Abstract

Deafness is the most common form of sensory impairment in humans. Several mutations have been reported in the myosin VI proteins that are responsible for autosomal dominant and recessive deafness. One such missense mutation is that which changes glutamate (E) to valine (V) at amino acid 216 (E216V). The mutation resides in the myosin VI head domain; however, detailed insights regarding the impact of this mutation on structural stability are not known. To characterize the potential impact of this mutation on protein stability and its association with deafness, we performed computational sequence and structural analysis of normal and mutated myosin VI. Overall, protein stability declined when the mutation was introduced, as predicted by I-mutant and Cologne University Protein Stability Analysis Tool (CUPSAT). Similarly, a decline in hydrophobicity around position 216 was observed.Phosphorylation of myosin VI was also observed to be influenced by the E216V mutation. Furthermore, a three-dimensional structure of myosin VI was studied using Swiss-PdbViewer to identify structural variations in the protein that may occur as a result of the E216V mutation. Distortion in the hydrogen bonding between Val216 and Ser449 in the mutated protein structure was observed, exposing the Ser449 hydroxyl group and reducing overall protein stability.

Key words: Myosin VI, genetics, deafness, hereditary mutations, structure analysis.