Mutation near the binding interfaces at α-hemoglobin stabilizing protein is highly pathogenic

Aggregation of free alpha-hemoglobin proteins forms harmful reactive oxygen radicals during the development of normal erythroid cell, which can be prevented by a chaperone, alpha hemoglobin stabilizing protein (AHSP). Mutations at the AHSP gene may affect its interacting ability with other globin proteins. Various state-of-the-art tools have been extensively used to identify the most deleterious nsSNPs at the AHSP and their pathogenic effect during AHSP-globin interaction. Comprehensive analysis revealed that the V56G of the AHS protein is the most pathogenic amino acid substitution, agreed consistently and significantly (P=1.27E-13) by all the state-of-the-art tools (PROVEAN <-2.5, SIFT=0, SNAP2 >50, SNPs&GO >0.5, PolyPhen >0.5, FATHMM >0.6, PANTHER <-3, VEST P<0.05) and protein-protein interaction analysis. The V56G exists near the hot spot and was found to be the highly pathogenic and it forms an extra helix on mutation. The unchaperoned HBA2 and KLF1 proteins with the AHSP mutant (V56G) chains denote the non-interactive nature. Binding energies were significantly varied upon highly deleterious mutation at AHSP and/or HBA1 gene. The study endorses the mutated AHSP protein, p.val56Gly for detailed confirmatory wet lab analysis.