Evaluation of point mutation of T۵۴R superoxide dismutase enzyme using bioinformatics methods

Backgrounds: Amyotrophic lateral sclerosis (ALS) is a progressive and fatal neurologicaldisorder caused by mis-folding and aggregation of superoxide dismutase (SOD۱). Consideringthe relationship between ALS and mutations in the gene encoding SOD۱, investigate enzymestructure of mutation at position ۵۴ enzyme (T۵۴R) of the Zinc loop in SOD۱ and identifymethods for the prevention or treatment of ALS using bioinformatics’ studies. Mutations in thisposition cause the spatial deformation of the enzyme and cause the mis-folding that wasassociated with pathogenesisMaterials and Methods: Using Chimera software and Project hope server, enzyme structure, istableand DUTE servers, enzyme structural stability and with Predic-SNP server, the stability ofwild and mutant enzyme activity were studied. Finally, the predisposition to mutant amyloidaccumulations was investigated using PASTA and AGGRESCAN servers.Results: The T۵۴R replacement mutation, by changing the charge and spatial shape of theenzyme, causes instability of the enzyme structure, and with a high confidence level of %۷۲, isclassified as destructive mutations. Also, the number of points of amyloid fibrils was ۱۴, the bestenergy of amyloid points was -۶.۷۷۳۸۹۴, and the number of hot spots of aggregation formationwas ۶, which is similar to wild enzyme.Conclusion: The mutated residue is located in a domain that is important for binding of othermolecules and in contact with residues in a domain that is important for the activity of theprotein. The mutation might affect this interaction and thereby disturb signal transfer frombinding domain to the activity domain and interaction between these two domains and as suchaffect the function of the protein. Studies reveal that the T۵۴R mutation has destructive effectsupon SOD۱ T۵۴R dimer stability due to increased fuctuation of mutation-residing loop distantfrom the dimer interface (Ghosh, D. K., ۲۰۲۰).

کلیدواژه ها:

Amyotrophic lateral sclerosis ، Superoxide dismutase۱ ، Zinc loops ، T۵۴R mutant