Structural and Functional Analysis of Mutated Human Pyrin B30.2 Domain

Abstract

Background: Familial Mediterranean Fever (FMF) is a prototypical hereditary autoinflammatory disease affecting principally Mediterranean populations and characterized by recurrent frequent fever and inflammation. The disease is essentially caused by inherited mutations in the MEFV gene which encodes pyrin protein. The reported mutations are mostly located on the B30.2 domain in the C-terminal end of the protein. Objective: The present study reports a structural comparison of the five most common mutated structures including M694V, V726A, M694I, R761H, and M680I. The aim of this study was to determine the structural and functional disorders caused by the mutations in the human pyrin protein. Results: The comparison revealed that all mutations make overall changes in the structure of the domain. Further, the effects of these mutations on structural and molecular behavior of the B30.2 domain were compared with the native structure using MD simulation by GROMACS software. The results revealed that all the studied mutants have a destabilizing effect on the protein structure. Additionally, analyzing the projection of the motions of the proteins in phase space demonstrates high rigidity of the mutated structures in comparison with the native protein. Conclusion: The results of simulations elucidate how the mutations affect the physiological functioning of the pyrin B30.2 domain and cause the occurrence of the FMF disease.