STRUCTURAL STUDIES OF THE HIGH AFFINITY IGE RECEPTOR

许多造血细胞表达细胞表面受体， 通过与抗体的相互作用确定抗体类别（例如IgE或IgG）- Fc区。 这些Fc受体在许多不同细胞上的表达 类型将抗体应答的多样性与细胞介导的 免疫机制，包括细胞毒性、去颗粒作用和吞噬作用 反应. 对IgE和IgE和IgG具有特异性的Fc受体属于免疫球蛋白受体。 具有同源细胞外免疫球蛋白的共同结构类别 负责抗体结合的结构域。 抗原抗体 复合物触发Fc受体的聚集，从而激活 细胞，使用类似于T和B的信号传导途径 细胞受体。 关于特定的结构相互作用知之甚少 控制不同Fc受体对抗体类别的识别 或随后形成的信号复合物。 这个提议的目标是在原子细节上理解Fc是如何 受体区分抗体分子， 构象变化可能在调节结合或信号传导中的作用 这些受体。 为了解决这些问题，我们选择 研究肥大细胞的高亲和力IgE-Fc受体（Fc受体RI）。 FcepsilonRI在触发即刻型 超敏反应，如常见的过敏性疾病和过敏性休克。 该提案的具体目标是：（1）确定 通过X射线晶体学测定FcepsilonRI;（2）测定 单独和复合物中IgE-Fc区的晶体结构 关于FcepsilonRI 我们有细胞外区域的初始晶体 结合抗体的Fceptide RI。 此外，IgE的Fc片段 分子正在生成，并将用于进一步结晶 实验 这三个拟议的结构将在原子层面得到澄清 水平Fc受体与抗体的相互作用，并可能导致新的 用于治疗变态反应、关节炎和抗体介导的 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.