Structure of PLA2R reveals presentation of the dominant membranous nephropathy epitope and an immunogenic patch

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Abstract

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 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 non-redundant 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 highresolution
structure of PLA2R to 3.4 Å resolution which shows that
the dominant epitope and key residues within the CysR 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.

Bibliographical metadata

Original languageEnglish
JournalProceedings of the National Academy of Sciences
Publication statusPublished - 2022