Comparison of transferrin sequences from different species.

1. Amino acid sequences of transferrins from eight species, from human to tobacco hornworm, have been compared. Eighty-four amino acids (12%) are invariant, including three of the four ligands for the N-terminal Fe3+ ion. 2. The most highly conserved regions of both lobes of transferrin are the internal beta-sheets of domains 1 and 2, and helices 5 and 7 which abut the Fe3+ binding site. Two small patches of conserved surface residues, which may be involved in receptor binding, have also been identified. 3. Phylogenies have been deduced from pairwise alignment of the sequences of the N- and C-terminal lobes independently. The phylogenies are consistent with the evolutionary tree derived from the fossil record, and with the observation that the gene duplication which created the N- and C-terminal lobes of transferrin occurred before the divergence of the mammalian and insect lines. 4. The phylogenies predict that the lactotransferrin family diverged some 200 Myr ago, after the separation of the lines leading to mammals and birds. In contrast, the phylogenies predict that melanotransferrin diverged before the separation of the mammalian and avian lines. 5. Sequence comparisons also suggest that the stoichiometry of the transferrin receptor:transferrin complex is 2:1.