Dystroglycan (DG) is a cell surface receptor which is composed of two subunits that interact noncovalently, namely alpha and beta DG. Given its sarcolemmal localization at the interface between the cytoskeleton and the basal lamina, DG is thought to be involved in the pathogenesis of several congenital muscular disorders [1]. To date only the 3D-structure of the N-terminal domain of alpha DG has been solved by X-ray crystallography [2], and the structures of the other DG domains need still to be determined. We generated a first theoretical 3D-model on a portion of the alpha DG's C-terminal domain. An initial model was established using the I-TASSER algorithm which combines the methods of threading and ab initio modeling [3]. Subsequent refinement by molecular dynamics simulation led to an improved model structure which was analyzed by different protein analysis programs, including PROCHECK for the evaluation of Ramachandran plot quality, PROSA for testing interaction energies and VERIFY3D for identifying regions of improper folding. The resulting alpha DG's C-terminal domain (between residues 505-596) model is remarkably similar to the N-terminal domain (residues 60-158) solved at high resolution (PDB 1u2c), revealing the presence of another Ig-like domain within alpha DG. Such domain model includes the beta DG binding epitope of alpha DG and, confirming our previous experimental results, suggests that the epitope assumes a beta strand conformation [4]. References: 1. Sciandra et al. Trends Biotechnol. 2007; 25:262-268. 2. Bozic et al. J. Biol. Chem. 2004; 279:44812-44816. 3. Zhang Proteins2007; 69:108-117. 4. Sciandra et al. FEBS J. 2009; 276:4933-4945
Modeling and molecular dynamics of alpha-dystroglycan's C-terminus reveals the presence of an Ig-like domain encompassing its beta-dystroglycan binding epitope
Davide Pirolli;Francesca Sciandra;Bruno Giardina;Andrea Brancaccio;Maria Cristina De Rosa
2010
Abstract
Dystroglycan (DG) is a cell surface receptor which is composed of two subunits that interact noncovalently, namely alpha and beta DG. Given its sarcolemmal localization at the interface between the cytoskeleton and the basal lamina, DG is thought to be involved in the pathogenesis of several congenital muscular disorders [1]. To date only the 3D-structure of the N-terminal domain of alpha DG has been solved by X-ray crystallography [2], and the structures of the other DG domains need still to be determined. We generated a first theoretical 3D-model on a portion of the alpha DG's C-terminal domain. An initial model was established using the I-TASSER algorithm which combines the methods of threading and ab initio modeling [3]. Subsequent refinement by molecular dynamics simulation led to an improved model structure which was analyzed by different protein analysis programs, including PROCHECK for the evaluation of Ramachandran plot quality, PROSA for testing interaction energies and VERIFY3D for identifying regions of improper folding. The resulting alpha DG's C-terminal domain (between residues 505-596) model is remarkably similar to the N-terminal domain (residues 60-158) solved at high resolution (PDB 1u2c), revealing the presence of another Ig-like domain within alpha DG. Such domain model includes the beta DG binding epitope of alpha DG and, confirming our previous experimental results, suggests that the epitope assumes a beta strand conformation [4]. References: 1. Sciandra et al. Trends Biotechnol. 2007; 25:262-268. 2. Bozic et al. J. Biol. Chem. 2004; 279:44812-44816. 3. Zhang Proteins2007; 69:108-117. 4. Sciandra et al. FEBS J. 2009; 276:4933-4945I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
