期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2022
卷号：119
期号：29
DOI：10.1073/pnas.2202209119
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：Significance
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Phospholipase A2 receptor (PLA2R) is the major autoantigen responsible for causing the rare autoimmune kidney disease, membranous nephropathy (MN).
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PLA2R autoantibodies primarily bind to a dominant epitope located within a 28-amino acid peptide in the cysteine-rich domain of PLA2R.
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We generated a minimal peptide necessary for binding autoantibodies with high affinity for developing future therapies.
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We report the high-resolution structure of PLA2R with its domain orientation and define key regions within the domain epitope critical for its immunogenicity in MN.
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.
