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TitleStructure of PLA2R reveals presentation of the dominant membranous nephropathy epitope and an immunogenic patch.
Journal, issue, pagesProc Natl Acad Sci U S A, Vol. 119, Issue 29, Page e2202209119, Year 2022
Publish dateJul 19, 2022
AuthorsMaryline Fresquet / Michael P Lockhart-Cairns / Samuel J Rhoden / Thomas A Jowitt / David C Briggs / Clair Baldock / Paul E Brenchley / Rachel Lennon /
PubMed AbstractMembranous nephropathy is an autoimmune kidney disease caused by autoantibodies targeting antigens present on glomerular podocytes, instigating a cascade leading to glomerular injury. The most ...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.
External linksProc Natl Acad Sci U S A / PubMed:35858348 / PubMed Central
MethodsEM (single particle)
Resolution3.4 Å
Structure data

14077

7qsr

EMDB-14077: Structure of PLA2R at pH 6.2
PDB-7qsr: CryoEM structure of the Ectodomain of Human PLA2R
Method: EM (single particle) / Resolution: 3.4 Å

Chemicals

ChemComp-NAG:
2-acetamido-2-deoxy-beta-D-glucopyranose

Source
  • homo sapiens (human)
KeywordsMEMBRANE PROTEIN / Receptor / Ectodomain / Glycoprotein / Nephrology

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