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：
9751201
负责人：
LAWRENCE S SHAPIRO
金额：
$ 49.21万
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/9751201
关键词：
Acantholysis Adherens Junction Adhesions Adhesives Affinity Antibodies Antibody Binding Sites Antigen Targeting Antigens Autoantibodies Autoimmune Diseases Autoimmune Process 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.

Pemphigus是一组潜在的威胁生命的抗体介导的自身免疫性疾病皮肤和其他分层的上皮细胞 - 乙糖液（细胞粘附的丧失）导致皮肤和上皮皮肤起泡和侵蚀。 Pemphigus中的acantholysy是由定向的自身抗体引起的针对脱骨细胞粘附连接 - 特别针对跨膜钙粘蛋白 - 结合细胞之间的家族蛋白介导脱骨体中的粘附。几个子类型已知的Pemphigus疾病，包括两种主要形式的Pemphigus vulgaris（PV）和 Pemphigus叶子（PF）。从广义上讲，PV的特征是在粘膜（粘膜形式）或粘膜和皮肤（粘膜形式），而PF为特征在皮肤的下层上层中特征在于。已经从每种形式的患者中鉴定出病原性Pemphigus自身抗体疾病，但缺乏有关Pemphigus自身抗体的结构信息。那，精度 Pemphigus自身抗体靶向的表位和抗体区域（羊皮体）中介识别，仍然未知。这里提出的研究的总体目标是通过应用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 Pemphigus自身抗体与钙粘蛋白细胞粘附之间的介导识别它们靶向的蛋白质。此外，要确定不同的pempigus自身抗体如何损害深层结构并引起起泡，我们将分析它们对重构的影响使用Cryo-Em层析成像以高分辨率的脱骨连接。研究提出了这将产生对Pemphigus自身抗体相互作用的原子水平的理解与脱糖体有关，并有望改变我们对雌性疾病的理解。