The Goodpasture antigen has been identified as the non-collagenous (NC1) domain of a3(IV), a novel collagen IV chain (Saus, J., Wieslander, J., Langeveld, J., Quinones, S., and Hudson, B. G. (1988) J. Biol. Chern. 263, 13374-13380). In the present study, the exon/ intron structure and sequence for 285 amino acids of human a3(IV), comprising 53 amino acids of the triplehelical domain and the complete NC1 domain (232 amino acids), were determined. Based on the comparison of the amino acid

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... s of the al(IV), a2(IV), a3(IV), and a5(IV) NC1 domains, a phylogenetic tree was constructed which indicates that a2(IV) was the first chain to evolve, followed by a3(IV), and then by al(1V) and a5(IV). The exon/intron structure of these domains is consistent with this evolution model. In addition, it appears that a3(IV) changed most after diverging from the parental gene. Analysis of its primary structure reveals that, at the junction between the triple-helical and NC1 domains, there exists a previously unrecognized, highly hydrophilic region (GLKGKRGDSGSPATWTTR) which is unique to the human a3(IV) chain, containing a cell adhesion motif (RGD) as an integral part of a sequence (KRGDSGSP) conforming to a number of protein kinase recognition sites. Based on primary structure data, we outline new aspects to be explored concerning the molecular basis of collagen IV function and Goodpasture syndrome.