Computational analysis of histidine mutationson the structural stability of human tyrosinasesleading to albinism insurgence

摘要

Misfolding and structural alteration in proteins lead to serious malfunctions and cause various diseases inhumans. Mutations at the active binding site in tyrosinase impair structural stability and cause lethalalbinism by abolishing copper binding. To evaluate the histidine mutational effect, all mutated structureswere built using homology modelling. The protein sequence was retrieved from the UniProt database,and 3D models of original and mutated human tyrosinase sequences were predicted by changing theresidual positions within the target sequence separately. Structural and mutational analyses wereperformed to interpret the significance of mutated residues (N180, R202, Q202, R211, Y363, R367, Y367 andD390) at the active binding site of tyrosinases. Cspritz analysis depicted that 23.25% residues activelyparticipate in the instability of tyrosinase. The accuracy of predicted models was confirmed throughonline servers ProSA-web, ERRAT score and VERIFY 3D values. The theoretical pI and GRAVY generatedresults also showed the accuracy of the predicted models. The CCA negative correlation resultsdepicted that the replacement of mutated residues at His within the active binding site disturbs thestructural stability of tyrosinases. The predicted CCA scores of Tyr367 (0.079) and Q/R202 (0.032)revealed that both mutations have more potential to disturb the structural stability. MD simulationanalyses of all predicted models justified that Gln202, Arg202, Tyr367 and D390 replacement made theprotein structures more susceptible to destabilization. Mutational results showed that the replacementof His with Q/R202 and Y/R363 has a lethal effect and may cause melanin associated diseases such asOCA1. Taken together, our computational analysis depicts that the mutated residues such as Q/R202 andY/R363 actively participate in instability and misfolding of tyrosinases, which may govern OCA1 throughdisturbing the melanin biosynthetic pathway.