IN SILICO STUDY OF GLYCOSYLATION EFFECTS ON INTEGRIN STRUCTURE AND FUNCTION

这个子项目是许多研究子项目中的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可以在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 整合素作为异二聚体跨膜糖蛋白，在心血管功能或疾病的多种正常生物学过程和病理生理学事件中是必不可少的，包括：细胞粘附、形态发生、肿瘤发生、血管止血和免疫功能障碍。已知整合素通过由内而外的信号传导机制激活，该机制触发全局构象变化，其最终调节整合素对配体的亲和力。它是新兴的整合素活性可以通过其他机制，包括信号传导诱导的N-糖基化的变化，这反过来又影响整合素与配体的结合进行调节。然而，很少有人知道β 1整合素的结构变化和β 1整合素和纤维连接蛋白之间的结合亲和力的变化所引起的糖基化改变，以及构象变化如何调节整合素的功能。β 1 I样结构域是一个对配体结合很重要的区域，在三个天冬酰胺残基处携带N-聚糖，表明这些位点处聚糖组成的差异可能显著改变整联蛋白对配体的亲和力。在本研究中，我们将使用分子动力学模拟来确定N-糖基化改变对β 1整联蛋白结构以及β 1整联蛋白和纤连蛋白之间结合亲和力的影响。我们假设糖基化改变导致β 1整合素的构象变化，从而影响整合素与纤连蛋白的结合，以调节心血管事件中的细胞粘附。糖基化对β 1整联蛋白结构及其与纤连蛋白结合的影响的计算机模拟研究将有助于理解糖基化和变体唾液酸化对整联蛋白功能调节的影响，提供有助于通过引入人工N-聚糖改变β 1整联蛋白构象来调节整联蛋白功能的见解，并有助于鉴定干扰聚糖谱以调节β 1整联蛋白结构和功能的抑制剂。

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.