Quality Control of MHC Class I Restricted Antigen Processing

MHC I 类限制性抗原加工的质量控制

• 批准号: 8662182
• 负责人: PETER CRESSWELL
• 金额: $ 39.33万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 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/8662182
• 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

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（由申请方提供）：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应答至关重要。它们是与小分子形成异源二聚体的糖蛋白。2-微球蛋白（？2 m），并在细胞的内质网（ER）中与来源于细胞蛋白质的肽缔合。其中，当细胞 是被感染的病原体编码蛋白MHC I类分子与病原体衍生肽的表面复合物被CD 8阳性T细胞识别，其可以杀死感染的细胞。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，该复合物含有非常高亲和力的肽，这对于可以清除感染的CD 8-T细胞应答是必需的。 病原体的个体。肽与MHC I类分子的结合发生在称为肽装载复合物或PLC的多蛋白质组装体中。PLC由MHC I类分子本身、将肽递送到ER中的称为与抗原加工相关的转运蛋白（TAP）的异二聚体转运蛋白、tapasin（一种膜糖蛋白，其与可溶性分子ERp 57形成二硫键连接的异二聚体，其可以介导I类分子的肽交换以最终产生高亲和力复合物）和称为钙网蛋白的第二可溶性蛋白组成。负责PLC稳定性的相互作用涉及TAP和tapasin在膜内的特异性结合，以及tapasin的管腔结构域和MHC I类分子之间的特异性结合。ERp 57和钙网蛋白之间也存在相互作用，以及MHC I类糖蛋白与钙网蛋白的聚糖依赖性相互作用，这些相互作用由ER中的其他折叠糖蛋白共享。聚糖结构的特征是通过两种相反的酶的作用动态地维持，一种是葡糖苷酶II，其去除末端葡萄糖残基，另一种是UDP-葡萄糖蛋白转移酶1（UGT 1），其在携带聚糖的糖蛋白不正确折叠时取代葡萄糖。该建议旨在确定这些各种相互作用和酶促机制在介导MHC I类分子与ER中的高亲和力肽的组装中的作用。