IN SILICO STUDY OF GLYCOSYLATION EFFECTS ON INTEGRIN STRUCTURE AND FUNCTION

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This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Integrins, as heterodimeric transmembrane glycoproteins, are essential in a variety of normal biological processes and pathophysiological events in cardiovascular function or disease including: cell adhesion, morphogenesis, tumorigenesis, vascular haemostasis and immune dysfunction. Integrins are known to be activated by inside-out signaling mechanisms that trigger global conformational changes, which ultimately modulate integrin affinity for a ligand. It is emerging that integrin activity can be regulated by other mechanisms, including signaling-induced changes in N-glycosylation, which in turn affects integrin binding to ligand. However, little has been know about the structural changes of beta1 integrin and the change of binding affinity between beta1 integrin and fibronectin induced by altered glycosylation, and how the conformation changes modulate integrin function. The beta1 I-like domain, a region important for ligand binding, carries N-glycans at three asparagine residues, suggesting that differences in glycan composition at these sites could significantly alter integrin affinity for ligand. In this study, we will use molecular dynamics simulations to determine the effect of altered N-glycosylation on the structure of the beta1 integrin, and on the binding affinity between the beta1 integrin and fibronectin. We hypothesize that altered glycosylation results in conformational changes of the beta1 integrin, and thereby affects integrin binding to fibronectin to regulate cell adhesion in cardiovascular events. This in silico study of glycosylation effects on the structure of beta1 integrin and its binding with fibronectin will facilitate understanding of the effect of glycosylation and variant sialyation on the regulation of integrin function, provide insight that will help to modulate integrin function by introducing artificial N-glycan to change the conformation of beta1 integrin, and aid in the identification of inhibitors to perturb the glycan profile to regulate beta1 integrin structure and function.