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复层上皮，其中棘层松解（细胞粘附丧失）导致天疱疮的皮肤起泡和糜烂是由自身抗体引起的。对抗桥粒细胞粘附连接——特别是对抗跨膜钙粘蛋白—— 细胞之间结合以介导桥粒粘附的家族蛋白。已知的天疱疮疾病包括两种主要形式：寻常型天疱疮 (PV) 和落叶型天疱疮 (PF) 广泛而言，PV 的特点是基底层棘层松解。粘膜（粘膜形式）或粘膜和皮肤（粘膜皮肤形式），而 PF 是其特点是棘层松解，特别是在皮肤的角层下上层。已从患有每种类型天疱疮的患者中鉴定出致病性天疱疮自身抗体疾病，但缺乏天疱疮自身抗体的结构信息，因此，缺乏精确的信息。天疱疮自身抗体靶向的表位和抗体区域（互补位）介导识别，仍然未知。这里提出的研究的总体目标是。通过应用将原子级定义带入天疱疮疾病的研究原子分辨率共晶结构的现代方法。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此外，还确定不同的天疱疮自身抗体如何损害。桥粒结构和起泡原因，我们将分析它们对重构的影响该研究提出使用冷冻电镜断层扫描以高分辨率观察桥粒连接。这里将对天疱疮自身抗体的相互作用产生原子水平的理解与桥粒，有望改变我们对天疱疮疾病的理解。