Wellcome Centre for Cell-Matrix Research, The University of Manchester, Manchester, M13 9PT, United Kingdom.
Division of Cell-Matrix Biology and Regenerative Medicine, School of Biological Sciences, Faculty of Biology Medicine and Health, The University of Manchester, Manchester Academic Health Science Centre, Manchester, M13 9PT, United Kingdom.
Proc Natl Acad Sci U S A. 2022 Jul 19;119(29):e2202209119. doi: 10.1073/pnas.2202209119. Epub 2022 Jul 11.
Membranous nephropathy is an autoimmune kidney disease caused by autoantibodies targeting antigens present on glomerular podocytes, instigating a cascade leading to glomerular injury. The most prevalent circulating autoantibodies in membranous nephropathy are against phospholipase A2 receptor (PLA2R), a cell surface receptor. The dominant epitope in PLA2R is located within the cysteine-rich domain, yet high-resolution structure-based mapping is lacking. In this study, we define the key nonredundant amino acids in the dominant epitope of PLA2R involved in autoantibody binding. We further describe two essential regions within the dominant epitope and spacer requirements for a synthetic peptide of the epitope for drug discovery. In addition, using cryo-electron microscopy, we have determined the high-resolution structure of PLA2R to 3.4 Å resolution, which shows that the dominant epitope and key residues within the cysteine-rich domain are accessible at the cell surface. In addition, the structure of PLA2R not only suggests a different orientation of domains but also implicates a unique immunogenic signature in PLA2R responsible for inducing autoantibody formation and recognition.
膜性肾病是一种由自身抗体针对肾小球足细胞上的抗原引起的自身免疫性肾脏疾病，引发级联反应导致肾小球损伤。在膜性肾病中最常见的循环自身抗体是针对磷脂酶 A2 受体（PLA2R）的，PLA2R 是一种细胞表面受体。PLA2R 的主要表位位于富含半胱氨酸的结构域内，但缺乏基于高分辨率结构的映射。在这项研究中，我们确定了参与自身抗体结合的 PLA2R 主要表位中的关键非冗余氨基酸。我们进一步描述了主要表位内的两个必需区域和表位合成肽的间隔要求，用于药物发现。此外，我们使用冷冻电子显微镜以 3.4 Å 的分辨率确定了 PLA2R 的高分辨率结构，该结构表明，主要表位和富含半胱氨酸结构域内的关键残基在细胞表面是可及的。此外，PLA2R 的结构不仅表明了结构域的不同取向，还暗示了 PLA2R 中独特的免疫原性特征，该特征负责诱导自身抗体的形成和识别。
