Tyr1 and Ile7 of glucose-dependent insulinotropic polypeptide (GIP) confer differential ligand selectivity toward GIP and glucagon-like peptide-1 receptors

Mi Jin Moon, Hee Young Kim, Sin Gon Kim, Juri Park, Dong Seop Choi, Jong-Ik Hwang, Jae Young Seong

Research output: Contribution to journalArticle

13 Citations (Scopus)

Abstract

Glucagon like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) are incretin hormones released in response to food intake and potentiate insulin secretion from pancreatic β cells through their distinct yet related G protein-coupled receptors, GLP1R and GIPR. While GLP-1 and GIP exhibit similarity in their N-terminal sequence and overall α-helical structure, GLP-1 does not bind to GIPR and vice versa. To determine which amino acid residues of these peptide ligands are responsible for specific interaction with their respective receptors, we generated mutant GIP in which several GLP-1-specific amino acid residues were substituted for the original amino acids. The potency of the mutant ligands was examined using HEK293 cells transfected with GLP1R or GIPR expression plasmids together with a cAMP-responsive element-driven luciferase (CRE-luc) reporter plasmid. A mutated GIP peptide in which Tyr1, Ile7, Asp15, and His18 were replaced by His, Thr, Glu, and Ala, respectively, was able to activate both GLP1R and GIPR with moderate potency. Replacing the original Tyr1 and/or Ile7 in the N-terminal moiety of this mutant peptide allowed full activation of GIPR but not of GLP1R. However, reintroducing Asp15 and/or His18 in the central α-helical region did not significantly alter the ligand potency. These results suggest that Tyr/His1 and Ile/Thr7 of GIP/GLP-1 peptides confer differential ligand selectivity toward GIPR and GLP1R.

Original languageEnglish
Pages (from-to)149-154
Number of pages6
JournalMolecules and Cells
Volume30
Issue number2
DOIs
Publication statusPublished - 2010 Aug 1

Fingerprint

Glucagon-Like Peptide 1
Ligands
Glucose
Peptides
Amino Acids
Plasmids
Gastric Inhibitory Polypeptide
Incretins
Peptide Hormones
HEK293 Cells
G-Protein-Coupled Receptors
Glucagon-Like Peptide-1 Receptor
Luciferases
Eating
Insulin

Keywords

  • GIP
  • GLP-1
  • GPCR
  • Insulin
  • Ligand selectivity
  • Pancreas

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

Cite this

Tyr1 and Ile7 of glucose-dependent insulinotropic polypeptide (GIP) confer differential ligand selectivity toward GIP and glucagon-like peptide-1 receptors. / Moon, Mi Jin; Kim, Hee Young; Kim, Sin Gon; Park, Juri; Choi, Dong Seop; Hwang, Jong-Ik; Seong, Jae Young.

In: Molecules and Cells, Vol. 30, No. 2, 01.08.2010, p. 149-154.

Research output: Contribution to journalArticle

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abstract = "Glucagon like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) are incretin hormones released in response to food intake and potentiate insulin secretion from pancreatic β cells through their distinct yet related G protein-coupled receptors, GLP1R and GIPR. While GLP-1 and GIP exhibit similarity in their N-terminal sequence and overall α-helical structure, GLP-1 does not bind to GIPR and vice versa. To determine which amino acid residues of these peptide ligands are responsible for specific interaction with their respective receptors, we generated mutant GIP in which several GLP-1-specific amino acid residues were substituted for the original amino acids. The potency of the mutant ligands was examined using HEK293 cells transfected with GLP1R or GIPR expression plasmids together with a cAMP-responsive element-driven luciferase (CRE-luc) reporter plasmid. A mutated GIP peptide in which Tyr1, Ile7, Asp15, and His18 were replaced by His, Thr, Glu, and Ala, respectively, was able to activate both GLP1R and GIPR with moderate potency. Replacing the original Tyr1 and/or Ile7 in the N-terminal moiety of this mutant peptide allowed full activation of GIPR but not of GLP1R. However, reintroducing Asp15 and/or His18 in the central α-helical region did not significantly alter the ligand potency. These results suggest that Tyr/His1 and Ile/Thr7 of GIP/GLP-1 peptides confer differential ligand selectivity toward GIPR and GLP1R.",
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