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

DOI: 10.1073/pnas.2202209119 DOI Help

Authors: Maryline Fresquet (The University of Manchester) , Michael P. Lockhart-Cairns (The University of Manchester) , Samuel J. Rhoden (The University of Manchester) , Thomas A. Jowitt (The University of Manchester) , David C. Briggs (The Francis Crick Institute) , Clair Baldock (The University of Manchester) , Paul E. Brenchley (The University of Manchester) , Rachel Lennon (The University of Manchester; Manchester University Hospitals NHS Foundation Trust)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Proceedings Of The National Academy Of Sciences , VOL 119

State: Published (Approved)
Published: July 2022
Diamond Proposal Number(s): 17773 , 22724

Open Access Open Access

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 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.

Journal Keywords: PLA2R epitope; antigenic residues; 3.4 Å; resolution croyEM structure

Diamond Keywords: Kidney Disease

Subject Areas: Biology and Bio-materials, Chemistry, Medicine

Diamond Offline Facilities: Electron Bio-Imaging Centre (eBIC)
Instruments: B21-High Throughput SAXS , Krios IV-Titan Krios IV at Diamond

Added On: 21/07/2022 09:48

Documents:
pnas.2202209119.pdf

Discipline Tags:

Non-Communicable Diseases Autoimmune Diseases Health & Wellbeing Biochemistry Chemistry Structural biology Biophysics Drug Discovery Life Sciences & Biotech

Technical Tags:

Microscopy Scattering Electron Microscopy (EM) Cryo Electron Microscopy (Cryo EM) Small Angle X-ray Scattering (SAXS)