Structure and Function of superantigens

超抗原(SAG)会导致许多人类疾病。尽管人们对它的结构和结构有很多了解 金黄色葡萄球菌和链球菌编码的热原性下垂的功能，人们知之甚少 关于非致热性下垂，如关节炎相关的有丝分裂原支原体(MAM)和克罗恩病 疾病相关蛋白12(PfiT)。MAM在结构上，可能在功能上，与其他凹陷截然不同。 与其他SAG不同，MAM不仅与TCR V0直接相互作用，而且与TCR Va直接相互作用。然而， TCR Va是否以及如何影响MAM识别尚不清楚。12及其编码的全长蛋白PfiT 荧光假单胞菌是一种新的肠道下垂。12和PfiT是重要的致病因子。 克罗恩病的血清学标志物，一种炎症性肠病。然而，尽管MAM和 PfiT在炎症性自身免疫性疾病中发挥着重要作用，MAM和PfiT是如何发挥其作用的 其生物学功能及其在炎症性疾病中的作用尚不清楚。了解致病机理 MAM和PfiT等因子被宿主受体识别是解决这些问题的关键 为我们理解疾病的发病机制奠定了基础。我们的长期目标是确定 是由宿主受体识别的。此应用程序的目标是确定结构和 MAM和PfiT的功能。具体目标是：1)确定MAM的分子机制 由TCR识别。PMHC、MAM和TCR三元络合物的晶体结构 将测定CD4+T细胞，并与从CD8+T细胞衍生的TCR的三元复合体进行比较 细胞。这些结构应该可以解决来自CD4+和CD8+T细胞的TCR识别MAM的方式 以及TCR a链如何影响它们与MAM的相互作用。诱变、遗传、生化和 然后将使用免疫学方法来确定TCR Va在MAM识别中的作用。2) 克罗恩病相关SAG PfiT结构和功能的测定。晶体结构的研究 PfiT及其近亲同系物PA2885将被测定和比较。人类受体(TCR和 PMHC)将被确定。然后，PfiT与TCR和pMHC结合的亲和力和动力学参数将 然后测定PfiT与宿主受体-TCR和PfiT的结构 PMHC。这些研究的总和将有助于我们对疾病发病机制的理解，并将 为治疗干预提供新的途径。

Superantigens (SAgs) causes many human diseases. Although much is known about the structure and function of the pyrogenic SAgs encoded by staphylococcal and streptococcal bacteria, far less is known about the non-pyrogenic SAgs such as arthritis-related Mycoplasma arthritidis mitogen (MAM) and Crohn's disease-associated protein 12 (PfiT). MAM is structurally, and possibly functionally, distinct from other SAgs. In contrast to other SAgs, MAM was found to directly interact with not only TCR V0 but TCR Va. However, whether and how TCR Va affects MAM recognition is not known. 12 and its full-length protein PfiT encoded by Pseudomonas fluorescens are novel enteric SAgs. 12 and PfiT are important pathogenic factors and serological markers of Crohn's disease, an inflammatory bowel disease. However, although both MAM and PfiT play important roles in autoimmune diseases of inflammatory nature, how MAM and PfiT perform their biological function and their roles in inflammatory diseases are not known. Understanding how pathogenic factors such as MAM and PfiT are recognized by host receptors is key to resolve these issues and is fundamental for our understanding of disease pathogenesis. Our long-range goal is to determine how SAgs are recognized by host receptors. The objective of this application is to determine the structures and functions of MAM and PfiT. The specific aims are: 1) Determination of the molecular mechanism of MAM recognition by TCR. Crystal structure of a ternary complex between pMHC, MAM, and TCR derived from CD4+ T cells will be determined and compared with a ternary complex with a TCR derived from CD8+ T cells. These structures should resolve how TCRs derived from both CD4+ and CD8+ T cells recognize MAM as well as how TCR a chains affect their interactions with MAM. Mutagenesis, genetic, biochemical, and immunological approaches will then be used to determine the role of TCR Va in MAM recognition. 2) Determination of the structure and function of the Crohn's disease-assocaited SAg PfiT. Crystal structures of PfiT and its close homolog PA2885 will be determined and compared. The human receptors (TCR and pMHC) will be determined. The affinity and kinetic parameters of PfiT binding to TCR and to pMHC will then be determined, followed by determination of structures of PfiT in complex with host receptors-TCR and pMHC. The sum of these studies will contribute to our understanding of disease pathogenesis, and will provide new avenues for therapeutic intervention.