STRUCTURAL STUDIES OF THE HIGH AFFINITY IGE RECEPTOR

许多造血细胞表达细胞表面受体，这些受体可以区分 通过与抗体相互作用而产生的抗体类别(例如，IgE或IgG)- FC区域。这些Fc受体在多种不同细胞上的表达 不同类型的抗体对细胞介导的反应不同 免疫机制包括细胞毒性、脱粒细胞和吞噬 反应。Ig E和Ig E和Ig G特异性Fc受体落入 具有同源细胞外免疫球蛋白的共同结构类 负责抗体结合的结构域。抗原抗体 复合体触发Fc受体的聚集，从而激活 细胞，使用与T和B相似的信号通路 细胞受体。对具体的结构相互作用知之甚少。 管理不同Fc受体对抗体类别的识别 或随后形成的信号复合体。 这项建议的目标是详细了解FC如何 受体区分抗体分子并确定 构象变化可能在调节结合或信号转导中起作用 这些受体。为了解决这些问题，我们选择了 肥大细胞高亲和力IgE-Fc受体(Fcepsilon RI)的研究 FcepsilonRI在触发即时型中很重要 过敏反应，如常见的过敏性疾病和过敏性休克。 这项建议的具体目的是：(1)确定 用X射线结晶学和(2)测定Fcepsilon RI。 IgE-Fc区单独和复合体的晶体结构 和FcepsilonRI一起。我们已经有了胞外区的初始晶体 结合抗体的Fcepsilon RI。此外，免疫球蛋白E的Fc片段 分子正在生成，并将用于进一步的结晶 实验。三个拟议的结构将在原子会议上澄清 Fc受体与抗体的相互作用并可能导致新的 变态反应、关节炎和抗体介导的治疗方法 肿瘤免疫。

Many hematopoietic cells express cell-surface receptors that distinguish antibody classes (e.g. IgE or IgG) through interactions with the antibody- Fc regions. The expression of these Fc receptors on many different cell types couples the diversity of the antibody response to cell-mediated immune mechanisms that include cytotoxic, degranulatory, and phagocytic reactions. Fc receptors specific for IgE and IgE and IgG fall into a common structural class with homologous extracellular immunoglobulin domains that are responsible for antibody binding. Antigen antibody complexes trigger the aggregation of Fc receptors and thereby activate cells, using signaling pathways that are analogous to those of the T and B cell receptor. Little is known about the specific structural interactions that govern the recognition of antibody classes by different Fc receptors or the subsequent signaling complexes that are formed. The goal of this proposal is to understand in atomic detail how Fc receptors discriminate between antibody molecules and to determine what role conformational changes may have in regulating binding or signaling of these receptors. In order to address these questions we have chosen to study the high affinity IgE-Fc receptor (Fcepsilon RI) from mast cells. The FcepsilonRI is important in triggering immediate-type hypersensitivities such as common allergic diseases and anaphylactic shock. The specific aims this proposal are to (1) determine the structure of the FcepsilonRI by X-ray crystallography and (2) to determine the crystallographic structures of the IgE-Fc region alone and in a complex with FcepsilonRI. We have initial crystals of the extracellular region of the Fcepsilon RI that binds antibody. In addition, Fc-fragments of the IgE molecule are being generated and will be used for further crystallization experiments. The three proposed structures will clarify at the atomic level the interaction of Fc receptor with antibody and may lead to new approaches for the treatment of allergy, arthritis, and antibody-mediated tumor immunity.