Understanding ERAP molecular mechanism of MHC I antigen processing

了解 MHC I 抗原加工的 ERAP 分子机制

基本信息

批准号：
10180881
负责人：
MARLENE BOUVIER
金额：
$ 39.98万
依托单位：
UNIVERSITY OF ILLINOIS AT CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-07-15 至 2023-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10180881
关键词：
Address Affect Alleles Aminopeptidase Ankylosing spondylitis Antigen Presentation Pathway Autoimmune Diseases Binding Biochemical Biological Cell-Free System Cells Characteristics Chronic Disease Communicable Diseases Complex Computational Technique Crystallization Cytotoxic T-Lymphocytes Data Development Disease Endoplasmic Reticulum Enzymes Event Genetic Polymorphism Goals HLA-B Antigens HLA-B27 Antigen Histocompatibility Antigens Class I Human I-antigen Immune response Immune system Immunologics Immunotherapy In Vitro Invaded Knowledge Length Light Link Major Histocompatibility Complex Mediating Medical Modeling Molecular Molecular Conformation Molecular Mechanisms of Action Molecular Structure N-terminal Pathogenesis Peptide Transport Peptides Physiological Play Process Property Proteins Publishing Roentgen Rays Role Specificity Structure Structure-Activity Relationship System Techniques antigen processing base chronic autoimmune disease genetic linkage insight interest novel pathogen peptide I response tapasin tool

项目摘要

ABSTRACT Advances in characterization of the class I antigen presentation pathway over the last decade have taught us that antigen processing, peptide transport, peptide trimming, peptide selection, and peptide loading are critical events for the development of optimal peptide repertoires presented by major histocompatibility complex (MHC) class I molecules to cytotoxic T lymphocytes (CTLs). These events influence the tight binding of peptides needed to generate conformationally stable MHC I/peptide complexes. Evidence has been provided that changes in the overall quality of the MCH I peptide repertoire can have profound effects on CTL responses. Therefore, studies that characterize basic biological events in MHC I maturation are essential not only for advances in fundamental principles of antigen processing and presentation, but also to better comprehend how these maturation events modulates immune responses. We have studied the molecular and structural basis of mechanisms of peptide loading and selection by MHC I for more than 20 years. Recently, the endoplasmic reticulum-aminopeptidases associated with antigen processing (ERAP1, ERAP2, and ERAP1,2 heterodimer; referred to as ERAP) have emerged as key proteins for influencing formation of the MHC I peptide repertoire. To date, our understanding of how ERAP functions as a peptide editor is however obscure. Similarly, the question of how ERAP1 and ERAP2 polymorphisms play a role in chronic autoimmune diseases such as HLA-B*27-associated ankylosing spondylitis (AS), and how ERAP1 and ERAP2 interact with disease-associated MHC I molecules, still remain unclear. In this application, we will use a comprehensive approach to shed some light on the function of ERAPs and on the molecular crosstalk between ERAPs and MHC I molecules. Using a cell-free system composed of ERAPs, MHC class I molecules, and synthetic and natural N-terminally extended peptides, and in combination with biochemical, molecular, and crystallographic techniques, we will characterize the function of ERAPs towards free and MHC I-bound peptides (Aim #1); elucidate the functional links between ERAP1, HLA-B*27, and AS (Aim #2); and determine the x-ray crystal structure of an HLA-B*0801/precursor complex, with and without ERAP1 (Aim #3). Overall, our study is fundamentally significant because it will provide new knowledge to better understand how ERAPs function and influence formation of the MHC I peptide repertoire, novel insights into molecular events underlying the pathogenesis of AS, and will reveal the molecular interaction between ERAP1 and MHC I molecules. The medical relevance of our studies is immense.

抽象的在过去的十年中，I级抗原演示途径的表征进步我们认为抗原加工，肽转运，肽修剪，选择肽和肽负荷为主要组织相容性提出的最佳肽库发展的关键事件复合物（MHC）I类分子到细胞毒性T淋巴细胞（CTL）。这些事件会影响紧密的绑定需要产生构象稳定的MHC I/肽复合物所需的肽。证据已经存在前提，MCH I肽库的整体质量的变化可能会对CTL产生深远的影响回答。因此，表征MHC I成熟中基本生物学事件的研究不是必不可少的仅用于抗原加工和演示的基本原则的进步，但也要改善理解这些成熟事件如何调节免疫反应。我们研究了肽负荷和选择机制的分子和结构基础 MHC I已有20多年了。最近，与抗原相关的内质网氨基肽酶加工（ERAP1，ERAP2和ERAP1,2异二聚体；称为ERAP）已出现为关键蛋白影响MHC I肽库的形成。迄今为止，我们对ERAP如何发挥作用的理解但是，肽编辑器是晦涩的。同样，关于ERAP1和ERAP2多态性的问题在慢性自身免疫性疾病中的作用，例如HLA-B*27相关的强直性脊柱炎（AS），以及如何 ERAP1和ERAP2与疾病相关的MHC I分子相互作用，仍然不清楚。在此应用程序中我们将使用一种全面的方法来阐明ERAP和分子的功能 ERAPS和MHC I分子之间的串扰。使用由ERAPS组成的无单元系统，MHC类I类分子，合成和天然的N末端扩展的肽，并与生化相结合分子和晶体学技术，我们将表征ERAPS朝向自由和MHC的功能 I结合肽（AIM＃1）;阐明ERAP1，HLA-B*27和AS（AIM＃2）之间的功能链接；和确定HLA-B*0801/前体配合物的X射线晶体结构，带有和不带ERAP1（AIM＃3）。总体而言，我们的研究从根本上意义重大，因为它将提供新的知识以更好地了解 ERAPS如何功能和影响MHC I肽库的形成，对分子的新见解 AS发病机理的基础事件，并将揭示ERAP1与MHC之间的分子相互作用我的分子。我们研究的医学相关性是巨大的。

项目成果

期刊论文数量（10）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Trimming of MHC Class I Ligands by ERAP Aminopeptidases.

通过 ERAP 氨基肽酶修剪 MHC I 类配体。

DOI：
10.1007/978-1-4939-9450-2_3
发表时间：
2019
期刊：
Methods in molecular biology (Clifton, N.J.)
影响因子：
0
作者：
Weimershaus,Mirjana;Evnouchidou,Irini;Li,Lenong;vanEndert,Peter;Bouvier,Marlene
通讯作者：
Bouvier,Marlene

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