IN SILICO STUDY OF GLYCOSYLATION EFFECTS ON INTEGRIN STRUCTURE AND FUNCTION

糖基化对整合素结构和功能影响的计算机研究

• 批准号: 7956276
• 负责人: Yuhua Song
• 金额: $ 0.08万
• 依托单位: CARNEGIE-MELLON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-08-01 至 2010-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7956276
• 关键词: Affect; Affinity; Asparagine; Binding; Biological Process; Biomedical Research; Blood Vessels; CD29 Antigen; Cardiovascular Physiology; Cardiovascular system; Cell Adhesion; Computer Retrieval of Information on Scientific Projects Database; Computer Simulation; Disease; Event; Fibronectins; Funding; Glycoproteins; Grant; Hemostatic function; High Performance Computing; Immune System Diseases; Institution; Integrin Binding; Integrins; Ligand Binding; Ligands; Molecular Conformation; Morphogenesis; Polysaccharides; Regulation; Research; Research Personnel; Resources; Signal Transduction; Site; Source; Structure; United States National Institutes of Health; Variant; glycosylation; inhibitor/antagonist; insight; molecular dynamics; tumorigenesis

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.

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 作为异二聚体的跨膜糖蛋白，整合素在心血管功能或疾病的各种正常生物学过程和病理生理事件中是必不可少的，包括：细胞黏附、形态发生、肿瘤发生、血管止血和免疫功能障碍。已知整合素被由内向外的信号机制激活，触发全局构象变化，最终调节配体的整合素亲和力。研究表明，整合素的活性可以通过其他机制来调节，包括信号诱导的N-糖基化的变化，这反过来又会影响整合素与配体的结合。然而，关于β1整合素的结构变化以及糖基化引起的β1整合素与纤维连接蛋白结合亲和力的变化，以及构象变化如何调节整合素的功能，目前还知之甚少。β1类I结构域是配体结合的重要区域，在三个天冬酰胺残基上携带N-糖链，这表明这些位置的糖链组成的差异可能会显著改变整合素与配体的亲和力。在这项研究中，我们将使用分子动力学模拟来确定改变的N-糖基化对β1整合素结构的影响，以及对β1整合素与纤维连接蛋白结合亲和力的影响。我们假设糖基化改变会导致β1整合素的构象变化，从而影响整合素与纤维连接蛋白的结合，从而调节心血管事件中的细胞黏附。研究糖基化对β1整合素结构的影响及其与纤维连接蛋白的结合，将有助于理解糖基化和变异唾液酸化对整合素功能调节的影响，有助于通过引入人工N-糖链改变β1整合素的构象来调节整合素的功能，并有助于识别干扰糖链以调节β1整合素结构和功能的抑制剂。