The Effect of T192M Mutation in Stability of Alpha Dystroglycan: Study with Molecular Dynamics Simulation
Alpha-dystroglycan (α-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 α-DG receptor protein. However, T192M mutation in α-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 α-DG. This molecular insight will therefore be useful for developing new therapeutic approaches to overcome the disease state.
KeywordsAlpha-dystroglycan Mutation Molecular dynamics simulation Disulfide bond Disease Protein folding
Extra Cellular Matrix
Dystrophin Associated Protein Complex
Muscular Dystrophy, Dystroglycanopathy, type C9
Optimized potential for liquid simulations all atom force field
Root mean squared deviations
Root mean squared fluctuations
Solvent accessible surface area
The authors are really grateful to the BIF Center, Dept of Biochemistry and Biophysics, University of Kalyani for providing workstation to carry out the experiments. SB and AD also are thankful to UGC, India and CSIR, India for their respective fellowships. The authors would like to acknowledge the ongoing DST-PURSE program 2012-2015 and the DBT (project no. BT/PR6869/BID/7/417/2013) for the support.
Conflict of Interest
The authors declare no conflict of interests.
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