GLR_HUMAN
ID GLR_HUMAN Reviewed; 477 AA.
AC P47871; Q2M3M5;
DT 01-FEB-1996, integrated into UniProtKB/Swiss-Prot.
DT 01-FEB-1996, sequence version 1.
DT 03-AUG-2022, entry version 180.
DE RecName: Full=Glucagon receptor;
DE Short=GL-R;
DE Flags: Precursor;
GN Name=GCGR;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae;
OC Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA], FUNCTION, AND SUBCELLULAR LOCATION.
RC TISSUE=Liver;
RX PubMed=7507321; DOI=10.1006/bbrc.1994.1046;
RA Macneil D.J., Occi J.L., Hey P.J., Strader C.D., Graziano M.P.;
RT "Cloning and expression of a human glucagon receptor.";
RL Biochem. Biophys. Res. Commun. 198:328-334(1994).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA].
RX PubMed=8144028; DOI=10.1016/0378-1119(94)90545-2;
RA Lok S., Kuijper J.L., Jelinek L.J., Kramer J.M., Whitmore T.E.,
RA Sprecher C.A., Mathewes S., Grant F.J., Biggs S.H., Rosenberg G.B.;
RT "The human glucagon receptor encoding gene: structure, cDNA sequence and
RT chromosomal localization.";
RL Gene 140:203-209(1994).
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Liver;
RX PubMed=15489334; DOI=10.1101/gr.2596504;
RG The MGC Project Team;
RT "The status, quality, and expansion of the NIH full-length cDNA project:
RT the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [4]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 21-54.
RC TISSUE=Placenta;
RX PubMed=8020989; DOI=10.1006/geno.1994.1179;
RA Menzel S., Stoffel M., Espinosa R. III, Fernald A.A., Le Beau M.M.,
RA Bell G.I.;
RT "Localization of the glucagon receptor gene to human chromosome band
RT 17q25.";
RL Genomics 20:327-328(1994).
RN [5]
RP FUNCTION, SUBCELLULAR LOCATION, AND PHOSPHORYLATION.
RX PubMed=9287038; DOI=10.2337/diab.46.9.1400;
RA Buggy J.J., Heurich R.O., MacDougall M., Kelley K.A., Livingston J.N.,
RA Yoo-Warren H., Rossomando A.J.;
RT "Role of the glucagon receptor COOH-terminal domain in glucagon-mediated
RT signaling and receptor internalization.";
RL Diabetes 46:1400-1405(1997).
RN [6]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-456 AND SER-459, AND
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Liver;
RX PubMed=24275569; DOI=10.1016/j.jprot.2013.11.014;
RA Bian Y., Song C., Cheng K., Dong M., Wang F., Huang J., Sun D., Wang L.,
RA Ye M., Zou H.;
RT "An enzyme assisted RP-RPLC approach for in-depth analysis of human liver
RT phosphoproteome.";
RL J. Proteomics 96:253-262(2014).
RN [7]
RP X-RAY CRYSTALLOGRAPHY (1.2 ANGSTROMS) OF 412-420 IN COMPLEX WITH CLASS I
RP MHC.
RX PubMed=16221670; DOI=10.1074/jbc.m508528200;
RA Ruckert C., Fiorillo M.T., Loll B., Moretti R., Biesiadka J., Saenger W.,
RA Ziegler A., Sorrentino R., Uchanska-Ziegler B.;
RT "Conformational dimorphism of self-peptides and molecular mimicry in a
RT disease-associated HLA-B27 subtype.";
RL J. Biol. Chem. 281:2306-2316(2006).
RN [8]
RP X-RAY CRYSTALLOGRAPHY (2.64 ANGSTROMS) OF 28-123, FUNCTION, MUTAGENESIS OF
RP TYR-65 AND GLN-113, DISULFIDE BONDS, AND GLYCOSYLATION AT ASN-74 AND
RP ASN-78.
RX PubMed=22908259; DOI=10.1073/pnas.1206734109;
RA Koth C.M., Murray J.M., Mukund S., Madjidi A., Minn A., Clarke H.J.,
RA Wong T., Chiang V., Luis E., Estevez A., Rondon J., Zhang Y., Hotzel I.,
RA Allan B.B.;
RT "Molecular basis for negative regulation of the glucagon receptor.";
RL Proc. Natl. Acad. Sci. U.S.A. 109:14393-14398(2012).
RN [9]
RP X-RAY CRYSTALLOGRAPHY (3.3 ANGSTROMS) OF 123-432, FUNCTION, SUBCELLULAR
RP LOCATION, DISULFIDE BONDS, MEMBRANE TOPOLOGY, MUTAGENESIS OF TRP-36;
RP ASP-63; ALA-135; TYR-145; TYR-149; LEU-198; ARG-201; TYR-202; ASP-208;
RP TRP-215; GLN-232; TYR-233; LYS-286; GLU-290; CYS-294; TRP-295; TRP-304;
RP LEU-382 AND LEU-386, AND CHARACTERIZATION OF VARIANT MVAH SER-86.
RX PubMed=23863937; DOI=10.1038/nature12393;
RA Siu F.Y., He M., de Graaf C., Han G.W., Yang D., Zhang Z., Zhou C., Xu Q.,
RA Wacker D., Joseph J.S., Liu W., Lau J., Cherezov V., Katritch V.,
RA Wang M.W., Stevens R.C.;
RT "Structure of the human glucagon class B G-protein-coupled receptor.";
RL Nature 499:444-449(2013).
RN [10] {ECO:0007744|PDB:5EE7}
RP X-RAY CRYSTALLOGRAPHY (2.50 ANGSTROMS) OF 136-254; 256-256 AND 259-417 IN
RP COMPLEX WITH SYNTHETIC ANTAGONIST, FUNCTION, SUBCELLULAR LOCATION, AND
RP DISULFIDE BONDS.
RX PubMed=27111510; DOI=10.1038/nature17414;
RA Jazayeri A., Dore A.S., Lamb D., Krishnamurthy H., Southall S.M.,
RA Baig A.H., Bortolato A., Koglin M., Robertson N.J., Errey J.C.,
RA Andrews S.P., Teobald I., Brown A.J., Cooke R.M., Weir M., Marshall F.H.;
RT "Extra-helical binding site of a glucagon receptor antagonist.";
RL Nature 533:274-277(2016).
RN [11]
RP X-RAY CRYSTALLOGRAPHY (3.0 ANGSTROMS) OF 27-432 IN COMPLEX WITH THE
RP SYNTHETIC ANTAGONIST NNC0640, FUNCTION, SUBCELLULAR LOCATION, TOPOLOGY,
RP GLYCOSYLATION AT ASN-46; ASN-59; ASN-74 AND ASN-78, MUTAGENESIS OF GLN-113;
RP VAL-130; ASP-209; LEU-210; SER-350 AND THR-353, AND DISULFIDE BONDS.
RX PubMed=28514451; DOI=10.1038/nature22363;
RA Zhang H., Qiao A., Yang D., Yang L., Dai A., de Graaf C., Reedtz-Runge S.,
RA Dharmarajan V., Zhang H., Han G.W., Grant T.D., Sierra R.G., Weierstall U.,
RA Nelson G., Liu W., Wu Y., Ma L., Cai X., Lin G., Wu X., Geng Z., Dong Y.,
RA Song G., Griffin P.R., Lau J., Cherezov V., Yang H., Hanson M.A.,
RA Stevens R.C., Zhao Q., Jiang H., Wang M.W., Wu B.;
RT "Structure of the full-length glucagon class B G-protein-coupled
RT receptor.";
RL Nature 546:259-264(2017).
RN [12]
RP VARIANT SER-40.
RX PubMed=7589886; DOI=10.1007/bf00400589;
RA Fujisawa T., Ikegami H., Yamato E., Takekawa K., Nakagawa Y., Hamada Y.,
RA Ueda H., Fukuda M., Ogihara T.;
RT "A mutation in the glucagon receptor gene (Gly40Ser): heterogeneity in the
RT association with diabetes mellitus.";
RL Diabetologia 38:983-985(1995).
RN [13]
RP VARIANT MVAH SER-86, INVOLVEMENT IN MVAH, FUNCTION, SUBCELLULAR LOCATION,
RP AND CHARACTERIZATION OF VARIANT MVAH SER-86.
RX PubMed=19657311; DOI=10.1097/mpa.0b013e3181b2bb03;
RA Zhou C., Dhall D., Nissen N.N., Chen C.R., Yu R.;
RT "Homozygous P86S mutation of the human glucagon receptor is associated with
RT hyperglucagonemia, alpha cell hyperplasia, and islet cell tumor.";
RL Pancreas 38:941-946(2009).
RN [14]
RP VARIANTS MVAH HIS-225 AND MET-368, AND INVOLVEMENT IN MVAH.
RX PubMed=25695890; DOI=10.1210/jc.2014-4405;
RA Sipos B., Sperveslage J., Anlauf M., Hoffmeister M., Henopp T., Buch S.,
RA Hampe J., Weber A., Hammel P., Couvelard A., Hoebling W., Lieb W.,
RA Boehm B.O., Kloeppel G.;
RT "Glucagon cell hyperplasia and neoplasia with and without glucagon receptor
RT mutations.";
RL J. Clin. Endocrinol. Metab. 100:E783-E788(2015).
RN [15]
RP VARIANT MVAH ASN-63.
RX PubMed=30032256; DOI=10.1210/jc.2018-01074;
RA Gild M.L., Tsang V., Samra J., Clifton-Bligh R.J., Tacon L., Gill A.J.;
RT "Hypercalcemia in glucagon cell hyperplasia and neoplasia (Mahvash
RT syndrome): a new association.";
RL J. Clin. Endocrinol. Metab. 103:3119-3123(2018).
RN [16]
RP VARIANT MVAH PHE-320 DEL, CHARACTERIZATION OF VARIANT MVAH PHE-320 DEL,
RP FUNCTION, AND SUBCELLULAR LOCATION.
RX PubMed=30294546; DOI=10.1016/j.ymgmr.2018.09.006;
RA Li H., Zhao L., Singh R., Ham J.N., Fadoju D.O., Bean L.J.H., Zhang Y.,
RA Xu Y., Xu H.E., Gambello M.J.;
RT "The first pediatric case of glucagon receptor defect due to biallelic
RT mutations in GCGR is identified by newborn screening of elevated
RT arginine.";
RL Mol. Genet. Metab. Rep. 17:46-52(2018).
RN [17]
RP CHARACTERIZATION OF VARIANTS MVAH HIS-225 AND MET-368, VARIANTS SER-40;
RP MET-76; GLN-336; HIS-414; ARG-416; GLN-428; LEU-438; HIS-458; VAL-461 AND
RP LEU-476, CHARACTERIZATION OF VARIANTS SER-40; MET-76; GLN-336; HIS-414;
RP ARG-416; GLN-428; LEU-438; HIS-458; VAL-461 AND LEU-476, FUNCTION, AND
RP SUBCELLULAR LOCATION.
RX PubMed=32677665; DOI=10.1042/bcj20200235;
RA Lin G., Liu Q., Dai A., Cai X., Zhou Q., Wang X., Chen Y., Ye C., Li J.,
RA Yang D., Wang M.W.;
RT "Characterization of a naturally occurring mutation V368M in the human
RT glucagon receptor and its association with metabolic disorders.";
RL Biochem. J. 477:2581-2594(2020).
CC -!- FUNCTION: G-protein coupled receptor for glucagon that plays a central
CC role in the regulation of blood glucose levels and glucose homeostasis.
CC Regulates the rate of hepatic glucose production by promoting glycogen
CC hydrolysis and gluconeogenesis. Plays an important role in mediating
CC the responses to fasting. Ligand binding causes a conformation change
CC that triggers signaling via guanine nucleotide-binding proteins (G
CC proteins) and modulates the activity of down-stream effectors, such as
CC adenylate cyclase. Promotes activation of adenylate cyclase. Besides,
CC plays a role in signaling via a phosphatidylinositol-calcium second
CC messenger system. {ECO:0000269|PubMed:19657311,
CC ECO:0000269|PubMed:22908259, ECO:0000269|PubMed:23863937,
CC ECO:0000269|PubMed:27111510, ECO:0000269|PubMed:28514451,
CC ECO:0000269|PubMed:30294546, ECO:0000269|PubMed:32677665,
CC ECO:0000269|PubMed:7507321, ECO:0000269|PubMed:9287038}.
CC -!- SUBCELLULAR LOCATION: Cell membrane {ECO:0000269|PubMed:19657311,
CC ECO:0000269|PubMed:23863937, ECO:0000269|PubMed:27111510,
CC ECO:0000269|PubMed:28514451, ECO:0000269|PubMed:30294546,
CC ECO:0000269|PubMed:32677665, ECO:0000269|PubMed:7507321,
CC ECO:0000269|PubMed:9287038}; Multi-pass membrane protein
CC {ECO:0000269|PubMed:19657311, ECO:0000269|PubMed:23863937,
CC ECO:0000269|PubMed:27111510, ECO:0000269|PubMed:28514451,
CC ECO:0000269|PubMed:7507321, ECO:0000269|PubMed:9287038}. Note=Is
CC rapidly internalized after ligand-binding.
CC {ECO:0000269|PubMed:9287038}.
CC -!- PTM: Ligand-binding promotes phosphorylation of serine residues in the
CC C-terminal cytoplasmic domain. Phosphorylation is important for
CC receptor endocytosis after ligand-binding.
CC {ECO:0000269|PubMed:9287038}.
CC -!- DISEASE: Mahvash disease (MVAH) [MIM:619290]: An autosomal recessive
CC disorder characterized by alpha-cell hyperplasia of the pancreas,
CC hyperglucagonemia without glucagonoma syndrome, aminoacidemia, and
CC occasional hypoglycemia. The disease may lead to glucagonomas and/or
CC primitive neuroectodermal tumors. {ECO:0000269|PubMed:19657311,
CC ECO:0000269|PubMed:23863937, ECO:0000269|PubMed:25695890,
CC ECO:0000269|PubMed:30032256, ECO:0000269|PubMed:30294546,
CC ECO:0000269|PubMed:32677665}. Note=The disease is caused by variants
CC affecting the gene represented in this entry.
CC -!- SIMILARITY: Belongs to the G-protein coupled receptor 2 family.
CC {ECO:0000305}.
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DR EMBL; U03469; AAC52063.1; -; mRNA.
DR EMBL; L20316; AAA53628.1; -; mRNA.
DR EMBL; BC104854; AAI04855.1; -; mRNA.
DR EMBL; BC112041; AAI12042.1; -; mRNA.
DR EMBL; L24751; AAA35897.1; -; Genomic_DNA.
DR CCDS; CCDS54177.1; -.
DR PIR; JC2041; JC2041.
DR RefSeq; NP_000151.1; NM_000160.4.
DR RefSeq; XP_006722340.1; XM_006722277.1.
DR PDB; 2A83; X-ray; 1.40 A; C=412-420.
DR PDB; 3CZF; X-ray; 1.20 A; C=412-420.
DR PDB; 4ERS; X-ray; 2.64 A; A=28-123.
DR PDB; 4L6R; X-ray; 3.30 A; A=123-432.
DR PDB; 4LF3; X-ray; 2.74 A; C/F=29-123.
DR PDB; 5EE7; X-ray; 2.50 A; A=136-254, A=259-417.
DR PDB; 5XEZ; X-ray; 3.00 A; A/B=27-432.
DR PDB; 6LMK; EM; 3.70 A; R=27-432.
DR PDB; 6LML; EM; 3.90 A; R=27-432.
DR PDB; 6WHC; EM; 3.40 A; R=1-477.
DR PDB; 6WPW; EM; 3.10 A; R=27-477.
DR PDB; 7V35; EM; 3.40 A; R=27-432.
DR PDBsum; 2A83; -.
DR PDBsum; 3CZF; -.
DR PDBsum; 4ERS; -.
DR PDBsum; 4L6R; -.
DR PDBsum; 4LF3; -.
DR PDBsum; 5EE7; -.
DR PDBsum; 5XEZ; -.
DR PDBsum; 6LMK; -.
DR PDBsum; 6LML; -.
DR PDBsum; 6WHC; -.
DR PDBsum; 6WPW; -.
DR PDBsum; 7V35; -.
DR AlphaFoldDB; P47871; -.
DR SMR; P47871; -.
DR BioGRID; 108912; 152.
DR IntAct; P47871; 4.
DR STRING; 9606.ENSP00000383558; -.
DR BindingDB; P47871; -.
DR ChEMBL; CHEMBL1985; -.
DR DrugBank; DB15226; Dasiglucagon.
DR DrugBank; DB00040; Glucagon.
DR DrugCentral; P47871; -.
DR GuidetoPHARMACOLOGY; 251; -.
DR TCDB; 9.A.14.4.13; the g-protein-coupled receptor (gpcr) family.
DR GlyGen; P47871; 4 sites.
DR iPTMnet; P47871; -.
DR PhosphoSitePlus; P47871; -.
DR BioMuta; GCGR; -.
DR DMDM; 1346144; -.
DR MassIVE; P47871; -.
DR PaxDb; P47871; -.
DR PeptideAtlas; P47871; -.
DR PRIDE; P47871; -.
DR ABCD; P47871; 107 sequenced antibodies.
DR Antibodypedia; 4808; 443 antibodies from 36 providers.
DR DNASU; 2642; -.
DR Ensembl; ENST00000400723.8; ENSP00000383558.3; ENSG00000215644.10.
DR Ensembl; ENST00000671794.1; ENSP00000500297.1; ENSG00000288269.1.
DR GeneID; 2642; -.
DR KEGG; hsa:2642; -.
DR MANE-Select; ENST00000400723.8; ENSP00000383558.3; NM_000160.5; NP_000151.1.
DR UCSC; uc010wuw.2; human.
DR CTD; 2642; -.
DR DisGeNET; 2642; -.
DR GeneCards; GCGR; -.
DR HGNC; HGNC:4192; GCGR.
DR HPA; ENSG00000215644; Tissue enriched (liver).
DR MalaCards; GCGR; -.
DR MIM; 138033; gene.
DR MIM; 619290; phenotype.
DR neXtProt; NX_P47871; -.
DR OpenTargets; ENSG00000215644; -.
DR Orphanet; 438274; GCGR-related hyperglucagonemia.
DR PharmGKB; PA28607; -.
DR VEuPathDB; HostDB:ENSG00000215644; -.
DR eggNOG; KOG4564; Eukaryota.
DR GeneTree; ENSGT00940000157969; -.
DR HOGENOM; CLU_002753_4_0_1; -.
DR InParanoid; P47871; -.
DR OMA; ARQMHYA; -.
DR OrthoDB; 651627at2759; -.
DR PhylomeDB; P47871; -.
DR TreeFam; TF315710; -.
DR PathwayCommons; P47871; -.
DR SignaLink; P47871; -.
DR SIGNOR; P47871; -.
DR BioGRID-ORCS; 2642; 14 hits in 1078 CRISPR screens.
DR EvolutionaryTrace; P47871; -.
DR GeneWiki; Glucagon_receptor; -.
DR GenomeRNAi; 2642; -.
DR Pharos; P47871; Tclin.
DR PRO; PR:P47871; -.
DR Proteomes; UP000005640; Chromosome 17.
DR RNAct; P47871; protein.
DR Bgee; ENSG00000215644; Expressed in right lobe of liver and 72 other tissues.
DR ExpressionAtlas; P47871; baseline and differential.
DR Genevisible; P47871; HS.
DR GO; GO:0005768; C:endosome; IEA:Ensembl.
DR GO; GO:0016021; C:integral component of membrane; TAS:ProtInc.
DR GO; GO:0005887; C:integral component of plasma membrane; IDA:UniProtKB.
DR GO; GO:0005886; C:plasma membrane; IBA:GO_Central.
DR GO; GO:0008528; F:G protein-coupled peptide receptor activity; IBA:GO_Central.
DR GO; GO:0004967; F:glucagon receptor activity; IDA:UniProtKB.
DR GO; GO:0017046; F:peptide hormone binding; IBA:GO_Central.
DR GO; GO:0007189; P:adenylate cyclase-activating G protein-coupled receptor signaling pathway; IDA:UniProtKB.
DR GO; GO:0007188; P:adenylate cyclase-modulating G protein-coupled receptor signaling pathway; IMP:UniProtKB.
DR GO; GO:0007166; P:cell surface receptor signaling pathway; IEA:InterPro.
DR GO; GO:0071377; P:cellular response to glucagon stimulus; IDA:UniProtKB.
DR GO; GO:0009267; P:cellular response to starvation; ISS:ARUK-UCL.
DR GO; GO:0006887; P:exocytosis; IEA:Ensembl.
DR GO; GO:0006091; P:generation of precursor metabolites and energy; TAS:ProtInc.
DR GO; GO:0042593; P:glucose homeostasis; ISS:UniProtKB.
DR GO; GO:0009755; P:hormone-mediated signaling pathway; IEA:Ensembl.
DR GO; GO:0010628; P:positive regulation of gene expression; ISS:ARUK-UCL.
DR GO; GO:0008217; P:regulation of blood pressure; TAS:ProtInc.
DR GO; GO:0070873; P:regulation of glycogen metabolic process; ISS:UniProtKB.
DR GO; GO:0007584; P:response to nutrient; TAS:ProtInc.
DR GO; GO:0042594; P:response to starvation; ISS:UniProtKB.
DR Gene3D; 4.10.1240.10; -; 1.
DR InterPro; IPR017981; GPCR_2-like.
DR InterPro; IPR036445; GPCR_2_extracell_dom_sf.
DR InterPro; IPR001879; GPCR_2_extracellular_dom.
DR InterPro; IPR003290; GPCR_2_GLP1/glucagon_rcpt.
DR InterPro; IPR003291; GPCR_2_glucagon_rcpt.
DR InterPro; IPR000832; GPCR_2_secretin-like.
DR InterPro; IPR017983; GPCR_2_secretin-like_CS.
DR Pfam; PF00002; 7tm_2; 1.
DR Pfam; PF02793; HRM; 1.
DR PRINTS; PR01353; GLUCAGNFAMLY.
DR PRINTS; PR01354; GLUCAGONR.
DR PRINTS; PR00249; GPCRSECRETIN.
DR SMART; SM00008; HormR; 1.
DR SUPFAM; SSF111418; SSF111418; 1.
DR PROSITE; PS00649; G_PROTEIN_RECEP_F2_1; 1.
DR PROSITE; PS00650; G_PROTEIN_RECEP_F2_2; 1.
DR PROSITE; PS50227; G_PROTEIN_RECEP_F2_3; 1.
DR PROSITE; PS50261; G_PROTEIN_RECEP_F2_4; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Cell membrane; Diabetes mellitus; Disease variant;
KW Disulfide bond; G-protein coupled receptor; Glycoprotein; Membrane;
KW Phosphoprotein; Receptor; Reference proteome; Signal; Transducer;
KW Transmembrane; Transmembrane helix.
FT SIGNAL 1..25
FT /evidence="ECO:0000255"
FT CHAIN 26..477
FT /note="Glucagon receptor"
FT /id="PRO_0000012832"
FT TOPO_DOM 26..136
FT /note="Extracellular"
FT /evidence="ECO:0000269|PubMed:23863937,
FT ECO:0000269|PubMed:27111510, ECO:0000269|PubMed:28514451"
FT TRANSMEM 137..161
FT /note="Helical; Name=1"
FT /evidence="ECO:0000269|PubMed:23863937,
FT ECO:0000269|PubMed:27111510, ECO:0000269|PubMed:28514451"
FT TOPO_DOM 162..173
FT /note="Cytoplasmic"
FT /evidence="ECO:0000269|PubMed:23863937,
FT ECO:0000269|PubMed:27111510, ECO:0000269|PubMed:28514451"
FT TRANSMEM 174..198
FT /note="Helical; Name=2"
FT /evidence="ECO:0000269|PubMed:23863937,
FT ECO:0000269|PubMed:27111510, ECO:0000269|PubMed:28514451"
FT TOPO_DOM 199..225
FT /note="Extracellular"
FT /evidence="ECO:0000269|PubMed:23863937,
FT ECO:0000269|PubMed:27111510, ECO:0000269|PubMed:28514451"
FT TRANSMEM 226..249
FT /note="Helical; Name=3"
FT /evidence="ECO:0000269|PubMed:23863937,
FT ECO:0000269|PubMed:27111510, ECO:0000269|PubMed:28514451"
FT TOPO_DOM 250..263
FT /note="Cytoplasmic"
FT /evidence="ECO:0000269|PubMed:23863937,
FT ECO:0000269|PubMed:27111510, ECO:0000269|PubMed:28514451"
FT TRANSMEM 264..285
FT /note="Helical; Name=4"
FT /evidence="ECO:0000269|PubMed:23863937,
FT ECO:0000269|PubMed:27111510, ECO:0000269|PubMed:28514451"
FT TOPO_DOM 286..303
FT /note="Extracellular"
FT /evidence="ECO:0000269|PubMed:23863937,
FT ECO:0000269|PubMed:27111510, ECO:0000269|PubMed:28514451"
FT TRANSMEM 304..326
FT /note="Helical; Name=5"
FT /evidence="ECO:0000269|PubMed:23863937,
FT ECO:0000269|PubMed:27111510, ECO:0000269|PubMed:28514451"
FT TOPO_DOM 327..350
FT /note="Cytoplasmic"
FT /evidence="ECO:0000269|PubMed:23863937,
FT ECO:0000269|PubMed:27111510, ECO:0000269|PubMed:28514451"
FT TRANSMEM 351..369
FT /note="Helical; Name=6"
FT /evidence="ECO:0000269|PubMed:23863937,
FT ECO:0000269|PubMed:27111510, ECO:0000269|PubMed:28514451"
FT TOPO_DOM 370..381
FT /note="Extracellular"
FT /evidence="ECO:0000269|PubMed:23863937,
FT ECO:0000269|PubMed:27111510, ECO:0000269|PubMed:28514451"
FT TRANSMEM 382..402
FT /note="Helical; Name=7"
FT /evidence="ECO:0000269|PubMed:23863937,
FT ECO:0000269|PubMed:27111510, ECO:0000269|PubMed:28514451"
FT TOPO_DOM 403..477
FT /note="Cytoplasmic"
FT /evidence="ECO:0000269|PubMed:23863937,
FT ECO:0000269|PubMed:27111510, ECO:0000269|PubMed:28514451"
FT REGION 350..353
FT /note="Important for allosteric inhibitor binding"
FT /evidence="ECO:0000269|PubMed:27111510,
FT ECO:0000269|PubMed:28514451"
FT REGION 431..477
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT MOD_RES 456
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:24275569"
FT MOD_RES 459
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:24275569"
FT CARBOHYD 46
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000269|PubMed:28514451"
FT CARBOHYD 59
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000269|PubMed:28514451"
FT CARBOHYD 74
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000269|PubMed:22908259,
FT ECO:0000269|PubMed:28514451, ECO:0007744|PDB:4ERS"
FT CARBOHYD 78
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000269|PubMed:22908259,
FT ECO:0000269|PubMed:28514451, ECO:0007744|PDB:4ERS"
FT DISULFID 43..67
FT /evidence="ECO:0000269|PubMed:22908259,
FT ECO:0000269|PubMed:28514451, ECO:0007744|PDB:4ERS,
FT ECO:0007744|PDB:4LF3"
FT DISULFID 58..100
FT /evidence="ECO:0000269|PubMed:22908259,
FT ECO:0000269|PubMed:28514451, ECO:0007744|PDB:4ERS,
FT ECO:0007744|PDB:4LF3"
FT DISULFID 81..121
FT /evidence="ECO:0000269|PubMed:22908259,
FT ECO:0000269|PubMed:28514451, ECO:0007744|PDB:4ERS,
FT ECO:0007744|PDB:4LF3"
FT DISULFID 224..294
FT /evidence="ECO:0000269|PubMed:23863937,
FT ECO:0000269|PubMed:27111510, ECO:0000269|PubMed:28514451,
FT ECO:0007744|PDB:4L6R, ECO:0007744|PDB:5EE7"
FT VARIANT 40
FT /note="G -> S (no effect on glucagon-elicited cAMP
FT production; dbSNP:rs1801483)"
FT /evidence="ECO:0000269|PubMed:32677665,
FT ECO:0000269|PubMed:7589886"
FT /id="VAR_003581"
FT VARIANT 63
FT /note="D -> N (in MVAH)"
FT /evidence="ECO:0000269|PubMed:30032256"
FT /id="VAR_085613"
FT VARIANT 76
FT /note="T -> M (no effect on glucagon-elicited cAMP
FT production)"
FT /evidence="ECO:0000269|PubMed:32677665"
FT /id="VAR_085614"
FT VARIANT 86
FT /note="P -> S (in MVAH; abolishes glucagon binding)"
FT /evidence="ECO:0000269|PubMed:19657311,
FT ECO:0000269|PubMed:23863937"
FT /id="VAR_069815"
FT VARIANT 114
FT /note="P -> A (in dbSNP:rs5385)"
FT /id="VAR_014837"
FT VARIANT 225
FT /note="R -> H (in MVAH; when associated in cis with M-368;
FT decreased glucagon binding and decreased glucagon-elicited
FT cAMP production; decreased localization to the cell
FT membrane)"
FT /evidence="ECO:0000269|PubMed:25695890,
FT ECO:0000269|PubMed:32677665"
FT /id="VAR_085615"
FT VARIANT 303
FT /note="F -> C (in dbSNP:rs5387)"
FT /id="VAR_033966"
FT VARIANT 320
FT /note="Missing (in MVAH; loss of glucagon-elicited cAMP
FT production; no effect on localization to the cell
FT membrane)"
FT /evidence="ECO:0000269|PubMed:30294546"
FT /id="VAR_085616"
FT VARIANT 336
FT /note="R -> Q (no effect on glucagon-elicited cAMP
FT production)"
FT /evidence="ECO:0000269|PubMed:32677665"
FT /id="VAR_085617"
FT VARIANT 368
FT /note="V -> M (in MVAH; when associated in cis with H-225;
FT decreased glucagon binding and decreased glucagon-elicited
FT cAMP production; no effect on localization to the cell
FT membrane)"
FT /evidence="ECO:0000269|PubMed:25695890,
FT ECO:0000269|PubMed:32677665"
FT /id="VAR_085618"
FT VARIANT 414
FT /note="R -> H (no effect on glucagon-elicited cAMP
FT production)"
FT /evidence="ECO:0000269|PubMed:32677665"
FT /id="VAR_085619"
FT VARIANT 416
FT /note="H -> R (no effect on glucagon-elicited cAMP
FT production)"
FT /evidence="ECO:0000269|PubMed:32677665"
FT /id="VAR_085620"
FT VARIANT 428
FT /note="R -> Q (no effect on glucagon-elicited cAMP
FT production)"
FT /evidence="ECO:0000269|PubMed:32677665"
FT /id="VAR_085621"
FT VARIANT 438
FT /note="S -> L (no effect on glucagon-elicited cAMP
FT production)"
FT /evidence="ECO:0000269|PubMed:32677665"
FT /id="VAR_085622"
FT VARIANT 458
FT /note="D -> H (no effect on glucagon-elicited cAMP
FT production)"
FT /evidence="ECO:0000269|PubMed:32677665"
FT /id="VAR_085623"
FT VARIANT 461
FT /note="A -> V (no effect on glucagon-elicited cAMP
FT production)"
FT /evidence="ECO:0000269|PubMed:32677665"
FT /id="VAR_085624"
FT VARIANT 476
FT /note="P -> L (no effect on glucagon-elicited cAMP
FT production)"
FT /evidence="ECO:0000269|PubMed:32677665"
FT /id="VAR_085625"
FT MUTAGEN 36
FT /note="W->A: Abolishes glucagon binding."
FT /evidence="ECO:0000269|PubMed:23863937"
FT MUTAGEN 63
FT /note="D->A: Abolishes glucagon binding."
FT /evidence="ECO:0000269|PubMed:23863937"
FT MUTAGEN 65
FT /note="Y->A: Strongly reduced affinity for glucagon.
FT Increased constitutive signaling via G-proteins."
FT /evidence="ECO:0000269|PubMed:22908259"
FT MUTAGEN 113
FT /note="Q->A,N: No effect on affinity for glucagon."
FT /evidence="ECO:0000269|PubMed:22908259"
FT MUTAGEN 113
FT /note="Q->C: Causes the formation of an artifactual
FT disulfide bond that abolishes glucagon binding; when
FT associated with C-209."
FT /evidence="ECO:0000269|PubMed:28514451"
FT MUTAGEN 113
FT /note="Q->E: Strongly reduced affinity for glucagon."
FT /evidence="ECO:0000269|PubMed:22908259"
FT MUTAGEN 130
FT /note="V->C: Causes the formation of an artifactual
FT disulfide bond that interferes with glucagon binding; when
FT associated with C-210."
FT /evidence="ECO:0000269|PubMed:28514451"
FT MUTAGEN 135
FT /note="A->P: Abolishes glucagon binding."
FT /evidence="ECO:0000269|PubMed:23863937"
FT MUTAGEN 145
FT /note="Y->A: Abolishes glucagon binding."
FT /evidence="ECO:0000269|PubMed:23863937"
FT MUTAGEN 149
FT /note="Y->A: Abolishes expression at cell surface and
FT glucagon binding."
FT /evidence="ECO:0000269|PubMed:23863937"
FT MUTAGEN 198
FT /note="L->A: Abolishes glucagon binding."
FT /evidence="ECO:0000269|PubMed:23863937"
FT MUTAGEN 201
FT /note="R->D: Abolishes glucagon binding."
FT /evidence="ECO:0000269|PubMed:23863937"
FT MUTAGEN 202
FT /note="Y->A: Abolishes glucagon binding."
FT /evidence="ECO:0000269|PubMed:23863937"
FT MUTAGEN 208
FT /note="D->Q: Abolishes glucagon binding."
FT /evidence="ECO:0000269|PubMed:23863937"
FT MUTAGEN 209
FT /note="D->C: Causes the formation of an artifactual
FT disulfide bond that abolishes glucagon binding; when
FT associated with C-113."
FT /evidence="ECO:0000269|PubMed:28514451"
FT MUTAGEN 210
FT /note="L->C: Causes the formation of an artifactual
FT disulfide bond that interferes with glucagon binding; when
FT associated with C-130."
FT /evidence="ECO:0000269|PubMed:28514451"
FT MUTAGEN 215
FT /note="W->L: Abolishes glucagon binding."
FT /evidence="ECO:0000269|PubMed:23863937"
FT MUTAGEN 232
FT /note="Q->L: Abolishes expression at cell surface and
FT glucagon binding."
FT /evidence="ECO:0000269|PubMed:23863937"
FT MUTAGEN 233
FT /note="Y->A: Abolishes glucagon binding. Strongly reduces
FT expression at the cell surface."
FT /evidence="ECO:0000269|PubMed:23863937"
FT MUTAGEN 286
FT /note="K->L: Abolishes glucagon binding."
FT /evidence="ECO:0000269|PubMed:23863937"
FT MUTAGEN 290
FT /note="E->A: Abolishes glucagon binding."
FT /evidence="ECO:0000269|PubMed:23863937"
FT MUTAGEN 294
FT /note="C->A,S: Abolishes glucagon binding."
FT /evidence="ECO:0000269|PubMed:23863937"
FT MUTAGEN 295
FT /note="W->A,H: Abolishes glucagon binding."
FT /evidence="ECO:0000269|PubMed:23863937"
FT MUTAGEN 304
FT /note="W->Q: Abolishes glucagon binding."
FT /evidence="ECO:0000269|PubMed:23863937"
FT MUTAGEN 350
FT /note="S->A: Strongly decreases affinity for synthetic
FT antagonist."
FT /evidence="ECO:0000269|PubMed:28514451"
FT MUTAGEN 353
FT /note="T->A: Loss of synthetic antagonist binding."
FT /evidence="ECO:0000269|PubMed:28514451"
FT MUTAGEN 382
FT /note="L->A: Abolishes glucagon binding."
FT /evidence="ECO:0000269|PubMed:23863937"
FT MUTAGEN 386
FT /note="L->F: Abolishes glucagon binding."
FT /evidence="ECO:0000269|PubMed:23863937"
FT HELIX 31..49
FT /evidence="ECO:0007829|PDB:4ERS"
FT STRAND 54..58
FT /evidence="ECO:0007829|PDB:4ERS"
FT STRAND 64..68
FT /evidence="ECO:0007829|PDB:4LF3"
FT STRAND 75..80
FT /evidence="ECO:0007829|PDB:4ERS"
FT TURN 86..90
FT /evidence="ECO:0007829|PDB:4ERS"
FT STRAND 95..100
FT /evidence="ECO:0007829|PDB:4ERS"
FT STRAND 104..106
FT /evidence="ECO:0007829|PDB:4LF3"
FT STRAND 109..111
FT /evidence="ECO:0007829|PDB:6WPW"
FT HELIX 119..121
FT /evidence="ECO:0007829|PDB:4ERS"
FT STRAND 127..130
FT /evidence="ECO:0007829|PDB:5XEZ"
FT TURN 131..133
FT /evidence="ECO:0007829|PDB:6WHC"
FT HELIX 139..165
FT /evidence="ECO:0007829|PDB:5EE7"
FT HELIX 167..169
FT /evidence="ECO:0007829|PDB:5EE7"
FT HELIX 172..198
FT /evidence="ECO:0007829|PDB:5EE7"
FT STRAND 203..206
FT /evidence="ECO:0007829|PDB:5XEZ"
FT HELIX 209..211
FT /evidence="ECO:0007829|PDB:6WPW"
FT HELIX 213..215
FT /evidence="ECO:0007829|PDB:5EE7"
FT HELIX 218..253
FT /evidence="ECO:0007829|PDB:5EE7"
FT STRAND 255..258
FT /evidence="ECO:0007829|PDB:6WHC"
FT HELIX 264..271
FT /evidence="ECO:0007829|PDB:5EE7"
FT HELIX 273..289
FT /evidence="ECO:0007829|PDB:5EE7"
FT STRAND 293..295
FT /evidence="ECO:0007829|PDB:4L6R"
FT TURN 302..304
FT /evidence="ECO:0007829|PDB:6WPW"
FT HELIX 305..307
FT /evidence="ECO:0007829|PDB:5EE7"
FT HELIX 308..334
FT /evidence="ECO:0007829|PDB:5EE7"
FT TURN 338..340
FT /evidence="ECO:0007829|PDB:6WPW"
FT HELIX 343..369
FT /evidence="ECO:0007829|PDB:5EE7"
FT TURN 370..372
FT /evidence="ECO:0007829|PDB:6WPW"
FT HELIX 379..389
FT /evidence="ECO:0007829|PDB:5EE7"
FT HELIX 392..400
FT /evidence="ECO:0007829|PDB:5EE7"
FT TURN 401..403
FT /evidence="ECO:0007829|PDB:5EE7"
FT HELIX 405..417
FT /evidence="ECO:0007829|PDB:5EE7"
SQ SEQUENCE 477 AA; 54009 MW; ADBB477C6267AE6E CRC64;
MPPCQPQRPL LLLLLLLACQ PQVPSAQVMD FLFEKWKLYG DQCHHNLSLL PPPTELVCNR
TFDKYSCWPD TPANTTANIS CPWYLPWHHK VQHRFVFKRC GPDGQWVRGP RGQPWRDASQ
CQMDGEEIEV QKEVAKMYSS FQVMYTVGYS LSLGALLLAL AILGGLSKLH CTRNAIHANL
FASFVLKASS VLVIDGLLRT RYSQKIGDDL SVSTWLSDGA VAGCRVAAVF MQYGIVANYC
WLLVEGLYLH NLLGLATLPE RSFFSLYLGI GWGAPMLFVV PWAVVKCLFE NVQCWTSNDN
MGFWWILRFP VFLAILINFF IFVRIVQLLV AKLRARQMHH TDYKFRLAKS TLTLIPLLGV
HEVVFAFVTD EHAQGTLRSA KLFFDLFLSS FQGLLVAVLY CFLNKEVQSE LRRRWHRWRL
GKVLWEERNT SNHRASSSPG HGPPSKELQF GRGGGSQDSS AETPLAGGLP RLAESPF
