Molecular Evolution of Insulin in Non-Mammalian Vertebrates

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SYNOPSIS. The traditional view, based primarily on X-ray crystallographic data, is that the amino acid residues at positions B12, B16, B23-B26, A1-A5, A19 and A21 in the insulin molecule comprise the receptor-binding domain. More recently, however, it has been proposed that the conformation adopted by insulin in the crystal structure is an inactive one. The results of alanine-scanning mutagenesis studies suggest that GlyB23, PheB24, BeA2, ValA3, and TyrA19 interact directly with the receptor with LeuB6, GlyBS, LeuBll, GluB13 and PheB25, although not part of the binding epitope, being important in maintaining the receptor-binding conformation. A comparison of the primary structures of insulins from a wide range of non-mammalian vertebrates, from hagfish to birds, provides support for this revised view by demonstrating that strong evolutionary pressure has acted to ' conserve those amino acids postulated to be important in the biologically active conformation. In addition to the cysteine residues, the amino acids at B6, B8, Bll, B23, B24, A2, A3, and A19 are invariant'in all species yet studied with only conservative substitutions (Glu → Asp) at B13 and (Phe → Tyr) at B25. In contrast, several insulins containing substitutions at positions B16, AS and A21, sites of importance in maintaining the crystal structure conformation, have been identified. Although the amino acid sequences of insulin are not generally useful as molecular markers for inferring phylogenetic relationships between species, the presence of common structural features in insulins from closely related species may permit a valid inference. For example, the presence of an N-terminal pentapeptide extension to the B-chains of insulins isolated from both holarctic and southern hemisphere lampreys supports the monophyletic status of the Petromyzontiformes.

Original languageEnglish
Pages (from-to)200-212
Number of pages13
JournalAmerican Zoologist
Issue number2
Publication statusPublished (in print/issue) - 2000


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