title: A subdivided molecular architecture with separate features and stepwise emergence among proinsulin C-peptides.
abstract: The C-peptide of proinsulin exhibits multiple activities and several of the underlying molecular interactions are known. We recently showed that human C-peptide is sub-divided into a tripartite architecture and that the pattern, rather than the exact residue positions, is a characteristic feature. We have now analyzed 75 proinsulins, ranging from fish to human and find a limited co-evolution with insulin, but with many marked deviations. This suggests a complex relationship, in which not only insulin affects the evolution of C-peptide. A subdivided nature, however, is a characteristic feature among all C-peptides, with the N-terminal segment the one most conserved. This segment, ascribed chaperoning charge-interactions with insulin, suggests that the insulin interactions constitute a basic function, although largely shifting from Glu to Asp residues in C-peptides of lower life forms. A second conserved feature is a mid-segment with a high content of adjacent Pro and Gly residues, in mammalian C-peptides compatible with a turn structure, but with fewer and more distantly interspaced such residues in the non-mammalian forms, and even absent in several fish forms. However, this segment of coelacanth C-peptide possesses a unique Cys distribution, capable of forming a disulfide-stabilized turn. Finally, the C-terminal segment of mammalian C-peptides, ascribed a possible receptor-interacting function, is not really discernable in the sub-mammalian forms. Combined, these patterns suggest an evolutionary stepwise acquisition of the tripartite mammalian C-peptide molecule, with insulin-interaction being ancestral, various turn stabilizations apparently of intermediate emergence, and possible receptor-interaction the most recent addition.
authors.affiliation: Division of Physiological Chemistry I, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, S-171 77 Stockholm, Sweden.
authors.forename: Michael
authors.initials: M
authors.lastname: Landreh
authors.affiliation: Division of Physiological Chemistry I, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, S-171 77 Stockholm, Sweden; Science for Life Laboratory, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, S-171 77 Stockholm, Sweden.
authors.forename: Linus J
authors.initials: LJ
authors.lastname: Ostberg
authors.affiliation: Division of Physiological Chemistry I, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, S-171 77 Stockholm, Sweden. Electronic address: Hans.Jornvall@ki.se.
authors.forename: Hans
authors.initials: H
authors.lastname: Jörnvall
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D002096:C-Peptide / Q000737:chemistry*; D006801:Humans; D008969:Molecular Sequence Data; D011487:Protein Conformation; D017386:Sequence Homology, Amino Acid
chemical_list: D002096:C-Peptide
keywords: Bioactive peptides; Evolution; Molecular interactions; Protein folding