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 theAHSPgene 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 atAHSPand/orHBA1gene. The study endorses the mutated AHSP protein, p.val56Gly for detailed confirmatory wet lab analysis.
Department of Genetic Research, Institute for Research and Medical Consultation (IRMC), University of Dammam Dammam, Saudi Arabia.
Jesu Francis
JF
Borgio
Department of Pediatrics, King Fahd Hospital of the University Al-Khobar, Saudi Arabia.
Mohammed S
MS
Al-Madan
Department of Genetic Research, Institute for Research and Medical Consultation (IRMC), University of Dammam Dammam, Saudi Arabia.
Sayed
S
AbdulAzeez
bioinformatics; globin genes; interaction sites; interface residues; molecular modeling; mutation; nsSNPs; protein-protein interaction; α-Hemoglobin stabilizing protein (AHSP)