title: Functional association of the N-terminal residues with the central region in glucagon-related peptides.
abstract: GLP-1 is an incretin peptide involved in the regulation of glucose metabolism and the glucose-dependent stimulation of insulin secretion. Ex-4 is a paralog of GLP-1 that has comparable GLP-1R potency but extended physiological action. GLP-1 and Ex-4 are helical peptides that share ∼50% sequence homology but differ at several residues, notably the second amino acid which controls susceptibility to DPP-IV cleavage. This single amino acid difference yields divergent receptor potency when studied in the context of the two hormone sequences. Ex-4 uniquely tolerates Gly2 through select amino acid differences in the middle region of the peptide that are absent in GLP-1. We report that substitution of Ex-4 amino acids Glu16, Leu21, and Glu24 to the GLP-1 sequence enabled Gly2 tolerance. The coordination of the N-terminus with these central residues shows an interaction of substantial importance not only to DPP-IV stability but also to receptor activation. Extension of this observation to glucagon-based co-agonist peptides showed different structural requirements for effective communication between the N-terminus and the mid-section of these peptides in achieving high potency agonism at the GLP-1 and GCGRs.
authors.affiliation: Department of Chemistry, Indiana University, Bloomington, IN 47405, USA.
authors.forename: James T
authors.initials: JT
authors.lastname: Patterson
authors.forename: Jonathan W
authors.initials: JW
authors.lastname: Day
authors.forename: Vasily M
authors.initials: VM
authors.lastname: Gelfanov
authors.forename: Richard D
authors.initials: RD
authors.lastname: DiMarchi
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D018819:Dipeptidyl Peptidase 4 / Q000378:metabolism; D000077270:Exenatide; D052216:Glucagon-Like Peptide 1 / Q000737:chemistry*; D004763:Glucagon-Like Peptides / Q000737:chemistry; D006801:Humans; D010455:Peptides / Q000737:chemistry*; D018027:Receptors, Glucagon / Q000737:chemistry; D017386:Sequence Homology, Amino Acid; D014688:Venoms / Q000737:chemistry*
chemical_list: D010455:Peptides; D018027:Receptors, Glucagon; D014688:Venoms; D004763:Glucagon-Like Peptides; D052216:Glucagon-Like Peptide 1; D000077270:Exenatide; D018819:Dipeptidyl Peptidase 4