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P47871 (GLR_HUMAN) Reviewed, UniProtKB/Swiss-Prot

Last modified April 16, 2014. Version 122. Feed History...

Clusters with 100%, 90%, 50% identity | Documents (7) | Third-party data text xml rdf/xml gff fasta
to top of pageNames·Attributes·General annotation·Ontologies·Sequence annotation·Sequences·References·Cross-refs·Entry info·DocumentsCustomize order

Names and origin

Protein namesRecommended name:
Glucagon receptor

Short name=GL-R
Gene names
Name:GCGR
OrganismHomo sapiens (Human) [Reference proteome]
Taxonomic identifier9606 [NCBI]
Taxonomic lineageEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo

Protein attributes

Sequence length477 AA.
Sequence statusComplete.
Sequence processingThe displayed sequence is further processed into a mature form.
Protein existenceEvidence at protein level

General annotation (Comments)

Function

G-protein coupled receptor for glucagon that plays a central role in the regulation of blood glucose levels and glucose homeostasis. Regulates the rate of hepatic glucose production by promoting glycogen hydrolysis and gluconeogenesis. Plays an important role in mediating the responses to fasting. Ligand binding causes a conformation change that triggers signaling via guanine nucleotide-binding proteins (G proteins) and modulates the activity of down-stream effectors, such as adenylate cyclase. Promotes activation of adenylate cyclase. Besides, plays a role in signaling via a phosphatidylinositol-calcium second messenger system. Ref.1 Ref.5 Ref.7 Ref.8 Ref.10

Subcellular location

Cell membrane; Multi-pass membrane protein. Note: Is rapidly internalized after ligand-binding. Ref.1 Ref.5 Ref.8 Ref.10

Post-translational modification

Ligand-binding promotes phosphorylation of serine residues in the C-terminal cytoplasmic domain. Phosphorylation is important for receptor endocytosis after ligand-binding.

Sequence similarities

Belongs to the G-protein coupled receptor 2 family.

Ontologies

Keywords
   Cellular componentCell membrane
Membrane
   Coding sequence diversityPolymorphism
   DiseaseDiabetes mellitus
   DomainSignal
Transmembrane
Transmembrane helix
   Molecular functionG-protein coupled receptor
Receptor
Transducer
   PTMDisulfide bond
Glycoprotein
Phosphoprotein
   Technical term3D-structure
Complete proteome
Reference proteome
Gene Ontology (GO)
   Biological_processadenylate cyclase-activating G-protein coupled receptor signaling pathway

Inferred from electronic annotation. Source: Ensembl

adenylate cyclase-modulating G-protein coupled receptor signaling pathway

Inferred from mutant phenotype Ref.5. Source: UniProtKB

cellular response to glucagon stimulus

Inferred from direct assay Ref.5. Source: UniProtKB

energy reserve metabolic process

Traceable author statement. Source: Reactome

exocytosis

Inferred from electronic annotation. Source: Ensembl

generation of precursor metabolites and energy

Traceable author statement PubMed 7773293. Source: ProtInc

glucose homeostasis

Inferred from sequence or structural similarity. Source: UniProtKB

hormone-mediated signaling pathway

Inferred from electronic annotation. Source: Ensembl

regulation of GTPase activity

Traceable author statement. Source: GOC

regulation of blood pressure

Traceable author statement PubMed 8563746. Source: ProtInc

regulation of glycogen metabolic process

Inferred from sequence or structural similarity. Source: UniProtKB

response to nutrient

Traceable author statement PubMed 7773293. Source: ProtInc

response to starvation

Inferred from sequence or structural similarity. Source: UniProtKB

small molecule metabolic process

Traceable author statement. Source: Reactome

   Cellular_componentendosome

Inferred from electronic annotation. Source: Ensembl

integral component of membrane

Traceable author statement Ref.2. Source: ProtInc

integral component of plasma membrane

Inferred from direct assay Ref.5. Source: UniProtKB

plasma membrane

Traceable author statement. Source: Reactome

   Molecular_functionglucagon receptor activity

Inferred from direct assay Ref.5. Source: UniProtKB

guanyl-nucleotide exchange factor activity

Traceable author statement. Source: Reactome

peptide hormone binding

Inferred from electronic annotation. Source: Ensembl

Complete GO annotation...

Sequence annotation (Features)

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifier

Molecule processing

Signal peptide1 – 2525 Potential
Chain26 – 477452Glucagon receptor
PRO_0000012832

Regions

Topological domain26 – 136111Extracellular Ref.8
Transmembrane137 – 16125Helical; Name=1
Topological domain162 – 17312Cytoplasmic Ref.8
Transmembrane174 – 19825Helical; Name=2
Topological domain199 – 22527Extracellular Ref.8
Transmembrane226 – 24924Helical; Name=3
Topological domain250 – 26314Cytoplasmic Ref.8
Transmembrane264 – 28522Helical; Name=4
Topological domain286 – 30318Extracellular Ref.8
Transmembrane304 – 32623Helical; Name=5
Topological domain327 – 35024Cytoplasmic Ref.8
Transmembrane351 – 36919Helical; Name=6
Topological domain370 – 38112Extracellular Ref.8
Transmembrane382 – 40221Helical; Name=7
Topological domain403 – 47775Cytoplasmic Ref.8

Amino acid modifications

Glycosylation461N-linked (GlcNAc...) Potential
Glycosylation591N-linked (GlcNAc...) Potential
Glycosylation741N-linked (GlcNAc...) Ref.7
Glycosylation781N-linked (GlcNAc...) Ref.7
Disulfide bond43 ↔ 67 Ref.7 Ref.8
Disulfide bond58 ↔ 100 Ref.7 Ref.8
Disulfide bond81 ↔ 121 Ref.7 Ref.8

Natural variations

Natural variant401G → S. Ref.9
Corresponds to variant rs1801483 [ dbSNP | Ensembl ].
VAR_003581
Natural variant861P → S Abolishes glucagon binding. Ref.8 Ref.10
VAR_069815
Natural variant1141P → A.
Corresponds to variant rs5385 [ dbSNP | Ensembl ].
VAR_014837
Natural variant3031F → C.
Corresponds to variant rs5387 [ dbSNP | Ensembl ].
VAR_033966

Experimental info

Mutagenesis361W → A: Abolishes glucagon binding. Ref.8
Mutagenesis631D → A: Abolishes glucagon binding. Ref.8
Mutagenesis651Y → A: Strongly reduced affinity for glucagon. Increased constitutive signaling via G-proteins. Ref.7
Mutagenesis1131Q → A or N: No effect on affinity for glucagon. Ref.7
Mutagenesis1131Q → E: Strongly reduced affinity for glucagon. Ref.7
Mutagenesis1351A → P: Abolishes glucagon binding. Ref.8
Mutagenesis1451Y → A: Abolishes glucagon binding. Ref.8
Mutagenesis1491Y → A: Abolishes expression at cell surface and glucagon binding. Ref.8
Mutagenesis1981L → A: Abolishes glucagon binding. Ref.8
Mutagenesis2011R → D: Abolishes glucagon binding. Ref.8
Mutagenesis2021Y → A: Abolishes glucagon binding. Ref.8
Mutagenesis2081D → Q: Abolishes glucagon binding. Ref.8
Mutagenesis2151W → L: Abolishes glucagon binding. Ref.8
Mutagenesis2321Q → L: Abolishes expression at cell surface and glucagon binding. Ref.8
Mutagenesis2331Y → A: Abolishes glucagon binding. Strongly reduces expression at the cell surface. Ref.8
Mutagenesis2861K → L: Abolishes glucagon binding. Ref.8
Mutagenesis2901E → A: Abolishes glucagon binding. Ref.8
Mutagenesis2941C → A or S: Abolishes glucagon binding. Ref.8
Mutagenesis2951W → A or H: Abolishes glucagon binding. Ref.8
Mutagenesis3041W → Q: Abolishes glucagon binding. Ref.8
Mutagenesis3821L → A: Abolishes glucagon binding. Ref.8
Mutagenesis3861L → F: Abolishes glucagon binding. Ref.8

Secondary structure

.......................................................... 477
Helix Strand Turn

Details...

Sequences

Sequence LengthMass (Da)Tools
P47871 [UniParc].

Last modified February 1, 1996. Version 1.
Checksum: ADBB477C6267AE6E

FASTA47754,009
        10         20         30         40         50         60 
MPPCQPQRPL LLLLLLLACQ PQVPSAQVMD FLFEKWKLYG DQCHHNLSLL PPPTELVCNR 

        70         80         90        100        110        120 
TFDKYSCWPD TPANTTANIS CPWYLPWHHK VQHRFVFKRC GPDGQWVRGP RGQPWRDASQ 

       130        140        150        160        170        180 
CQMDGEEIEV QKEVAKMYSS FQVMYTVGYS LSLGALLLAL AILGGLSKLH CTRNAIHANL 

       190        200        210        220        230        240 
FASFVLKASS VLVIDGLLRT RYSQKIGDDL SVSTWLSDGA VAGCRVAAVF MQYGIVANYC 

       250        260        270        280        290        300 
WLLVEGLYLH NLLGLATLPE RSFFSLYLGI GWGAPMLFVV PWAVVKCLFE NVQCWTSNDN 

       310        320        330        340        350        360 
MGFWWILRFP VFLAILINFF IFVRIVQLLV AKLRARQMHH TDYKFRLAKS TLTLIPLLGV 

       370        380        390        400        410        420 
HEVVFAFVTD EHAQGTLRSA KLFFDLFLSS FQGLLVAVLY CFLNKEVQSE LRRRWHRWRL 

       430        440        450        460        470 
GKVLWEERNT SNHRASSSPG HGPPSKELQF GRGGGSQDSS AETPLAGGLP RLAESPF 

« Hide

References

« Hide 'large scale' references
[1]"Cloning and expression of a human glucagon receptor."
Macneil D.J., Occi J.L., Hey P.J., Strader C.D., Graziano M.P.
Biochem. Biophys. Res. Commun. 198:328-334(1994) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [MRNA], FUNCTION, SUBCELLULAR LOCATION.
Tissue: Liver.
[2]"The human glucagon receptor encoding gene: structure, cDNA sequence and chromosomal localization."
Lok S., Kuijper J.L., Jelinek L.J., Kramer J.M., Whitmore T.E., Sprecher C.A., Mathewes S., Grant F.J., Biggs S.H., Rosenberg G.B.
Gene 140:203-209(1994) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [MRNA].
[3]"The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC)."
The MGC Project Team
Genome Res. 14:2121-2127(2004) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
Tissue: Liver.
[4]"Localization of the glucagon receptor gene to human chromosome band 17q25."
Menzel S., Stoffel M., Espinosa R. III, Fernald A.A., Le Beau M.M., Bell G.I.
Genomics 20:327-328(1994) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 21-54.
Tissue: Placenta.
[5]"Role of the glucagon receptor COOH-terminal domain in glucagon-mediated signaling and receptor internalization."
Buggy J.J., Heurich R.O., MacDougall M., Kelley K.A., Livingston J.N., Yoo-Warren H., Rossomando A.J.
Diabetes 46:1400-1405(1997) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION, SUBCELLULAR LOCATION, PHOSPHORYLATION.
[6]"Conformational dimorphism of self-peptides and molecular mimicry in a disease-associated HLA-B27 subtype."
Ruckert C., Fiorillo M.T., Loll B., Moretti R., Biesiadka J., Saenger W., Ziegler A., Sorrentino R., Uchanska-Ziegler B.
J. Biol. Chem. 281:2306-2316(2006) [PubMed] [Europe PMC] [Abstract]
Cited for: X-RAY CRYSTALLOGRAPHY (1.2 ANGSTROMS) OF 412-420 IN COMPLEX WITH CLASS I MHC.
[7]"Molecular basis for negative regulation of the glucagon receptor."
Koth C.M., Murray J.M., Mukund S., Madjidi A., Minn A., Clarke H.J., Wong T., Chiang V., Luis E., Estevez A., Rondon J., Zhang Y., Hotzel I., Allan B.B.
Proc. Natl. Acad. Sci. U.S.A. 109:14393-14398(2012) [PubMed] [Europe PMC] [Abstract]
Cited for: X-RAY CRYSTALLOGRAPHY (2.64 ANGSTROMS) OF 28-123, FUNCTION, MUTAGENESIS OF TYR-65 AND GLN-113, DISULFIDE BONDS, GLYCOSYLATION AT ASN-74 AND ASN-78.
[8]"Structure of the human glucagon class B G-protein-coupled receptor."
Siu F.Y., He M., de Graaf C., Han G.W., Yang D., Zhang Z., Zhou C., Xu Q., Wacker D., Joseph J.S., Liu W., Lau J., Cherezov V., Katritch V., Wang M.W., Stevens R.C.
Nature 499:444-449(2013) [PubMed] [Europe PMC] [Abstract]
Cited for: X-RAY CRYSTALLOGRAPHY (3.3 ANGSTROMS) OF 123-432, FUNCTION, SUBCELLULAR LOCATION, DISULFIDE BONDS, MEMBRANE TOPOLOGY, MUTAGENESIS OF TRP-36; ASP-63; ALA-135; TYR-145; TYR-149; LEU-198; ARG-201; TYR-202; ASP-208; TRP-215; GLN-232; TYR-233; LYS-286; GLU-290; CYS-294; TRP-295; TRP-304; LEU-382 AND LEU-386, CHARACTERIZATION OF VARIANT SER-86.
[9]"A mutation in the glucagon receptor gene (Gly40Ser): heterogeneity in the association with diabetes mellitus."
Fujisawa T., Ikegami H., Yamato E., Takekawa K., Nakagawa Y., Hamada Y., Ueda H., Fukuda M., Ogihara T.
Diabetologia 38:983-985(1995) [PubMed] [Europe PMC] [Abstract]
Cited for: VARIANT SER-40.
[10]"Homozygous P86S mutation of the human glucagon receptor is associated with hyperglucagonemia, alpha cell hyperplasia, and islet cell tumor."
Zhou C., Dhall D., Nissen N.N., Chen C.R., Yu R.
Pancreas 38:941-946(2009) [PubMed] [Europe PMC] [Abstract]
Cited for: VARIANT SER-86, FUNCTION, SUBCELLULAR LOCATION, CHARACTERIZATION OF VARIANT SER-86.
+Additional computationally mapped references.

Cross-references

Sequence databases

EMBL
GenBank
DDBJ
U03469 mRNA. Translation: AAC52063.1.
L20316 mRNA. Translation: AAA53628.1.
BC104854 mRNA. Translation: AAI04855.1.
BC112041 mRNA. Translation: AAI12042.1.
L24751 Genomic DNA. Translation: AAA35897.1.
PIRJC2041.
RefSeqNP_000151.1. NM_000160.3.
UniGeneHs.208.

3D structure databases

PDBe
RCSB PDB
PDBj
EntryMethodResolution (Å)ChainPositionsPDBsum
3CZFX-ray1.20C412-420[»]
4ERSX-ray2.64A28-123[»]
4L6RX-ray3.30A123-432[»]
4LF3X-ray2.74C/F29-123[»]
ProteinModelPortalP47871.
SMRP47871. Positions 28-429.
ModBaseSearch...
MobiDBSearch...

Protein-protein interaction databases

BioGrid108912. 3 interactions.
IntActP47871. 2 interactions.
STRING9606.ENSP00000383558.

Chemistry

BindingDBP47871.
ChEMBLCHEMBL1985.
DrugBankDB00040. Glucagon recombinant.
GuidetoPHARMACOLOGY251.

Protein family/group databases

GPCRDBSearch...

PTM databases

PhosphoSiteP47871.

Polymorphism databases

DMDM1346144.

Proteomic databases

PaxDbP47871.
PRIDEP47871.

Protocols and materials databases

StructuralBiologyKnowledgebaseSearch...

Genome annotation databases

EnsemblENST00000400723; ENSP00000383558; ENSG00000215644.
GeneID2642.
KEGGhsa:2642.
UCSCuc010wuw.2. human.

Organism-specific databases

CTD2642.
GeneCardsGC17P079763.
HGNCHGNC:4192. GCGR.
MIM138033. gene.
neXtProtNX_P47871.
PharmGKBPA28607.
GenAtlasSearch...

Phylogenomic databases

eggNOGNOG263329.
HOGENOMHOG000008250.
HOVERGENHBG008318.
InParanoidP47871.
KOK04583.
OrthoDBEOG7TF78W.
PhylomeDBP47871.
TreeFamTF315710.

Enzyme and pathway databases

ReactomeREACT_111102. Signal Transduction.
REACT_111217. Metabolism.

Gene expression databases

ArrayExpressP47871.
BgeeP47871.
CleanExHS_GCGR.
GenevestigatorP47871.

Family and domain databases

InterProIPR017981. GPCR_2-like.
IPR001879. GPCR_2_extracellular_dom.
IPR003290. GPCR_2_GLP1/glucagon_rcpt.
IPR003291. GPCR_2_glucagon_rcpt.
IPR000832. GPCR_2_secretin-like.
IPR017983. GPCR_2_secretin-like_CS.
[Graphical view]
PANTHERPTHR12011:SF71. PTHR12011:SF71. 1 hit.
PfamPF00002. 7tm_2. 1 hit.
PF02793. HRM. 1 hit.
[Graphical view]
PRINTSPR01353. GLUCAGNFAMLY.
PR01354. GLUCAGONR.
PR00249. GPCRSECRETIN.
SMARTSM00008. HormR. 1 hit.
[Graphical view]
PROSITEPS00649. G_PROTEIN_RECEP_F2_1. 1 hit.
PS00650. G_PROTEIN_RECEP_F2_2. 1 hit.
PS50227. G_PROTEIN_RECEP_F2_3. 1 hit.
PS50261. G_PROTEIN_RECEP_F2_4. 1 hit.
[Graphical view]
ProtoNetSearch...

Other

EvolutionaryTraceP47871.
GeneWikiGlucagon_receptor.
GenomeRNAi2642.
NextBio10416.
PROP47871.
SOURCESearch...

Entry information

Entry nameGLR_HUMAN
AccessionPrimary (citable) accession number: P47871
Secondary accession number(s): Q2M3M5
Entry history
Integrated into UniProtKB/Swiss-Prot: February 1, 1996
Last sequence update: February 1, 1996
Last modified: April 16, 2014
This is version 122 of the entry and version 1 of the sequence. [Complete history]
Entry statusReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program
DisclaimerAny medical or genetic information present in this entry is provided for research, educational and informational purposes only. It is not in any way intended to be used as a substitute for professional medical advice, diagnosis, treatment or care.

Relevant documents

SIMILARITY comments

Index of protein domains and families

PDB cross-references

Index of Protein Data Bank (PDB) cross-references

MIM cross-references

Online Mendelian Inheritance in Man (MIM) cross-references in UniProtKB/Swiss-Prot

Human polymorphisms and disease mutations

Index of human polymorphisms and disease mutations

Human entries with polymorphisms or disease mutations

List of human entries with polymorphisms or disease mutations

Human chromosome 17

Human chromosome 17: entries, gene names and cross-references to MIM

7-transmembrane G-linked receptors

List of 7-transmembrane G-linked receptor entries