P01275 (GLUC_HUMAN) Reviewed, UniProtKB/Swiss-Prot

Names and origin

Protein names

Recommended 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

Organism

Homo sapiens (Human) [Reference proteome]

Taxonomic identifier

9606 [NCBI]

Taxonomic lineage

cellular organisms › Eukaryota › Opisthokonta › Metazoa › Eumetazoa › Bilateria › Deuterostomia › Chordata › Craniata › Vertebrata › Gnathostomata › Teleostomi › Euteleostomi › Sarcopterygii › Tetrapoda › Amniota › Mammalia › Theria › Eutheria › Euarchontoglires › Primates › Haplorrhini › Simiiformes › Catarrhini › Hominoidea › Hominidae › Homininae › Homo

Protein attributes

Sequence length	180 AA.
Sequence status	Complete.
Sequence processing	The displayed sequence is further processed into a mature form.
Protein existence	Evidence 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 component	Secreted
Coding sequence diversity	Polymorphism
Domain	Signal
Molecular function	Hormone
PTM	Amidation Cleavage on pair of basic residues
Technical term	3D-structure Complete proteome Direct protein sequencing Pharmaceutical Reference proteome
Gene Ontology (GO)
Biological_process	G-protein coupled receptor signaling pathway Traceable author statement PubMed 9990065. Source: ProtInc cell proliferation Traceable author statement PubMed 10861272. Source: ProtInc 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 electronic annotation. Source: Compara positive regulation of ERK1 and ERK2 cascade Inferred from electronic annotation. Source: Compara positive regulation of cAMP biosynthetic process Inferred from electronic annotation. Source: Compara positive regulation of calcium ion import Inferred from electronic annotation. Source: Compara positive regulation of insulin secretion involved in cellular response to glucose stimulus Inferred from electronic annotation. Source: Compara positive regulation of peptidyl-serine phosphorylation Inferred from electronic annotation. Source: Compara positive regulation of peptidyl-threonine phosphorylation Inferred from electronic annotation. Source: Compara positive regulation of protein binding Inferred from electronic annotation. Source: Compara positive regulation of protein kinase activity Inferred from electronic annotation. Source: Compara protein kinase A signaling cascade Inferred from electronic annotation. Source: Compara regulation of insulin secretion Traceable author statement. Source: Reactome small molecule metabolic process Traceable author statement. Source: Reactome
Cellular_component	endoplasmic reticulum lumen Traceable author statement. Source: Reactome extracellular region Traceable author statement. Source: Reactome extracellular space Inferred from electronic annotation. Source: Compara plasma membrane Traceable author statement. Source: Reactome secretory granule Traceable author statement. Source: Reactome
Molecular_function	receptor binding Traceable author statement PubMed 9990065. Source: ProtInc
Complete GO annotation...

Sequence annotation (Features)

Feature key

Position(s)

Length

Description

Graphical view

Feature identifier

Molecule processing

Signal peptide

1 – 20

20

Peptide

21 – 89

69

Glicentin By similarity

PRO_0000011253

Peptide

21 – 50

30

Glicentin-related polypeptide By similarity Ref.1

PRO_0000011254

Peptide

53 – 89

37

Oxyntomodulin By similarity

PRO_0000011255

Peptide

53 – 81

29

Glucagon Ref.7

PRO_0000011256

Propeptide

84 – 89

6

PRO_0000011257

Peptide

92 – 128

37

Glucagon-like peptide 1

PRO_0000011258

Peptide

98 – 128

31

Glucagon-like peptide 1(7-37)

PRO_0000011259

Peptide

98 – 127

30

Glucagon-like peptide 1(7-36) Ref.8

PRO_0000011260

Propeptide

131 – 145

15

By similarity

PRO_0000011261

Peptide

146 – 178

33

Glucagon-like peptide 2 By similarity

PRO_0000011262

Sites

Site

52 – 53

2

Cleavage; by PCSK2

Site

83 – 84

2

Cleavage; by PCSK1 and PCSK2

Site

91 – 92

2

Cleavage; by PCSK1

Site

97 – 98

2

Cleavage; by PCSK1

Site

130 – 131

2

Cleavage; by PCSK1

Site

145 – 146

2

Cleavage; by PCSK1

Amino acid modifications

Modified residue

127

1

Arginine amide Ref.8

Natural variations

Natural variant

115

1

A → V.
Corresponds to variant rs5650 [ dbSNP | Ensembl ].

VAR_014596

Experimental info

Sequence conflict

82

1

K → N in CAA27627. Ref.2

Secondary structure

1

.

.

.

.

.

.

.

.

.

.

.

.

180

Helix Strand Turn

Details...

Turn

59 – 62

4

Beta strand

76 – 78

3

Helix

104 – 124

21

Helix

150 – 153

4

Helix

154 – 156

3

Helix

157 – 172

16

Turn

173 – 177

5

Sequences

	Sequence		Length	Mass (Da)
	P01275 [UniParc]. Last modified February 6, 2007. Version 3. Checksum: 7A99EEC629B2862C	FASTA	180	20,909
	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

References

	« Hide 'large scale' referencesShow '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. , 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.

IPI

IPI00744153.

PIR

GCHU. A24377.

RefSeq

NP_002045.1. NM_002054.4.

UniGene

Hs.516494.

3D structure databases

PDBe
RCSB PDB
PDBj

Entry	Method	Resolution (Å)	Chain	Positions	PDBsum
1BH0	X-ray	3.00	A	53-81	[»]
1D0R	NMR	-	A	98-127	[»]
1NAU	NMR	-	A	59-81	[»]
2G49	X-ray	2.50	C/D	53-81	[»]
2L63	NMR	-	A	146-178	[»]
2L64	NMR	-	A	146-178	[»]
3IOL	X-ray	2.10	B	98-128	[»]

ProteinModelPortal

P01275.

ModBase

Search...

Protein-protein interaction databases

DIP

DIP-46470N.

STRING

9606.ENSP00000387662.

PTM databases

PhosphoSite

P01275.

Polymorphism databases

DMDM

125987831.

Proteomic databases

PaxDb

P01275.

PRIDE

P01275.

Protocols and materials databases

DNASU

2641.

StructuralBiologyKnowledgebase

Search...

Genome annotation databases

Ensembl

ENST00000375497; ENSP00000364647; ENSG00000115263.
ENST00000418842; ENSP00000387662; ENSG00000115263.

GeneID

2641.

KEGG

hsa:2641.

UCSC

uc002ucc.3. human.

Organism-specific databases

CTD

2641.

GeneCards

GC02M162963.

HGNC

HGNC:4191. GCG.

HPA

CAB000040.

MIM

138030. gene.

neXtProt

NX_P01275.

PharmGKB

PA28606.

GenAtlas

Search...

Phylogenomic databases

eggNOG

NOG42743.

HOGENOM

HOG000231876.

HOVERGEN

HBG003010.

KO

K05259.

OMA

RNKNNIA.

OrthoDB

EOG40K818.

Enzyme and pathway databases

Pathway_Interaction_DB

hnf3apathway. FOXA1 transcription factor network.

Reactome

REACT_111102. Signal Transduction.
REACT_111217. Metabolism.

Gene expression databases

Bgee

P01275.

CleanEx

HS_GCG.

Genevestigator

P01275.

GermOnline

ENSG00000115263. Homo sapiens.

Family and domain databases

InterPro

IPR015550. Glucagon-like.
IPR000532. Glucagon_GIP_secretin_VIP.
[Graphical view]

PANTHER

PTHR11418. PTHR11418. 1 hit.

Pfam

PF00123. Hormone_2. 3 hits.
[Graphical view]

PRINTS

PR00275. GLUCAGON.

SMART

SM00070. GLUCA. 3 hits.
[Graphical view]

PROSITE

PS00260. GLUCAGON. 4 hits.
[Graphical view]

ProtoNet

Search...

Other

BindingDB

P01275.

ChEMBL

CHEMBL5736.

ChiTaRS

GCG. human.

DrugBank

DB01276. Exenatide.
DB00692. Phentolamine.

EvolutionaryTrace

P01275.

GenomeRNAi

2641.

NextBio

10412.

PMAP-CutDB

P01275.

SOURCE

Search...

Entry information

Entry name

GLUC_HUMAN

Accession

Primary (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:	May 1, 2013
This is version 148 of the entry and version 3 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation program

Chordata Protein Annotation Program

Disclaimer

Any 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.