Molecular modeling of complete tertiary structure of pyrin and influence of mutations on it

Abstract

Pyrin protein is the product of the MEFV gene, mutations in which cause the manifestation of Familial Mediterranean Fever (FMF). Complete tertiary structure of pyrin and the effects of mutations on it are still experimentally not studied. Mutations - E148Q, M680I, M694V, M694I, V726A, A744S and R761H of pyrin induce manifestation of the most widespread and severe forms of FMF. One striking feature of FMF is the phenomenon of complex allele mutations. In case of complex allele mutations, the pyrin protein will contain more than one mutated amino acids. From currently known complex allele mutations there are those that combine the most widespread and severe single mutations - M680I-M694I, E148Q-M694V, E148Q-M694I, E148Q-V726A, E148Q-A744S, E148Q-R761H, E148Q-V726A-R761H. In complex alleles, one mutation may have a modifying effect on the other one. The other striking feature of FMF is the fact that despite the fact that the FMF is considered as an autosomal recessive autoinflammatory syndrome, were detected mutations - T577N и T577S for which was proved autosomal dominant inheritance. Understanding the correlation between the FMF phenotype and genotype is further obscured by the existence of complex allele and dominant mutations. Therefore, we suggest that computational modeling of native and mutated pyrin complete tertiary structure and their comparative investigation will help to understand the effects of abovementioned mutations on pyrin and on FMF manifestation in general.