Internal duplication and evolution of human ceruloplasmin.

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Abstract
With the completion of the primary structure of the 50,000- and 19,000-dalton fragments of human ceruloplasmin [EC 1.16.3.1], over half of the covalent structure of the single polypeptide chain of this protein is known. Visual and computer analysis of the sequence of the 564 amino acid residues in the 2 fragments gives clear evidence of statistically significant internal homology suggestive of evolutionary replication of 2 smaller units. Two homology regions, each composed of 224 residues, were defined by an intrasequence alignment that required only 3 gaps in each 224-residue segment. The 2 homology regions exhibited 43% identity in sequence, and 13% of the remaining positions had similar residues. The sequence of a 160-residue segment in ceruloplasmin exhibits significant homology to the active (Cu-binding) sites of blue electron-transfer proteins such as azurins and plastocyanins and multicopper oxidases such as cytochrome oxidase and superoxide dismutase. It is proposed that a primitive ceruloplasmin gene was formed by the fusion of 2 genes coding, respectively, for proteins about 160 and 190 amino acid residues in length; this precursor gene coding for about 350 amino acids was later triplicated to form the gene for the present-day ceruloplasmin molecule of about 1050 amino acids.