ZFIN ID: ZDB-PUB-051031-5
Zebrafish to humans: evolution of the alpha3-chain of type IV collagen and emergence of the autoimmune epitopes associated with Goodpasture syndrome
Macdonald, B.A., Sund, M., Grant, M.A., Pfaff, K.L., Holthaus, K., Zon, L.I., Kalluri, R.
Goodpasture's syndrome is an autoimmune vascular disease associated with kidney and lung failure, with pathogenic circulating autoantibodies targeted to a set of discontinuous epitope sequences within the non-collagenous domain-1 (NC1) of the alpha3 chain of type IV collagen [alpha3(IV)NC1], the Goodpasture's autoantigen. We demonstrate that basement membrane extracted NC1 domain preparations from C. elegans, Drosophila melanogaster and Danio rerio do not bind Goodpasture's autoantibodies, while Xenopus laevis, chicken, mouse and human alpha3(IV)NC1 domains bind autoantibodies. The alpha3(IV)-chain is not present in C. elegans and Drosophila melanogaster, but is first detected in the Danio rerio. Interestingly, native Danio rerio alpha3(IV)NC1 does not bind Goodpasture's autoantibodies. Next, we cloned, sequenced and generated recombinant Danio rerio alpha3(IV)NC1 domain. In contrast to recombinant human alpha3(IV)NC1 domain, there was complete absence of autoantibody binding to recombinant Danio rerio alpha3(IV)NC1. 3D molecular modeling from existing x-ray co-ordinates of human NC1 domain suggest that evolutionary alteration of electrostatic charge and polarity due to the emergence of critical serine, aspartic acid and lysine residues, accompanied by the loss of asparagine and glutamine contributes to the emergence of the two major Goodpasture's epitopes on the human alpha3(IV)NC1 domain, as it evolved from the Danio rerio over 450 million years.