MOLECULAR CHARACTERISTICS OF THE GOODPASTURE AUTOANTIGEN

Goodpasture syndrome is an autoimmune disease causing rapidly progressive glomerulonephritis and pulmonary hemorrhage. The clinical manifestations are caused by autoantibodies that bind to a constituent, termed the Goodpasture autoantigen, of alveolar and glomerular basement membranes. Searches for the identity of this constituent have recently culminated in the discovery of two new chains (alpha3 and alpha4) of type IV collagen and the identification of the alpha3 chain as the Goodpasture autoantigen. The gene, COL4A3, encoding this autoantigen was recently cloned and localized to the q35-37 region of chromosome 2. The major protomeric form of the alpha3 chain is a homotrimer. The alpha3-protomers associate through NC1-to-NC1 interactions mainly with each other to form a suprastructure, although some associate with protomers containing the alpha1(IV) and alpha2(IV) chains. The alpha3-protomers also form suprastructures involving triple helical interactions of three or more protomers. The Goodpasture epitope is localized to the carboxyl-terminal region of the alpha3(IV) chain, encompassing the last 36 residues of the chain, as the primary interaction site, and its structure is discontinuous.