Pressure to conserve the primary structures of regulatory peptides during the evolution of vertebrates has been distinctly non-uniform. It is proposed that the major factor determining the extent to which the amino acid sequence of a peptide is conserved is the need to maintain high affinity binding to one or more specific receptors. In the case of peptides such as neuropeptide Y and somatostatin, that bind to multiple receptor subtypes via different signal epitopes, the complete primary structure has been strongly conserved throughout evolution. However, one or more duplications of the gene encoding such a peptide, for example to produce the peptide tyrosine-tyrosine (PYY) and pancreatic polypeptide (PPY) genes, result in a relaxation of conservative pressure on the copies. For peptides such as insulin, gastrin-releasing peptide and urotensin-II, selective pressure has acted primarily to conserve the receptor-binding domain and those residues in the peptide that maintain the domain in its correct conformation. Glucagon-like peptide-1 (GLP-1) is exceptional in that the GLP-1 receptor in the pancreata of tetrapods that is linked to the stimulation of insulin release exerts relatively strong conservative pressure on its ligand whereas the GLP-1 receptor in fish liver that is linked to glycogenolysis and gluconeogenesis does not. Evolutionary pressure to conserve sequence has been weakest in the case of peptides whose mechanism of action involves a non-specific interaction with the cell membrane rather than binding to a specific receptor. Examples include peptide families involved in host defense, such as the cationic, alpha-helical antimicrobial peptides synthesized in frog skin.
03 - 04 Dec 2001
Society for Endocrinology