Fig. 1: Overview of human secretin-like hormones.
a Mammalian genomes contain 6 genes that encode 10 secretin-like hormones. GLP-1 glucagon-like peptide 1, GLP-2 glucagon-like peptide 2, GIP gastric inhibitory polypeptide, ADCYAP adenylate cyclase activating peptide, PACAP pituitary adenylate cyclase activating protein, PRP PACAP-related peptide, PHI peptide histidine isoleucine, PHM: peptide histidine methionine, VIP vasoactive intestinal peptide, GNRH growth hormone releasing hormone, SCT secretin. Orthologues of the gene encoding exendins were found in various vertebrates, but not in mammals. b Primary sequences of the (human) secretin-like hormone polypeptides share high similarity despite their distinct physiological roles. (Glucagon-family hormone sequences of the different vertebrate species are compared in Supplementary Fig. 1) The evolutionarily conserved residues in the aggregation-prone regions (APR) of the investigated peptides are highlighted in yellow. Acidic residues (pKa < 5) are depicted in red. All peptide ligands adopt a partially disordered/nascent helix in the solution along the whole sequence (PDB entries are as follows GLP-1: 1D0R; GLP-2: 2L63; GIP: 2OBU; glucagon: 1GCN; exendin-4: 1JRJ; E19: 2MJ9; Tc5b: 1L2Y). c Superimposed ligand-receptor complexes reveal a common receptor-binding mechanism in the glucagon-like subfamily of the Class B1 GPCRs. The segment close to the C-terminal of the ligands recognizes the binding surface of the receptor’s extracellular domain, while the also highly homologous N-terminal segment of the already bounded ligand occupies the cavity formed by 7TM helices inducing conformational changes in the helices, which activate the receptor. d–h The highlighted ligand-APR sequences interact at identical positions with the extracellular domain of their respective receptor in the hormone ligand-receptor complexes. (PDBs: (d): GLP-1-GLP1R: 5VAI; (e): GLP-2-GLP2R: 7D68; (f): GIP-GIPR: 7DTY; (g): Glucagon-GCGR: 6LMK; (h): exendin-4-GLP1R: 7LLL). The conserved aromatic residues play a crucial role in partner recognition via aromatic interactions. The APR hexapeptide segments are also illustrated as schematic β-strands (without any terminal protection), and termed as APRGLP1, APRGLP2, APRGIP, APRgluc, APRex-4, and APRTc5b. Glucagon-like peptides (blue) carry negatively charged side chains at the first position of their APR segments, while exendin-4 sequence (green) has it in the middle of its APR. The synthetic exendin-like APR, LYIQWL, does not contain acidic side chains.
