The Effect of T192M Mutation in Stability of Alpha Dystroglycan: Study with Molecular Dynamics Simulation

Alpha-dystroglycan (alpha-DG), a cell surface receptor links extracellular matrix with cellular cytoskeleton. Its post translational modification is carried out with number of glycosyltransferases, depending on cell types to make the ligand specific mature alpha-DG receptor protein. However, T192M mutation in alpha-DG has been found to cause hypo-glycosylation of the protein disabling its Laminin binding form and thereby triggering the onset of a limb girdle muscular dystrophy affecting early childhood. Here for the first time we exploit the effect of this mutation in protein conformational stability. We have found that this mutation leads to significant changes in secondary structure of the protein as well as in the accessible surface area. All these changes also hamper the crucial disulfide bond that is required to maintain the globular fold at the N terminus of alpha-DG. This molecular insight will therefore be useful for developing new therapeutic approaches to overcome the disease state.