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Three distinct epitopes on the extracellular face of the glucagon receptor determine specificity for the glucagon amino terminus

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Three distinct epitopes on the extracellular face of the glucagon receptor determine specificity for the glucagon amino terminus. / Runge, Steffen; Gram, Christian; Bräuner-Osborne, Hans; Madsen, Kjeld; Knudsen, Lotte B; Wulff, Birgitte S.

I: Journal of Biological Chemistry, Bind 278, Nr. 30, 25.07.2003, s. 28005-10.

Publikation: Bidrag til tidsskriftTidsskriftartikel

Harvard

Runge, S, Gram, C, Bräuner-Osborne, H, Madsen, K, Knudsen, LB & Wulff, BS 2003, 'Three distinct epitopes on the extracellular face of the glucagon receptor determine specificity for the glucagon amino terminus', Journal of Biological Chemistry, bind 278, nr. 30, s. 28005-10. https://doi.org/10.1074/jbc.M301085200

APA

Runge, S., Gram, C., Bräuner-Osborne, H., Madsen, K., Knudsen, L. B., & Wulff, B. S. (2003). Three distinct epitopes on the extracellular face of the glucagon receptor determine specificity for the glucagon amino terminus. Journal of Biological Chemistry, 278(30), 28005-10. https://doi.org/10.1074/jbc.M301085200

Vancouver

Runge S, Gram C, Bräuner-Osborne H, Madsen K, Knudsen LB, Wulff BS. Three distinct epitopes on the extracellular face of the glucagon receptor determine specificity for the glucagon amino terminus. Journal of Biological Chemistry. 2003 jul 25;278(30):28005-10. https://doi.org/10.1074/jbc.M301085200

Author

Runge, Steffen ; Gram, Christian ; Bräuner-Osborne, Hans ; Madsen, Kjeld ; Knudsen, Lotte B ; Wulff, Birgitte S. / Three distinct epitopes on the extracellular face of the glucagon receptor determine specificity for the glucagon amino terminus. I: Journal of Biological Chemistry. 2003 ; Bind 278, Nr. 30. s. 28005-10.

Bibtex

@article{e0ed259d45594ec194039a254106c46a,
title = "Three distinct epitopes on the extracellular face of the glucagon receptor determine specificity for the glucagon amino terminus",
abstract = "The glucagon and glucagon-like peptide-1 (GLP-1) receptors are homologous family B seven-transmembrane (7TM) G protein-coupled receptors, and they selectively recognize the homologous peptide hormones glucagon (29 amino acids) and GLP-1 (30-31 amino acids), respectively. The amino-terminal extracellular domain of the glucagon and GLP-1 receptors (140-150 amino acids) determines specificity for the carboxyl terminus of glucagon and GLP-1, respectively. In addition, the glucagon receptor core domain (7TM helices and connecting loops) strongly determines specificity for the glucagon amino terminus. Only 4 of 15 residues are divergent in the glucagon and GLP-1 amino termini; Ser2, Gln3, Tyr10, and Lys12 in glucagon and the corresponding Ala8, Glu9, Val16, and Ser18 in GLP-1. In this study, individual substitution of these four residues of glucagon with the corresponding residues of GLP-1 decreased the affinity and potency at the glucagon receptor relative to glucagon. Substitution of distinct segments of the glucagon receptor core domain with the corresponding segments of the GLP-1 receptor rescued the affinity and potency of specific glucagon analogs. Site-directed mutagenesis identified the Asp385 --> Glu glucagon receptor mutant that specifically rescued Ala2-glucagon. The results show that three distinct epitopes of the glucagon receptor core domain determine specificity for the N terminus of glucagon. We suggest a glucagon receptor binding model in which the extracellular ends of TM2 and TM7 are close to and determine specificity for Gln3 and Ser2 of glucagon, respectively. Furthermore, the second extracellular loop and/or proximal segments of TM4 and/or TM5 are close to and determine specificity for Lys12 of glucagon.",
keywords = "Amino Acid Sequence, Aspartic Acid, Cell Line, DNA, Complementary, Dose-Response Relationship, Drug, Epitopes, Genes, Reporter, Glucagon, Glutamic Acid, Humans, Inhibitory Concentration 50, Models, Biological, Molecular Sequence Data, Point Mutation, Protein Binding, Protein Structure, Tertiary, Receptors, Glucagon, Sequence Homology, Amino Acid",
author = "Steffen Runge and Christian Gram and Hans Br{\"a}uner-Osborne and Kjeld Madsen and Knudsen, {Lotte B} and Wulff, {Birgitte S}",
year = "2003",
month = "7",
day = "25",
doi = "10.1074/jbc.M301085200",
language = "English",
volume = "278",
pages = "28005--10",
journal = "Journal of Biological Chemistry",
issn = "0021-9258",
publisher = "American Society for Biochemistry and Molecular Biology, Inc.",
number = "30",

}

RIS

TY - JOUR

T1 - Three distinct epitopes on the extracellular face of the glucagon receptor determine specificity for the glucagon amino terminus

AU - Runge, Steffen

AU - Gram, Christian

AU - Bräuner-Osborne, Hans

AU - Madsen, Kjeld

AU - Knudsen, Lotte B

AU - Wulff, Birgitte S

PY - 2003/7/25

Y1 - 2003/7/25

N2 - The glucagon and glucagon-like peptide-1 (GLP-1) receptors are homologous family B seven-transmembrane (7TM) G protein-coupled receptors, and they selectively recognize the homologous peptide hormones glucagon (29 amino acids) and GLP-1 (30-31 amino acids), respectively. The amino-terminal extracellular domain of the glucagon and GLP-1 receptors (140-150 amino acids) determines specificity for the carboxyl terminus of glucagon and GLP-1, respectively. In addition, the glucagon receptor core domain (7TM helices and connecting loops) strongly determines specificity for the glucagon amino terminus. Only 4 of 15 residues are divergent in the glucagon and GLP-1 amino termini; Ser2, Gln3, Tyr10, and Lys12 in glucagon and the corresponding Ala8, Glu9, Val16, and Ser18 in GLP-1. In this study, individual substitution of these four residues of glucagon with the corresponding residues of GLP-1 decreased the affinity and potency at the glucagon receptor relative to glucagon. Substitution of distinct segments of the glucagon receptor core domain with the corresponding segments of the GLP-1 receptor rescued the affinity and potency of specific glucagon analogs. Site-directed mutagenesis identified the Asp385 --> Glu glucagon receptor mutant that specifically rescued Ala2-glucagon. The results show that three distinct epitopes of the glucagon receptor core domain determine specificity for the N terminus of glucagon. We suggest a glucagon receptor binding model in which the extracellular ends of TM2 and TM7 are close to and determine specificity for Gln3 and Ser2 of glucagon, respectively. Furthermore, the second extracellular loop and/or proximal segments of TM4 and/or TM5 are close to and determine specificity for Lys12 of glucagon.

AB - The glucagon and glucagon-like peptide-1 (GLP-1) receptors are homologous family B seven-transmembrane (7TM) G protein-coupled receptors, and they selectively recognize the homologous peptide hormones glucagon (29 amino acids) and GLP-1 (30-31 amino acids), respectively. The amino-terminal extracellular domain of the glucagon and GLP-1 receptors (140-150 amino acids) determines specificity for the carboxyl terminus of glucagon and GLP-1, respectively. In addition, the glucagon receptor core domain (7TM helices and connecting loops) strongly determines specificity for the glucagon amino terminus. Only 4 of 15 residues are divergent in the glucagon and GLP-1 amino termini; Ser2, Gln3, Tyr10, and Lys12 in glucagon and the corresponding Ala8, Glu9, Val16, and Ser18 in GLP-1. In this study, individual substitution of these four residues of glucagon with the corresponding residues of GLP-1 decreased the affinity and potency at the glucagon receptor relative to glucagon. Substitution of distinct segments of the glucagon receptor core domain with the corresponding segments of the GLP-1 receptor rescued the affinity and potency of specific glucagon analogs. Site-directed mutagenesis identified the Asp385 --> Glu glucagon receptor mutant that specifically rescued Ala2-glucagon. The results show that three distinct epitopes of the glucagon receptor core domain determine specificity for the N terminus of glucagon. We suggest a glucagon receptor binding model in which the extracellular ends of TM2 and TM7 are close to and determine specificity for Gln3 and Ser2 of glucagon, respectively. Furthermore, the second extracellular loop and/or proximal segments of TM4 and/or TM5 are close to and determine specificity for Lys12 of glucagon.

KW - Amino Acid Sequence

KW - Aspartic Acid

KW - Cell Line

KW - DNA, Complementary

KW - Dose-Response Relationship, Drug

KW - Epitopes

KW - Genes, Reporter

KW - Glucagon

KW - Glutamic Acid

KW - Humans

KW - Inhibitory Concentration 50

KW - Models, Biological

KW - Molecular Sequence Data

KW - Point Mutation

KW - Protein Binding

KW - Protein Structure, Tertiary

KW - Receptors, Glucagon

KW - Sequence Homology, Amino Acid

U2 - 10.1074/jbc.M301085200

DO - 10.1074/jbc.M301085200

M3 - Journal article

C2 - 12724331

VL - 278

SP - 28005

EP - 28010

JO - Journal of Biological Chemistry

JF - Journal of Biological Chemistry

SN - 0021-9258

IS - 30

ER -

ID: 45596711