Conformational diversity of the Goodpasture antigen, the noncollagenous-1 domain of the alpha3 chain of collagen IV.
The noncollagenous-1 domain of the alpha3 chain of collagen IV networks of basement membranes is the target of an antibody-mediated inflammatory response in Goodpasture autoimmune disease. This domain when excised from basement membranes by bacterial collagenase digestion exists in two molecular forms, M(H) and M(L), that differ in cleavage site and mobility in SDS-PAGE. In the present study, M(H) and M(L) were shown to also differ with respect to epitope exposure, susceptibility to endoprotease digestion, and redox states of specific cystene residues, as determined by MS. Moreover, M(H) and M(L) assemble to form different quaternary structures, critically influencing pathogenic epitope(s) exposure and autoantibody binding. Collectively, our findings reveal that M(H) and M(L) are conformational isomers stabilized by a distinct disulfide bond connectivity, and coexist in basement membranes. The hitherto unrecognized conformational diversification of the Goodpasture autoantigen may be of relevance in pathogenesis.
Consejo Superior de Investigaciones Científicas, Instituto de Biomedicina de Valencia, Valencia , Spain.
Juan J
JJ
Calvete
Fernando
F
Revert
Mario
M
Blanco
Javier
J
Cervera
Céline
C
Tárrega
Libia
L
Sanz
Francisco
F
Revert-Ros
Froilán
F
Granero
Enrique
E
Pérez-Payá
Billy G
BG
Hudson
Juan
J
Saus
D000818:Animals; D019867:Anti-Glomerular Basement Membrane Disease / Q000276:immunology; D001324:Autoantigens / Q000737:chemistry* / Q000276:immunology; D015551:Autoimmunity / Q000276:immunology; D002417:Cattle; D024141:Collagen Type IV / Q000737:chemistry* / Q000276:immunology; D000939:Epitopes / Q000737:chemistry / Q000276:immunology; D008297:Male; D020033:Protein Isoforms / Q000737:chemistry / Q000276:immunology; D017434:Protein Structure, Tertiary
D001324:Autoantigens; D024141:Collagen Type IV; D000939:Epitopes; D020033:Protein Isoforms; C057112:type IV collagen alpha3 chain