Effect of altered glycosylation on the structure of the I-like domain of β1 integrin: A molecular dynamics study

Glycosylation plays an important role in the regulation of integrin function. Molecular mechanisms underlying the effects of altered glycosylation on beta 1 integrin structure and function are still largely unknown. In this study, we used a molecular modeling approach to study the effects of altered glycosylation, with alpha 2-6 sialic acid and without alpha 2-6 sialic acid, on the structure of the I-like domain of the PI integrin. Our results demonstrated that altered glycosylation affected the interactions between oligosaccharides and the I-like domain, which in turn changed the accessibility of the specificity-determining loop for ligand binding. Altered glycosylation caused significant conformational changes for most of the key functional regions of the I-Re domain of beta 1 integrin, including the metal ion-dependent adhesion site that contains a DLSYS motif, and other critical residues for ligand binding (Asn-224, Glu-229, Asp-233, Asp-267, and Asp-295). In addition, altered glycosylation caused significant movement of the alpha 1 and alpha 7 helices, which are important for the activation of beta 1 integrin. The results from this study offered molecular mechanisms for the experimental observations that variant glycosylation regulates integrin function.