LARS SOTTRUP-JENSEN*, TERRENCE M. STEPANIK*t, TORSTEN KRISTENSEN*1, PETER B. L0NBLAD*,

A comparison of the sequence of the subunit of human a2-macroglobulin (a2M; 1451 amino acid residues) with that of murine complement component pro-C3 (1639 ami- no acid residues) reveals eight extended regions of sequence similarity. These regions contain between 19% and 31% iden- tically placed residues and account for 75% and 67%, respec- tively, of the polypeptide chains of a2M and pro-C3. Published sequence data for complement component C4 show that seg- ments of this protein match well with corresponding stretches in a2M and pro-C3. It is proposed that a2M, C3, and C4, which all contain a unique activatable f-cysteinyl-y-glutamyl thiol ester, have a common evolutionary origin and are ho- mologous proteins. Several larger regions of low sequence sim- ilarity indicate the presence of structural domains in each of these proteins that specifically modify an underlying common gross structure. The quartets of basic residues in pro-C3 and pro-C4, at which cleavage takes place to produce the mature subunits of these proteins, and most of the residues forming the anaphylatoxin peptides of C3 and C4 (C3a and C4a) are absent in a2M. In addition, C3 and C4 contain large portions, which extend beyond the COOH terminus of a2M.