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Published on: March 5, 2018
Complex formation dynamics of native and mutated pyrin's B30.2 domain with caspase-1
Grigor Arakelov1,2, Vahram Arakelov1, Karen Nazaryan1,2
1Russian-Armenian University, Yerevan, 0051, Armenia.
Abstract:
Pyrin protein is the product of the MEFV gene, mutations in which cause manifestation of familial Mediterranean fever (FMF). Functions of pyrin are not completely clear. The secondary structure of the pyrin is represented with four domains and two motifs. Mutations p.M680I, p.M694V, p.M694I, p.K695R, p.V726A, and p.A744S, which are located in the B30.2 domain of pyrin protein, are responsible for manifestation of the most common and severe forms of FMF. All the domains and the motifs of pyrin, are directly or indirectly, involved in the protein-protein interaction with proteins of apoptosis and regulate the cascade of inflammatory reactions, which is impaired due to pyrin mutations. It is well known, that malfunction of the pyrin-caspase-1 complex is the main reason of inflammation during FMF. Complete tertiary structure of pyrin and the effects of mutations in it are experimentally not studied yet. The aim of this study was to identify possible effects of the abovementioned mutations in the B30.2 domain tertiary structure and to determine their potential consequences in formation of the B30.2-caspase-1 complex. Using in silico methods, it was found, that these mutations led to structural rearrangements in B30.2 domain tertiary structure, causing shifts of binding sites and altering the interaction energy between B30.2 and caspase-1.
Insights
Familial Mediterranean fever (FMF) mutations in the pyrin protein
Area of Science:
- Molecular Biology
- Genetics
- Immunology
Background:
- Pyrin protein, encoded by the MEFV gene, is implicated in familial Mediterranean fever (FMF).
- Specific mutations in the pyrin B30.2 domain are linked to severe FMF forms.
- Pyrin's role in apoptosis and inflammation regulation is known, but its tertiary structure and mutation effects are unstudied.
Purpose of the Study:
- To investigate the in silico effects of common FMF-associated mutations on pyrin's B30.2 domain tertiary structure.
- To determine the potential consequences of these structural changes on the pyrin-caspase-1 complex formation.
Main Methods:
- Computational (in silico) analysis of pyrin's B30.2 domain tertiary structure.
- Assessment of mutation-induced structural rearrangements and their impact on binding sites and interaction energy with caspase-1.
Main Results:
- Identified structural rearrangements within the pyrin B30.2 domain due to specific FMF mutations.
- Observed alterations in binding sites and changes in interaction energy between the pyrin B30.2 domain and caspase-1.
- These structural changes suggest a mechanism for impaired pyrin-caspase-1 complex formation in FMF.
Conclusions:
- In silico findings reveal that FMF-associated mutations disrupt the tertiary structure of the pyrin B30.2 domain.
- Structural alterations impact pyrin's interaction with caspase-1, potentially explaining FMF pathogenesis.
- Further experimental studies are warranted to validate these computational predictions.
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