The Deleterious F109S Mutation Disrupts Binding of Sex-Determining Region Y with DNA

摘要

Sex-determining region Y (SRY) protein is the master switch in the initiation of male sex differentiation. Mutation in SRY gene results in ambiguous genitalia and abnormalities in reproductive organs. Its function is mainly controlled by its high mobility group (HMG) box. Damage to the HMG box may cause dysfunction of the SRY protein, which may, in turn, lead to sex reversal. This study was conducted to prioritize the deleterious effects of the non-synonymous single nucleotide polymorphisms (nsSNPs) on SRY protein. A series of computational tools were applied to predict nsSNPs with the most harmful effects on protein structure, function, and stability. Molecular docking experiments were performed to identify the possible role of these nsSNPs in altering protein binding potentials with receptors. Cumulative results indicated that three nsSNPs would have highly deleterious effects, namely I90M, F109S, and Y127F. Docking analyses revealed no participation of both I90M and Y127F in modulating the binding of SRY with its receptor DNA sequences, while F109S induced a noticeable alteration in SRY by inducing a conformational change in its HMG box. In conclusion, the predictive tools showed that I90M, F109S, and Y127F are the most drastic SNPs in the SRY, signifying possible destructive consequences of these SNPs on sex development. Both I90M and Y127F undergo such harmful effects on the structure, function, and stability without being involved in modulating SRY binding with its DNA receptor sequences. This study provides a comprehensive platform for assessing the pattern of damaging effects of nsSNPs on the SRY gene, which may be linked with the grade of sexual dysfunction syndromes.