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Structure and mechanism of pemphigus autoantibodies

天疱疮自身抗体的结构和机制

基本信息

批准号：
10405529
负责人：
LAWRENCE S SHAPIRO
金额：
$ 48.72万
依托单位：
COLUMBIA UNIVERSITY HEALTH SCIENCES
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-08-01 至 2023-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10405529
关键词：
Acantholysis Adherens Junction Adhesions Adhesives Affinity Antibodies Antibody Binding Sites Antigen Targeting Antigens Autoantibodies Autoimmune Autoimmune Diseases Binding Binding Proteins Bulla Cadherin Domain Cadherins Cell Adhesion Cell Adhesion Molecules Cell Communication Cell-Cell Adhesion Cell-Matrix Junction Cells Complex Cryo-electron tomography Crystallization Data Data Reporting Desmosomes Disease Electron Microscopy Epitopes Extracellular Structure Family Goals Immunoglobulin Somatic Hypermutation Impairment Integral Membrane Protein Life Liposomes Mediating Membrane Methods Modernization Molecular Mucous Membrane Mutagenesis Pathogenesis Pathogenicity Patients Pemphigus Pemphigus Vulgaris Phenotype Protein Family Proteins Research Resolution Role Skin South America Stratified Epithelium Stratum Basale Structure Surface Plasmon Resonance System Tertiary Protein Structure antigen binding base biophysical analysis design desmocollin desmoglein desmoglein 1 desmoglein III disorder subtype experimental study extracellular mutant pathogen reconstitution reconstruction skin disorder structural biology

项目摘要

Pemphigus is a group of potentially life-threatening antibody-mediated autoimmune diseases of the skin and other stratified epithelia in which acantholysis – the loss of cell adhesion – causes skin blistering and erosions. Acantholysis in pemphigus is caused by autoantibodies directed against desmosome cell-adhesive junctions – specifically against the transmembrane cadherin- family proteins that bind between cells to mediate adhesion in desmosomes. Several subtypes of pemphigus disease are known, including two major forms pemphigus vulgaris (PV) and pemphigus foliaceus (PF). Broadly, PV is characterized by acantholysis in the basal layers of mucosae (mucosal form) or mucosae and skin (muco-cutaneous form), while PF is characterized by acantholysis specifically in the subcorneal upper layers of the skin. Pathogenic pemphigus autoantibodies have been identified from patients with each form of the disease, but structural information on pemphigus autoantibodies is lacking. Thus, the precise epitopes targeted by pemphigus autoantibodies, and the antibody regions (paratopes) that mediate recognition, remain unknown. The overall goal of the research proposed here is to bring atomic-level definition to the study of pemphigus disease through the application of modern methods of structural biology. Atomic resolution co-crystal structures will unambiguously identify functional regions and define the precise molecular interactions mediating recognition between pemphigus autoantibodies and the cadherin cell-adhesion proteins they target. In addition, to determine how different pemphigus autoantibodies impair desmosome structure and cause blistering, we will analyze their effects on reconstituted desmosome junctions at high resolution using cryo-EM tomography. The research proposed here will produce an atomic-level understanding of the interaction of pemphigus autoantibodies with desmosomes, and is expected to transform our understanding of pemphigus disease.

天疱疮是一组可能危及生命的抗体介导的自身免疫性疾病，皮肤和其他分层上皮细胞，其中棘层松解-细胞粘附的丧失-导致皮肤起泡和糜烂。天疱疮中的溶血是由针对对抗桥粒细胞粘附连接--特别是跨膜钙粘蛋白-- 在细胞间结合以介导桥粒粘附的家族蛋白质。几种亚型天疱疮疾病的已知形式包括两种主要形式的寻常天疱疮（PV）和落叶性天疱疮（PF）。广义上讲，PV的特征在于基底层的棘层松解，粘膜（粘膜形式）或粘膜和皮肤（粘膜-皮肤形式），而PF是其特征在于特别是在皮肤的角膜下上层中的棘层松解。致病性天疱疮自身抗体已经从患有每种形式的天疱疮的患者中鉴定出来。疾病，但缺乏天疱疮自身抗体的结构信息。因此，天疱疮自身抗体靶向的表位，以及介导识别，仍然未知。本研究的总体目标是将原子级定义引入天疱疮疾病的研究，现代结构生物学方法。原子分辨率共晶结构将明确识别功能区域并定义精确的分子相互作用介导天疱疮自身抗体与钙粘蛋白细胞粘附之间的识别它们所针对的蛋白质。此外，为了确定不同的天疱疮自身抗体如何损害桥粒结构和引起起泡，我们将分析它们对重组的影响。桥粒连接的高分辨率使用冷冻EM断层扫描。研究提出，这里将产生天疱疮自身抗体相互作用的原子水平的理解并有望改变我们对天疱疮疾病的理解。