Dystroglycan (DG) is a cell surface receptor which is composed of two subunits that interact noncovalently, namely alpha- and beta-DG. In skeletal muscle, DG is the central component of the dystrophin-glycoprotein complex (DGC) that anchors the actin cytoskeleton to the extracellular matrix. To date only the three-dimensional structure of the N-terminal region of alpha-DG has been solved by X-ray crystallography. To expand such a structural analysis, a theoretical molecular model of the murine alpha-DG C-terminal region was built based on folding recognition/threading techniques. Although there is no a significant (<30\%) sequence homology with the N-terminal region of alpha-DG, protein fold recognition methods found a significant resemblance to the alpha-DG N-terminal crystallographic structure. Our in silico structural prediction identified two subdomains in this region. Amino acid residues similar to 500-600 of alpha-DG were predicted to adopt an immunoglobulin-like (Ig-like) beta-sandwich fold. Such modeled domain includes the beta-DG binding epitope of alpha-DG and, confirming our previous experimental results, suggests that the linear epitope (residues 550-565) assumes a beta-strand conformation. The remaining segment of the alpha-DG C-terminal region (residues 601-653) is organized in a coil-helix-coil motif. A 20-ns molecular dynamics simulation in explicit water solvent provided support to the predicted Ig-like model structure. The identification of a second Ig-like domain in DG represents another important step towards a full structural and functional description of the alpha/beta DG interface. Preliminary characterization of a novel recombinant peptide (505-600) encompassing this second lg-like domain demonstrates that it is soluble and stable, further corroborating our in silico analysis

De Rosa, M. C., Pirolli, D., Bozzi, M., Sciandra, F., Giardina, B., Brancaccio, A., A second Ig-like domain identified in dystroglycan by molecular modelling and dynamics, <<JOURNAL OF MOLECULAR GRAPHICS & MODELLING>>, 2011; 29 (8): 1015-1024. [doi:10.1016/j.jmgm.2011.04.008] [http://hdl.handle.net/10807/3345]

A second Ig-like domain identified in dystroglycan by molecular modelling and dynamics

De Rosa, Maria Cristina;Pirolli, Davide;Bozzi, Manuela;Giardina, Bruno;Brancaccio, Andrea
2011

Abstract

Dystroglycan (DG) is a cell surface receptor which is composed of two subunits that interact noncovalently, namely alpha- and beta-DG. In skeletal muscle, DG is the central component of the dystrophin-glycoprotein complex (DGC) that anchors the actin cytoskeleton to the extracellular matrix. To date only the three-dimensional structure of the N-terminal region of alpha-DG has been solved by X-ray crystallography. To expand such a structural analysis, a theoretical molecular model of the murine alpha-DG C-terminal region was built based on folding recognition/threading techniques. Although there is no a significant (<30\%) sequence homology with the N-terminal region of alpha-DG, protein fold recognition methods found a significant resemblance to the alpha-DG N-terminal crystallographic structure. Our in silico structural prediction identified two subdomains in this region. Amino acid residues similar to 500-600 of alpha-DG were predicted to adopt an immunoglobulin-like (Ig-like) beta-sandwich fold. Such modeled domain includes the beta-DG binding epitope of alpha-DG and, confirming our previous experimental results, suggests that the linear epitope (residues 550-565) assumes a beta-strand conformation. The remaining segment of the alpha-DG C-terminal region (residues 601-653) is organized in a coil-helix-coil motif. A 20-ns molecular dynamics simulation in explicit water solvent provided support to the predicted Ig-like model structure. The identification of a second Ig-like domain in DG represents another important step towards a full structural and functional description of the alpha/beta DG interface. Preliminary characterization of a novel recombinant peptide (505-600) encompassing this second lg-like domain demonstrates that it is soluble and stable, further corroborating our in silico analysis
Inglese
De Rosa, M. C., Pirolli, D., Bozzi, M., Sciandra, F., Giardina, B., Brancaccio, A., A second Ig-like domain identified in dystroglycan by molecular modelling and dynamics, <<JOURNAL OF MOLECULAR GRAPHICS & MODELLING>>, 2011; 29 (8): 1015-1024. [doi:10.1016/j.jmgm.2011.04.008] [http://hdl.handle.net/10807/3345]
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/10807/3345
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