title: In-silico structural analysis of E509K mutation in LARGE and T192M mutation in Alpha Dystroglycan in the inhibition of glycosylation of Alpha Dystroglycan by LARGE.
abstract: Impaired glycosylation of cellular receptor Alpha Dystroglycan (α-DG) leads to dystroglycanopathy. Glycoprotein α-DG is the receptor protein in the Dystrophin Associated Protein Complex (DAPC), a macromolecular gathering on muscle cell membrane to form a bridge between extracellular matrix (ECM) and cellular actin cytoskeleton. Proper glycosylation of α-DG is mediated by the glycosylating enzyme LARGE. Mutations either in α-DG or in LARGE lead to improper glycosylations of α-DG thereby hampering the formation of final Laminin binding form α-DG resulting in dystroglycanopathy. In our current work, we explored the structural changes associated with the presence of mutations in α-DG as well as in the enzyme LARGE. We further extended our research to understand the effect of the mutations onto protein-enzyme interactions. Moreover, since LARGE transfers the sugar moiety (glucuronic acid; GlcA) onto α-DG, we tried to analyze what effect the mutation in LARGE confers on this enzyme ligand interaction. This work for the first time addressed the molecular changes occurring in the structures α-DG, LARGE and their interactions and shed lights on the as yet poorly understood mechanism behind the dystroglycanopathy onset.
authors: Department of Biochemistry and Biophysics, University of Kalyani, Kalyani, Nadia 741235, West Bengal, India. Electronic address: simanti.bhattacharya@gmail.com.
authors: Simanti
authors: S
authors: Bhattacharya
authors: Department of Biochemistry and Biophysics, University of Kalyani, Kalyani, Nadia 741235, West Bengal, India. Electronic address: amit.das.ku@gmail.com.
authors: Amit
authors: A
authors: Das
authors: Department of Biochemistry and Biophysics, University of Kalyani, Kalyani, Nadia 741235, West Bengal, India. Electronic address: angshu@klyuniv.ac.in.
authors: Angshuman
authors: A
authors: Bagchi
mesh_terms: D003198:Computer Simulation; D049030:Dystroglycans / Q000235:genetics* / Q000378:metabolism*; D006031:Glycosylation; D016695:Glycosyltransferases / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D006801:Humans; D008024:Ligands; D008565:Membrane Proteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D008958:Models, Molecular; D056004:Molecular Dynamics Simulation; D009154:Mutation; D011485:Protein Binding / Q000235:genetics; D000072417:Protein Domains
chemical_list: D008024:Ligands; D008565:Membrane Proteins; D049030:Dystroglycans; D016695:Glycosyltransferases; C500430:LARGE2 protein, human
keywords: Alpha Dystroglycan; Disease; Dystroglycanopathy; LARGE; Molecular dynamics simulations; Molecular modelling