Structural Basis of Immue Cell Receptor Function

免疫细胞受体功能的结构基础

• 批准号: 6631885
• 负责人: GERHARD WAGNER
• 金额: $ 25.8万
• 依托单位: HARVARD MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 1996
• 资助国家: 美国
• 起止时间: 1996-07-15 至 2006-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6631885
• 关键词: CD2 molecule; CD3 molecule; CD4 molecule; MHC class II antigen; T cell receptor; T lymphocyte; biological signal transduction; intermolecular interaction; leukocyte activation /transformation; nuclear magnetic resonance spectroscopy; protein structure function; receptor binding; recombinant proteins; structural biology

DESCRIPTION (provided by applicant): Activation of T-cells depends on numerous interactions of surface receptors and cytoplasmic proteins. Cell adhesion and recognition of foreign peptides presented by MHC molecules is mediated by extracellular portions of T-cell receptors, such as the adhesion domains of CD2 and the Fv fragment of the alpha-beta heterodimer (Ti) of the T-cell receptor of antigens (TCR). During the previous granting period we have characterized structures of several extracellular portions of such receptors, such as the adhesion domains of CD2, CD58 and a Fv fragment of the class II-specific alpha-beta-TCR Dl0, and we have elucidated the role of glycans in the adhesion domains of CD2 and CD58. Finally, we determined the structures of the CD2/CD58 complex and a complex between the Dl0 Fv fragment and a peptide/MHC Class II complex. The proposed continuation of this research is focused on structural and functional characterization of CD3 components of the TCR, the signaling components of the TCR, and on proteins that mediate signaling via the cytoplasmic tail of CD2. We will pursued via three specific aims: 1. Structure and interactions of the heterodimer: We will solve the structure of a recently engineered correctly folded single chain epsilon-gamma-CD3 construct using NMR spectroscopy. Based on the structure we will investigate interactions between the epsilon-gamma-CD3 heterodimer and the alpha-beta-TCR. 2. Structure and interactions of the epsilon-delta-CD3 heterodimer: Using similar strategies we will engineer single-chain constructs of the epsilon-delta-CD3 heterodimer and study its interaction with the alpha-beta-TCR and CD4. 3. Structural and functional studies of CD2-BP2: We will solve the structure of the complex of the GYF domain of CD2-BP2 with a fragment of the CD2 tail. We will also study larger fragments of or full-length CD2-BP2 and investigate their interactions with CD2 or potential other factors. This research will provide new insights into the mechanism of T-cell activation at the receptor-cytoplasm border.

描述（由申请人提供）：T 细胞的激活取决于多种因素 表面受体和细胞质蛋白的相互作用。细胞粘附和 MHC 分子呈递的外源肽的识别是由 T 细胞受体的胞外部分，例如 CD2 的粘附结构域 和 T 细胞受体的 α-β 异二聚体 (Ti) 的 Fv 片段 抗原（TCR）。在之前的授权期间，我们已经描述了 这些受体的几个细胞外部分的结构，例如 CD2、CD58 和 II 类特异性 Fv 片段的粘附结构域 α-β-TCR Dl0，我们已经阐明了聚糖在粘附中的作用 CD2 和 CD58 的结构域。最后，我们确定了CD2/CD58的结构 复合物以及D10 Fv片段与肽/MHC II类之间的复合物 复杂的。 建议继续开展这项研究，重点是结构和 TCR 的 CD3 成分的功能表征、信号传导 TCR 的组成部分，以及通过 TCR 介导信号传导的蛋白质 CD2 的胞质尾。我们将通过三个具体目标来追求： 1.异二聚体的结构和相互作用：我们将解决结构 最近设计的正确折叠的单链 epsilon-gamma-CD3 使用核磁共振波谱构建。根据结构我们将调查 ε-γ-CD3 异二聚体和 α-β-TCR 之间的相互作用。 2. ε-δ-CD3 异二聚体的结构和相互作用：使用 类似的策略，我们将设计单链结构 ε-δ-CD3 异二聚体并研究其与 α-β-TCR 的相互作用 和CD4。 3. CD2-BP2的结构和功能研究：我们将解决CD2-BP2的结构 CD2-BP2 的 GYF 结构域与 CD2 尾部片段的复合体。我们 还将研究更大的片段或全长 CD2-BP2 并调查 它们与 CD2 或潜在的其他因素的相互作用。 这项研究将为T细胞激活机制提供新的见解 在受体-细胞质边界。