Structural and functional resolution of the membranous nephropathy antigens THSD7A and PLA2R1
The discoveries of phospholipase A2 receptor 1 (PLA2R1) and thrombospondin type-1 domaincontaining 7A (THSD7A) as autoantigens in patients with membranous nephropathy (MN) have revolutionized both the diagnosis and monitoring of affected patients and the pathophysiologic understanding of this disease. In the first funding period, we characterized the key roles of antibodies against these podocyte proteins as disease-causing agents, introduced the first antigen-specific animal models of MN, characterized the molecular architecture of THSD7A in silico, identified the epitopes in THSD7A that are targeted by patient autoantibodies, and defined the landscape of podocyte signalling programs. Despite these advances, the structural and functional consequences of the antigen-antibody interaction remain elusive. Thus, we will pursue the following aims: 1) Characterization of the epitope-specific antigen-antibody interaction and its relation to pathogenicity. 2) Whole-protein structural characterization of the MN antigen THSD7A and high-resolution structural analysis of the immunodominant antibodybinding regions in THSD7A and PLA2R1 by means of cryo-electron microscopy and x-ray crystallography. 3) Investigation of the structure-function relationship between epitopedependent antibody binding and THSD7A-mediated signalling events. Taken together, the analysis of antigen-antibody interaction, high-resolution antigen structure, and epitopedependent signalling programs will lead to a novel molecular understanding of MN and eventually enable novel treatment strategies.
Seifert L, Hoxha E, Eichhoff AM, Zahner G, Dehde S, Reinhard L, Koch-Nolte F, Stahl RAK, Tomas NMJ Am Soc Nephrol. 2018 May
Tomas N, Meyer-Schwesinger C, von Spiegel H, Kotb A, Zahner G, Hoxha E, Helmchen U, Endlich N, Koch-Nolte F, Stahl R J Am Soc Nephrol. 2017 Nov
Tomas NM, Hoxha E, Reinicke AT, Fester L, Helmchen U, Gerth J, Bachmann F, Budde K, Koch-Nolte F, Zahner G, Rune G, Lambeau G, Meyer-Schwesinger C, Stahl RA.J Clin Invest. 2016 Jul