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P01275 (GLUC_HUMAN) Reviewed, UniProtKB/Swiss-Prot

Last modified April 16, 2014. Version 158. Feed History...

Clusters with 100%, 90%, 50% identity | Documents (6) | Third-party data text xml rdf/xml gff fasta
to top of pageNames·Attributes·General annotation·Ontologies·Interactions·Sequence annotation·Sequences·References·Web links·Cross-refs·Entry info·DocumentsCustomize order

Names and origin

Protein namesRecommended name:
Glucagon

Cleaved into the following 8 chains:

  1. Glicentin
  2. Glicentin-related polypeptide
    Short name=GRPP
  3. Oxyntomodulin
    Short name=OXM
    Short name=OXY
  4. Glucagon
  5. Glucagon-like peptide 1
    Short name=GLP-1
    Alternative name(s):
    Incretin hormone
  6. Glucagon-like peptide 1(7-37)
    Short name=GLP-1(7-37)
  7. Glucagon-like peptide 1(7-36)
    Short name=GLP-1(7-36)
  8. Glucagon-like peptide 2
    Short name=GLP-2
Gene names
Name:GCG
OrganismHomo sapiens (Human) [Reference proteome]
Taxonomic identifier9606 [NCBI]
Taxonomic lineageEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo

Protein attributes

Sequence length180 AA.
Sequence statusComplete.
Sequence processingThe displayed sequence is further processed into a mature form.
Protein existenceEvidence at protein level

General annotation (Comments)

Function

Glucagon plays a key role in glucose metabolism and homeostasis. Regulates blood glucose by increasing gluconeogenesis and decreasing glycolysis. A counterregulatory hormone of insulin, raises plasma glucose levels in response to insulin-induced hypoglycemia. Plays an important role in initiating and maintaining hyperglycemic conditions in diabetes. Ref.9 Ref.10 Ref.11

GLP-1 is a potent stimulator of glucose-dependent insulin release. Play important roles on gastric motility and the suppression of plasma glucagon levels. May be involved in the suppression of satiety and stimulation of glucose disposal in peripheral tissues, independent of the actions of insulin. Have growth-promoting activities on intestinal epithelium. May also regulate the hypothalamic pituitary axis (HPA) via effects on LH, TSH, CRH, oxytocin, and vasopressin secretion. Increases islet mass through stimulation of islet neogenesis and pancreatic beta cell proliferation. Inhibits beta cell apoptosis. Ref.9 Ref.10 Ref.11

GLP-2 stimulates intestinal growth and up-regulates villus height in the small intestine, concomitant with increased crypt cell proliferation and decreased enterocyte apoptosis. The gastrointestinal tract, from the stomach to the colon is the principal target for GLP-2 action. Plays a key role in nutrient homeostasis, enhancing nutrient assimilation through enhanced gastrointestinal function, as well as increasing nutrient disposal. Stimulates intestinal glucose transport and decreases mucosal permeability. Ref.9 Ref.10 Ref.11

Oxyntomodulin significantly reduces food intake. Inhibits gastric emptying in humans. Suppression of gastric emptying may lead to increased gastric distension, which may contribute to satiety by causing a sensation of fullness. Ref.9 Ref.10 Ref.11

Glicentin may modulate gastric acid secretion and the gastro-pyloro-duodenal activity. May play an important role in intestinal mucosal growth in the early period of life. Ref.9 Ref.10 Ref.11

Subcellular location

Secreted.

Tissue specificity

Glucagon is secreted in the A cells of the islets of Langerhans. GLP-1, GLP-2, oxyntomodulin and glicentin are secreted from enteroendocrine cells throughout the gastrointestinal tract. GLP-1 and GLP-2 are also secreted in selected neurons in the brain.

Induction

Glucagon release is stimulated by hypoglycemia and inhibited by hyperglycemia, insulin, and somatostatin. GLP-1 and GLP-2 are induced in response to nutrient ingestion.

Post-translational modification

Proglucagon is post-translationally processed in a tissue-specific manner in pancreatic A cells and intestinal L cells. In pancreatic A cells, the major bioactive hormone is glucagon cleaved by PCSK2/PC2. In the intestinal L cells PCSK1/PC1 liberates GLP-1, GLP-2, glicentin and oxyntomodulin. GLP-1 is further N-terminally truncated by post-translational processing in the intestinal L cells resulting in GLP-1(7-37) GLP-1-(7-36)amide. The C-terminal amidation is neither important for the metabolism of GLP-1 nor for its effects on the endocrine pancreas. Ref.12 Ref.13

Pharmaceutical use

Available under the names Glucagon (Eli Lilly) and GlucaGen or Glucagon Novo Nordisk (Novo Nordisk). Used to treat severe hypoglycemia in insulin-dependent diabetics.

Miscellaneous

In the glucagon antagonist, His-53 and Phe-58 are missing. This antagonist has been successfully utilized to reduce glucose concentration in vivo.

Sequence similarities

Belongs to the glucagon family.

Ontologies

Keywords
   Cellular componentSecreted
   Coding sequence diversityPolymorphism
   DomainSignal
   Molecular functionHormone
   PTMAmidation
Cleavage on pair of basic residues
   Technical term3D-structure
Complete proteome
Direct protein sequencing
Pharmaceutical
Reference proteome
Gene Ontology (GO)
   Biological_processG-protein coupled receptor signaling pathway

Traceable author statement PubMed 9990065. Source: ProtInc

adenylate cyclase-modulating G-protein coupled receptor signaling pathway

Inferred from Biological aspect of Ancestor. Source: RefGenome

cell proliferation

Traceable author statement PubMed 10861272. Source: ProtInc

cellular protein metabolic process

Traceable author statement. Source: Reactome

cellular response to glucagon stimulus

Traceable author statement. Source: Reactome

energy reserve metabolic process

Traceable author statement. Source: Reactome

feeding behavior

Traceable author statement PubMed 8538742. Source: ProtInc

negative regulation of apoptotic process

Inferred from Biological aspect of Ancestor. Source: RefGenome

negative regulation of execution phase of apoptosis

Inferred from electronic annotation. Source: Ensembl

negative regulation of intrinsic apoptotic signaling pathway

Inferred from electronic annotation. Source: Ensembl

positive regulation of ERK1 and ERK2 cascade

Inferred from electronic annotation. Source: Ensembl

positive regulation of cAMP biosynthetic process

Inferred from electronic annotation. Source: Ensembl

positive regulation of calcium ion import

Inferred from electronic annotation. Source: Ensembl

positive regulation of insulin secretion involved in cellular response to glucose stimulus

Inferred from Biological aspect of Ancestor. Source: RefGenome

positive regulation of peptidyl-serine phosphorylation

Inferred from electronic annotation. Source: Ensembl

positive regulation of peptidyl-threonine phosphorylation

Inferred from electronic annotation. Source: Ensembl

positive regulation of protein binding

Inferred from electronic annotation. Source: Ensembl

positive regulation of protein kinase activity

Inferred from electronic annotation. Source: Ensembl

protein kinase A signaling

Inferred from Biological aspect of Ancestor. Source: RefGenome

regulation of insulin secretion

Traceable author statement. Source: Reactome

response to starvation

Inferred from Biological aspect of Ancestor. Source: RefGenome

signal transduction

Traceable author statement PubMed 7929237. Source: ProtInc

small molecule metabolic process

Traceable author statement. Source: Reactome

   Cellular_componentendoplasmic reticulum lumen

Traceable author statement. Source: Reactome

extracellular region

Traceable author statement. Source: Reactome

extracellular space

Inferred from Biological aspect of Ancestor. Source: RefGenome

plasma membrane

Traceable author statement. Source: Reactome

secretory granule lumen

Traceable author statement. Source: Reactome

   Molecular_functionglucagon receptor binding

Inferred from Biological aspect of Ancestor. Source: RefGenome

hormone activity

Inferred from Biological aspect of Ancestor. Source: RefGenome

identical protein binding

Inferred from physical interaction PubMed 22212535. Source: IntAct

receptor binding

Traceable author statement PubMed 9990065. Source: ProtInc

Complete GO annotation...

Binary interactions

Sequence annotation (Features)

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifier

Molecule processing

Signal peptide1 – 2020
Peptide21 – 8969Glicentin By similarity
PRO_0000011253
Peptide21 – 5030Glicentin-related polypeptide By similarity Ref.1
PRO_0000011254
Peptide53 – 8937Oxyntomodulin By similarity
PRO_0000011255
Peptide53 – 8129Glucagon Ref.7
PRO_0000011256
Propeptide84 – 896
PRO_0000011257
Peptide92 – 12837Glucagon-like peptide 1
PRO_0000011258
Peptide98 – 12831Glucagon-like peptide 1(7-37)
PRO_0000011259
Peptide98 – 12730Glucagon-like peptide 1(7-36) Ref.8
PRO_0000011260
Propeptide131 – 14515 By similarity
PRO_0000011261
Peptide146 – 17833Glucagon-like peptide 2 By similarity
PRO_0000011262

Sites

Site52 – 532Cleavage; by PCSK2
Site83 – 842Cleavage; by PCSK1 and PCSK2
Site91 – 922Cleavage; by PCSK1
Site97 – 982Cleavage; by PCSK1
Site130 – 1312Cleavage; by PCSK1
Site145 – 1462Cleavage; by PCSK1

Amino acid modifications

Modified residue1271Arginine amide Ref.8

Natural variations

Natural variant1151A → V.
Corresponds to variant rs5650 [ dbSNP | Ensembl ].
VAR_014596

Experimental info

Sequence conflict821K → N in CAA27627. Ref.2

Secondary structure

.................. 180
Helix Strand Turn

Details...

Sequences

Sequence LengthMass (Da)Tools
P01275 [UniParc].

Last modified February 6, 2007. Version 3.
Checksum: 7A99EEC629B2862C

FASTA18020,909
        10         20         30         40         50         60 
MKSIYFVAGL FVMLVQGSWQ RSLQDTEEKS RSFSASQADP LSDPDQMNED KRHSQGTFTS 

        70         80         90        100        110        120 
DYSKYLDSRR AQDFVQWLMN TKRNRNNIAK RHDEFERHAE GTFTSDVSSY LEGQAAKEFI 

       130        140        150        160        170        180 
AWLVKGRGRR DFPEEVAIVE ELGRRHADGS FSDEMNTILD NLAARDFINW LIQTKITDRK 

« Hide

References

« Hide 'large scale' references
[1]"Glucagon gene expression in vertebrate brain."
Drucker D.J., Asa S.
J. Biol. Chem. 263:13475-13478(1988) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [MRNA].
[2]"Structure of the human glucagon gene."
White J.W., Saunders G.F.
Nucleic Acids Res. 14:4719-4730(1986) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA].
[3]"Exon duplication and divergence in the human preproglucagon gene."
Bell G.I., Sanchez-Pescador R., Laybourn P.J., Najarian R.C.
Nature 304:368-371(1983) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA].
Tissue: Liver.
[4]"Cloning of human full-length CDSs in BD Creator(TM) system donor vector."
Kalnine N., Chen X., Rolfs A., Halleck A., Hines L., Eisenstein S., Koundinya M., Raphael J., Moreira D., Kelley T., LaBaer J., Lin Y., Phelan M., Farmer A.
Submitted (MAY-2003) to the EMBL/GenBank/DDBJ databases
Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
[5]"Generation and annotation of the DNA sequences of human chromosomes 2 and 4."
Hillier L.W., Graves T.A., Fulton R.S., Fulton L.A., Pepin K.H., Minx P., Wagner-McPherson C., Layman D., Wylie K., Sekhon M., Becker M.C., Fewell G.A., Delehaunty K.D., Miner T.L., Nash W.E., Kremitzki C., Oddy L., Du H. expand/collapse author list , Sun H., Bradshaw-Cordum H., Ali J., Carter J., Cordes M., Harris A., Isak A., van Brunt A., Nguyen C., Du F., Courtney L., Kalicki J., Ozersky P., Abbott S., Armstrong J., Belter E.A., Caruso L., Cedroni M., Cotton M., Davidson T., Desai A., Elliott G., Erb T., Fronick C., Gaige T., Haakenson W., Haglund K., Holmes A., Harkins R., Kim K., Kruchowski S.S., Strong C.M., Grewal N., Goyea E., Hou S., Levy A., Martinka S., Mead K., McLellan M.D., Meyer R., Randall-Maher J., Tomlinson C., Dauphin-Kohlberg S., Kozlowicz-Reilly A., Shah N., Swearengen-Shahid S., Snider J., Strong J.T., Thompson J., Yoakum M., Leonard S., Pearman C., Trani L., Radionenko M., Waligorski J.E., Wang C., Rock S.M., Tin-Wollam A.-M., Maupin R., Latreille P., Wendl M.C., Yang S.-P., Pohl C., Wallis J.W., Spieth J., Bieri T.A., Berkowicz N., Nelson J.O., Osborne J., Ding L., Meyer R., Sabo A., Shotland Y., Sinha P., Wohldmann P.E., Cook L.L., Hickenbotham M.T., Eldred J., Williams D., Jones T.A., She X., Ciccarelli F.D., Izaurralde E., Taylor J., Schmutz J., Myers R.M., Cox D.R., Huang X., McPherson J.D., Mardis E.R., Clifton S.W., Warren W.C., Chinwalla A.T., Eddy S.R., Marra M.A., Ovcharenko I., Furey T.S., Miller W., Eichler E.E., Bork P., Suyama M., Torrents D., Waterston R.H., Wilson R.K.
Nature 434:724-731(2005) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
[6]"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: Pancreas.
[7]"The amino acid sequence of human glucagon."
Thomsen J., Kristiansen K., Brunfeldt K., Sundby F.
FEBS Lett. 21:315-319(1972) [PubMed] [Europe PMC] [Abstract]
Cited for: PROTEIN SEQUENCE OF 53-81.
[8]"Complete sequences of glucagon-like peptide-1 from human and pig small intestine."
Orskov C., Bersani M., Johnsen A.H., Hoejrup P., Holst J.J.
J. Biol. Chem. 264:12826-12829(1989) [PubMed] [Europe PMC] [Abstract]
Cited for: PROTEIN SEQUENCE OF 98-127, AMIDATION AT ARG-127.
[9]"Biological effects and metabolic rates of glucagonlike peptide-1 7-36 amide and glucagonlike peptide-1 7-37 in healthy subjects are indistinguishable."
Orskov C., Wettergren A., Holst J.J.
Diabetes 42:658-661(1993) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION OF GLP1 BIOACTIVE FORMS.
[10]"Oxyntomodulin suppresses appetite and reduces food intake in humans."
Cohen M.A., Ellis S.M., Le Roux C.W., Batterham R.L., Park A., Patterson M., Frost G.S., Ghatei M.A., Bloom S.R.
J. Clin. Endocrinol. Metab. 88:4696-4701(2003) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION OF OXYNTOMODULIN.
[11]"Postnatal and postprandial changes in plasma concentrations of glicentin in term and preterm infants."
Tadokoro R., Shimizu T., Hosaka A., Kaneko N., Satoh Y., Yamashiro Y.
Acta Paediatr. 92:1175-1179(2003) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION OF GLICENTIN.
[12]"Role of the prohormone convertase PC2 in the processing of proglucagon to glucagon."
Rouille Y., Bianchi M., Irminger J.C., Halban P.A.
FEBS Lett. 413:119-123(1997) [PubMed] [Europe PMC] [Abstract]
Cited for: PROTEOLYTIC PROCESSING BY PCSK2.
[13]"Expression, purification, and PC1-mediated processing of human proglucagon, glicentin, and major proglucagon fragment."
Bonic A., Mackin R.B.
Protein Expr. Purif. 28:15-24(2003) [PubMed] [Europe PMC] [Abstract]
Cited for: PROTEOLYTIC PROCESSING BY PCSK1.
[14]"Direct and indirect mechanisms regulating secretion of glucagon-like peptide-1 and glucagon-like peptide-2."
Brubaker P.L., Anini Y.
Can. J. Physiol. Pharmacol. 81:1005-1012(2003) [PubMed] [Europe PMC] [Abstract]
Cited for: REVIEW.
[15]"Glucagon-like peptides: regulators of cell proliferation, differentiation, and apoptosis."
Drucker D.J.
Mol. Endocrinol. 17:161-171(2003) [PubMed] [Europe PMC] [Abstract]
Cited for: REVIEW.
[16]"Glucagon and regulation of glucose metabolism."
Jiang G., Zhang B.B.
Am. J. Physiol. 284:E671-E678(2003) [PubMed] [Europe PMC] [Abstract]
Cited for: REVIEW.
[17]"Glucagon-like peptide 2."
Drucker D.J.
Trends Endocrinol. Metab. 10:153-156(1999) [PubMed] [Europe PMC] [Abstract]
Cited for: REVIEW.
[18]"The glucagon-like peptides."
Kieffer T.J., Habener J.F.
Endocr. Rev. 20:876-913(1999) [PubMed] [Europe PMC] [Abstract]
Cited for: REVIEW.
[19]"Structure-function studies on positions 17, 18, and 21 replacement analogues of glucagon: the importance of charged residues and salt bridges in glucagon biological activity."
Sturm N.S., Lin Y., Burley S.K., Krstenansky J.L., Ahn J.-M., Azizeh B.Y., Trivedi D., Hruby V.J.
J. Med. Chem. 41:2693-2700(1998) [PubMed] [Europe PMC] [Abstract]
Cited for: X-RAY CRYSTALLOGRAPHY (3.0 ANGSTROMS) OF 53-81.
[20]"NMR studies of the aggregation of glucagon-like peptide-1: formation of a symmetric helical dimer."
Chang X., Keller D., O'Donoghue S.I., Led J.J.
FEBS Lett. 515:165-170(2002) [PubMed] [Europe PMC] [Abstract]
Cited for: STRUCTURE BY NMR OF 98-127.
[21]"NMR solution structure of the glucagon antagonist [desHis1, desPhe6, Glu9]glucagon amide in the presence of perdeuterated dodecylphosphocholine micelles."
Ying J., Ahn J.-M., Jacobsen N.E., Brown M.F., Hruby V.J.
Biochemistry 42:2825-2835(2003) [PubMed] [Europe PMC] [Abstract]
Cited for: STRUCTURE BY NMR OF GLUCAGON ANTAGONIST.
+Additional computationally mapped references.

Web resources

Glucagon at Eli Lilly

Clinical information on Eli Lilly glucagon products

Cross-references

Sequence databases

EMBL
GenBank
DDBJ
J04040 mRNA. Translation: AAA52567.1.
X03991 Genomic DNA. Translation: CAA27627.1.
V01515 Genomic DNA. Translation: CAA24759.1.
BT006813 mRNA. Translation: AAP35459.1.
AC007750 Genomic DNA. Translation: AAY24204.1.
BC005278 mRNA. Translation: AAH05278.1.
PIRGCHU. A24377.
RefSeqNP_002045.1. NM_002054.4.
UniGeneHs.516494.
Hs.741174.

3D structure databases

PDBe
RCSB PDB
PDBj
EntryMethodResolution (Å)ChainPositionsPDBsum
1BH0X-ray3.00A53-81[»]
1D0RNMR-A98-127[»]
1NAUNMR-A59-81[»]
2G49X-ray2.50C/D53-81[»]
2L63NMR-A146-178[»]
2L64NMR-A146-178[»]
2M5PNMR-X55-81[»]
2M5QNMR-X55-81[»]
3IOLX-ray2.10B98-128[»]
ProteinModelPortalP01275.
SMRP01275. Positions 53-81, 98-127, 146-178.
ModBaseSearch...
MobiDBSearch...

Protein-protein interaction databases

BioGrid108911. 2 interactions.
DIPDIP-46470N.
IntActP01275. 4 interactions.
MINTMINT-8090511.
STRING9606.ENSP00000387662.

Chemistry

BindingDBP01275.
ChEMBLCHEMBL5736.
DrugBankDB01276. Exenatide.
DB00692. Phentolamine.

PTM databases

PhosphoSiteP01275.

Polymorphism databases

DMDM125987831.

Proteomic databases

PaxDbP01275.
PRIDEP01275.

Protocols and materials databases

DNASU2641.
StructuralBiologyKnowledgebaseSearch...

Genome annotation databases

EnsemblENST00000375497; ENSP00000364647; ENSG00000115263.
ENST00000418842; ENSP00000387662; ENSG00000115263.
GeneID2641.
KEGGhsa:2641.
UCSCuc002ucc.4. human.

Organism-specific databases

CTD2641.
GeneCardsGC02M162963.
HGNCHGNC:4191. GCG.
HPACAB000040.
MIM138030. gene.
neXtProtNX_P01275.
PharmGKBPA28606.
GenAtlasSearch...

Phylogenomic databases

eggNOGNOG42743.
HOGENOMHOG000231876.
HOVERGENHBG003010.
KOK05259.
OMARNKNNIA.
OrthoDBEOG7WMCM1.
PhylomeDBP01275.
TreeFamTF332333.

Enzyme and pathway databases

ReactomeREACT_111102. Signal Transduction.
REACT_111217. Metabolism.
REACT_17015. Metabolism of proteins.

Gene expression databases

BgeeP01275.
CleanExHS_GCG.
GenevestigatorP01275.

Family and domain databases

InterProIPR015550. Glucagon-like.
IPR000532. Glucagon_GIP_secretin_VIP.
[Graphical view]
PANTHERPTHR11418. PTHR11418. 1 hit.
PfamPF00123. Hormone_2. 3 hits.
[Graphical view]
PRINTSPR00275. GLUCAGON.
SMARTSM00070. GLUCA. 3 hits.
[Graphical view]
PROSITEPS00260. GLUCAGON. 4 hits.
[Graphical view]
ProtoNetSearch...

Other

ChiTaRSGCG. human.
EvolutionaryTraceP01275.
GeneWikiGlucagon.
GenomeRNAi2641.
NextBio10412.
PMAP-CutDBP01275.
PROP01275.
SOURCESearch...

Entry information

Entry nameGLUC_HUMAN
AccessionPrimary (citable) accession number: P01275
Secondary accession number(s): A6NN65, Q53TP6
Entry history
Integrated into UniProtKB/Swiss-Prot: July 21, 1986
Last sequence update: February 6, 2007
Last modified: April 16, 2014
This is version 158 of the entry and version 3 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 2

Human chromosome 2: entries, gene names and cross-references to MIM