results Elastic net model analysis of SPRY of pyrin revealed the energy responsive pathway of the domain, which starts with the residue Tyr608 and ends at Phe721 and Tyr732. The residues on this pathway are overlapped with evolutionarily conserved amino acids of the SPRY domain. Tyr608 residue interacted strongly with Gln753, which is located at the bottom of the possible ligand-binding shallow cavity on one side of the SPRY domain. The most penetrant FMF-related variations, Met680Ile and Met694Val, are located at the either sides of this cavity. Molecular docking analyses suggested a strong binding affinity for caspase 1 to the domain through Met680, with a 5-residue tail of caspase 1 interacting with the cavity and energy pathways.
Conclusions These computational analyses support the critical role of the shallow cavity on one side of the SPRY domain as the ligand-binding site, which connects the ligand binding to the energy-transmission to the neighboring domains. This work reveals possible binding sites of caspase 1 on the SPRY domain and its interaction with the energy transmission pathway. Positioning the most penetrant MEFV variations around this region warrants further investigations for the clarification of their effects on the ligand binding and energy transmission.
Disclosure of Interest None Declared