Complement Receptor One (CRI): Structure/Function

描述（由申请方提供）：免疫粘附（IA）是指微生物在暴露于血清后附着于血细胞。这是一个基本的过程开始破坏一个传染性生物体和促进免疫反应。实验病理学家在世纪之交首次描述，然后在20世纪50年代重新发现，这种现象最终被证明依赖于用补体片段（特别是C3的片段）包被微生物（抗原），然后红细胞和白细胞上的C3受体识别所得复合物。我们的目标是继续我们20年的追求，阐明这种蛋白质的结构和功能，称为补体受体1（CR 1，CD 35或C3 b/C4 bIIA受体），它结合和处理补体免疫复合物。 在第一个具体目标中，我们建议定义CR 1的活性位点的结构。在前一个授权期间，获得了两个功能位点之一的NMR衍生结构。该结果现在将用于指导旨在限定C3 b和C4 b结合面的进一步诱变。第二个具体目标将采用NMR、晶体学和其他手段来定义与活性位点结合的C3 b和C4 b区域，并确定CR 1的其他主要功能位点的结构。我们的最终目标是确定C3 b和C4 b与CR 1相互作用的结构。 恶性疟原虫感染和未感染红细胞之间的玫瑰花结形成是严重疟疾感染的实验室标志物，由CR 1介导。我们假设这种粘附反应是一种病理过程，CR 1的几种结构变异，特别是在红细胞上表达的，是为了抑制这种粘附反应而引起的。在第三个具体目标中，我们专注于1）分析疟疾粘附素蛋白与CR 1的相互作用和2）确定这些CR 1结构变异的功能后果。特定的CR 1变异包括CCP 25的等位基因变异体，其在疟疾带的非洲原生动物中很常见，以及非人类灵长类动物的CR 1样免疫粘附受体。

DESCRIPTION (provided by applicant): Immune adherence (IA) refers to the attachment of microbes, upon their exposure to serum, to blood cells. It is a fundamental process for initiating the destruction of an infectious organism and for promoting an immunological response. First described by experimental pathologists around the turn of the 20th century and then rediscovered in the 1950s, this phenomenon was eventually demonstrated to be dependent upon the coating of the microbe (antigen) with complement fragments (specifically, those of C3) and then recognition of the resulting complex by a C3 receptor on erythrocytes and leukocytes. Our goal is to continue our 20 year pursuit relative to elucidating the structure and function of this protein, termed complement receptor 1 (CR1, CD35, or the C3b/C4bIIA receptor), which binds and processes complement-bearing immune complexes. In the first specific aim, we propose to define the structure of the active sites of CR1. During the preceding grant period, the NMR derived structure of one of the two functional sites was obtained. This result will now be used to guide further mutagenesis aimed at defining the C3b and C4b binding face. The second specific aim will employ NMR, crystallography and other means to define regions of C3b and C4b that bind to the active sites and to determine the structure of the other major functional site of CR1. Our ultimate goal is to define the structure of the C3b and C4b interaction with CR1. Rosette formation between P. falciparum infected and uninfected erythrocytes, a laboratory marker of severe malarial infection, is mediated by CR1. We hypothesize that this adherence reaction is a pathologic process and that several structural variations in CR1, especially as expressed on erythrocytes, arose in response to this infection in order to inhibit this adherence reaction. In the third specific aim, we focus on 1) analyzing the interaction of a malaria adhesin protein with CR1 and 2) determining the functional consequences of these CR1 structural variations. Specific CR1 variations include allelic variants of CCP 25 which are common in Africans native to the malaria belt, and the CR1-like immune adherence receptors of non-human primates.