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Blood, 1 March 2006, Vol. 107, No. 5, pp. 1908-1915.
Prepublished online as a Blood First Edition Paper on October 27, 2005; DOI 10.1182/blood-2005-05-1814.
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HEMOSTASIS, THROMBOSIS, AND VASCULAR BIOLOGY
Zebrafish to humans: evolution of the  3-chain of type IV collagen and emergence of the autoimmune epitopes associated with Goodpasture syndrome
Brian A. MacDonald,
Malin Sund,
Marianne A. Grant,
Kathleen L. Pfaff,
Kathryn Holthaus,
Leonard I. Zon, and
Raghu Kalluri
From the Center for Matrix Biology and Division of Molecular and Vascular Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School; Stem Cell Program and Division of Hematology and Oncology, Children's Hospital, Dana Farber Cancer Institute, Howard Hughes Medical Institute and Harvard Medical School; Division of Nephrology, Children's Hospital and Harvard Medical School; and Harvard-MIT Division of Health Sciences and Technology and Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA.
Goodpasture 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 noncollagenous domain-1 (NC1) of the  3 chain of type IV collagen (3(IV)NC1), the Goodpasture autoantigen. We demonstrate that basement membrane extracted NC1 domain preparations from Caenorhabditis elegans, Drosophila melanogaster, and Danio rerio do not bind Goodpasture autoantibodies, while Xenopus laevis, chicken, mouse and human 3(IV)NC1 domains bind autoantibodies. The 3(IV) chain is not present in C elegans and Drosophila melanogaster, but is first detected in the Danio rerio. Interestingly, native Danio rerio 3(IV)NC1 does not bind Goodpasture autoantibodies. Next, we cloned, sequenced, and generated recombinant Danio rerio 3(IV)NC1 domain. In contrast to recombinant human 3(IV)NC1 domain, there was complete absence of autoantibody binding to recombinant Danio rerio 3(IV)NC1. Three-dimensional molecular modeling from existing x-ray coordinates 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 2 major Goodpasture epitopes on the human 3(IV)NC1 domain, as it evolved from the Danio rerio over 450 million years.
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