Quality Control of MHC Class I Restricted Antigen Processing

MHC I 类限制性抗原加工的质量控制

基本信息

批准号：
8484346
负责人：
PETER CRESSWELL
金额：
$ 39.12万
依托单位：
YALE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-06-15 至 2016-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8484346
关键词：
Affinity Amino Acids Aminopeptidase Binding CD8B1 gene Calnexin Cell surface Cell-Free System Cells Complex Cytosol Disulfides ERp57 Endoplasmic Reticulum Enzymes Genes Glucose Glucosidase II Glycoproteins Goals HLA-A gene Human Immune response Individual Laboratories Lectin Link MHC Class I Genes Major Histocompatibility Complex Mediating Membrane Membrane Glycoproteins Modeling Molecular Molecular Chaperones Mus Mutagenesis Oxidoreductase Pathway interactions Peptides Play Polysaccharides Process Proteins Quality Control Regulation Role Structure Sulfhydryl Compounds Surface System T cell response T-Lymphocyte TAP1 gene Transferase Uridine Diphosphate Glucose Viral Proteins Virus antigen processing antigenic peptide transporter base calreticulin cell mediated immune response dimer killings pathogen public health relevance small molecule stoichiometry tapasin

项目摘要

DESCRIPTION (provided by applicant): Major Histocompatibility Complex (MHC) class I glycoproteins, the products of HLA-A, B and C genes in humans, are critical for T cell mediated immune responses to viruses and intracellular pathogens. They are glycoproteins that form a heterodimer with a small molecule, ?2-microglobulin (?2m), and associate in the endoplasmic reticulum (ER) of a cell with peptides derived from cellular proteins. These include, when the cell is infected, pathogen-encoded proteins. Surface complexes of MHC class I molecules with pathogen-derived peptides are recognized by CD8-positive T cells that can kill the infected cell. The goal of this proposal is to understand the detailed molecular processes that result in the formation and cell surface expression of MHC class I complexes that contain peptides of extraordinarily high affinity, which is essential for CD8-T cell responses that can rid an infected individual of the pathogen. Binding of peptides to MHC class I molecules occurs within a multi-protein assembly called the Peptide Loading Complex, or PLC. The PLC consists of MHC class I molecules themselves, a heterodimeric transporter called the Transporter associated with Antigen Processing (TAP) that delivers the peptides into the ER, tapasin, a membrane glycoprotein that, with a soluble molecule, ERp57, forms a disulfide-linked heterodimer that can mediate peptide exchange by the class I molecules to ultimately generate high affinity complexes, and a second soluble protein called calreticulin. The interactions responsible for the stability of the PLC involve specific associations of TAP and tapasin within the membrane, and between the luminal domains of tapasin and the MHC class I molecule. There are also interactions between ERp57 and calreticulin and a glycan-dependent interaction of the MHC class I glycoprotein with calreticulin that are shared by other folding glycoproteins in the ER. Th glycan structure is characteristically dynamically maintained by the action of two opposing enzymes, one, glucosidase II, that removes a terminal glucose residue, and a second, UDP-glucose glycoprotein transferase 1 (UGT1) that replaces the glucose when the glycoprotein bearing the glycan is improperly folded. This proposal seeks to determine the roles of these various interactions and enzymatic mechanisms in mediating the assembly of MHC class I molecules with high affinity peptides in the ER.

描述（由申请人提供）：主要组织相容性复合物（MHC）I 类糖蛋白是人类 HLA-A、B 和 C 基因的产物，对于 T 细胞介导的针对病毒和细胞内病原体的免疫反应至关重要。它们是与小分子 β2-微球蛋白 (β2m) 形成异二聚体的糖蛋白，并在细胞的内质网 (ER) 中与源自细胞蛋白的肽结合。这些包括，当细胞是受感染的病原体编码的蛋白质。 MHC I 类分子与病原体衍生肽的表面复合物被 CD8 阳性 T 细胞识别，可以杀死受感染的细胞。该提案的目标是了解导致 MHC I 类复合物形成和细胞表面表达的详细分子过程，该复合物含有极高亲和力的肽，这对于可以清除感染的 CD8-T 细胞反应至关重要病原体的个体。肽与 MHC I 类分子的结合发生在称为肽加载复合体 (PLC) 的多蛋白组装体内。 PLC 由 MHC I 类分子本身组成，一种称为抗原加工相关转运蛋白 (TAP) 的异二聚体转运蛋白，可将肽输送到 ER 中，tapasin 是一种膜糖蛋白，与可溶性分子 ERp57 形成二硫键连接异二聚体可以介导 I 类分子的肽交换，最终生成高亲和力复合物，以及第二种可溶性蛋白，称为钙网蛋白。负责 PLC 稳定性的相互作用涉及 TAP 和 tapasin 在膜内以及 tapasin 的腔域和 MHC I 类分子之间的特定关联。 ERp57 和钙网蛋白之间也存在相互作用，并且 MHC I 类糖蛋白与钙网蛋白之间存在聚糖依赖性相互作用，这些相互作用是 ER 中其他折叠糖蛋白所共有的。聚糖结构的特征是通过两种相反酶的作用动态维持，一种是葡萄糖苷酶 II，可去除末端葡萄糖残基，另一种是 UDP-葡萄糖糖蛋白转移酶 1 (UGT1)，当糖蛋白带有聚糖时，它会取代葡萄糖折叠不当。该提案旨在确定这些不同的相互作用和酶机制在介导内质网中具有高亲和力肽的 MHC I 类分子组装中的作用。