Molecular insight into the mechanism of antigen presentation: Role of transmembrane domains in MHC Class-II assembly

抗原呈递机制的分子洞察：跨膜结构域在 MHC II 类组装中的作用

• 批准号: G0601114/1
• 负责人: Ann Dixon
• 金额: $ 38.24万
• 依托单位: University of Warwick
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2007
• 资助国家: 英国
• 起止时间: 2007 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=G0601114%2F1
• 关键词: Molecular; insight; into; mechanism; antigen

The acquired immune system enables an organism to defend itself against assaults from invading pathogens, such as bacteria or viruses, by selectively attacking infected or cancerous cells. In order to locate and destroy these infected cells, a complex symphony of events takes place which is directed by the most important of immune cells, the helper T-cells. Helper T-cells respond to the presence of a foreign pathogen by releasing a range of chemicals that regulate all aspects of the immune system. Helper T-cells are themselves controlled by the Class II Major Histocompatibility Complex (MHC Class II), a complex composed of two membrane proteins found on the surface of antigen presenting cells. MHC Class II is responsible for binding and presenting small peptide antigens, derived from foreign proteins, on the surface of cells. This process of antigen presentation by MHC Class II activates helper T-cells and triggers an immune response. The failure of MHC Class II to activate helper T-cells in a normal way results in a severe collapse of the immune system. This is a key factor in autoimmune diseases as well as other serious human diseases. Therefore, correct transport of peptide-loaded Class II molecules to the cells surface is essential to healthy immune response. This transport is initiated by a chaperone molecule called the MHC Class II-associated invariant chain (Ii). A trimer of Ii binds three Class II heterodimers in the endoplasmic reticulum to form a nine-chain complex, and only as part of this complex are Class II molecules targeted to the cells surface. The assembly of the nine-chain complex is therefore an essential first step in antigen presentation. Assembly of the nine-chain complex involves a large number of specific protein-protein interactions, and recent evidence indicates that specific interactions between the transmembrane domains of all three proteins are of significant biological importance. The focus of this research is investigation of the structures and interactions of these domains in order to better understand the assembly of the complex and its role in cellular processes and disease. Work at this stage is primarily fundamental, however the interactions we will characterise can be used in design of molecules that target TM domain interactions and could be applied to design of drugs and therapeutics that target the large number of autoimmune diseases and cancers in which MHC Class II and MHC Ii are implicated.

获得性免疫系统使生物体能够通过选择性攻击受感染或癌细胞来防御细菌或病毒等入侵病原体的攻击。为了定位并摧毁这些受感染的细胞，在最重要的免疫细胞（辅助 T 细胞）的指挥下，发生了一系列复杂的事件。辅助 T 细胞通过释放一系列调节免疫系统各个方面的化学物质来对外来病原体的存在做出反应。辅助 T 细胞本身由 II 类主要组织相容性复合物（MHC II 类）控制，该复合物由抗原呈递细胞表面发现的两种膜蛋白组成。 MHC II 类负责在细胞表面结合和呈递源自外来蛋白质的小肽抗原。 MHC II 类抗原呈递过程会激活辅助 T 细胞并引发免疫反应。 MHC II 类无法以正常方式激活辅助 T 细胞会导致免疫系统严重崩溃。这是自身免疫性疾病以及其他严重人类疾病的关键因素。因此，将肽负载的 II 类分子正确转运至细胞表面对于健康的免疫反应至关重要。这种运输是由称为 MHC II 类相关不变链 (Ii) 的伴侣分子启动的。 Ii 三聚体在内质网中结合三个 II 类异二聚体，形成九链复合物，并且只有作为该复合物的一部分，II 类分子才靶向细胞表面。因此，九链复合物的组装是抗原呈递中必不可少的第一步。九链复合物的组装涉及大量特定的蛋白质-蛋白质相互作用，最近的证据表明所有三种蛋白质的跨膜结构域之间的特定相互作用具有重要的生物学意义。这项研究的重点是研究这些结构域的结构和相互作用，以便更好地了解复合物的组装及其在细胞过程和疾病中的作用。这一阶段的工作主要是基础性的，但是我们将描述的相互作用可以用于设计针对 TM 结构域相互作用的分子，并且可以应用于针对大量自身免疫性疾病和癌症的药物和疗法的设计，其中 MHC 类II 和 MHC Ii 参与其中。