Reviewed, UniProtKB/Swiss-Prot P01275 (GLUC_HUMAN)

Names and origin

Protein names

Recommended name:
    Glucagon
Cleaved into the following 8 chains:
    1- Recommended name:
            Glicentin
    2- Recommended name:
            Glicentin-related polypeptide
                Short name=GRPP
    3- Recommended name:
            Oxyntomodulin
                Short name=OXY
                Short name=OXM
    4- Recommended name:
            Glucagon
    5- Recommended name:
            Glucagon-like peptide 1
                Short name=GLP-1
    6- Recommended name:
            Glucagon-like peptide 1(7-37)
                Short name=GLP-1(7-37)
    7- Recommended name:
            Glucagon-like peptide 1(7-36)
                Short name=GLP-1(7-36)
    8- Recommended name:
            Glucagon-like peptide 2
                Short name=GLP-2

Gene names

Name:

GCG

Organism

Homo sapiens (Human)

Taxonomic identifier

9606 [NCBI]

Taxonomic lineage

Eukaryota › Metazoa › Chordata › Craniata › Vertebrata › Euteleostomi › Mammalia › Eutheria › Euarchontoglires › Primates › Haplorrhini › Catarrhini › Hominidae › 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. 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 proliferaton. Inhibits beta cell apoptosis. 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. 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. 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.
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. GLP1 and GLP2 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.
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 Direct protein sequencing Pharmaceutical
Gene Ontology (GO)
Biological process	G-protein coupled receptor protein signaling pathway Traceable author statement. Source: ProtInc cell proliferation Traceable author statement. Source: ProtInc feeding behavior Traceable author statement. Source: ProtInc hormone-mediated signaling Ref.16 Inferred from Experiment. Source: Reactome
Cellular component	extracellular region Inferred from electronic annotation. Source: InterPro soluble fraction Traceable author statement. Source: ProtInc
Molecular function	hormone activity Inferred from electronic annotation. Source: InterPro
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

PRO_0000011254

Peptide

53 – 89

37

Oxyntomodulin By similarity

PRO_0000011255

Peptide

53 – 81

29

Glucagon

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)

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

Natural variations

Natural variant

115

1

A → V: dbSNP rs5650.

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

Helix

63 – 77

15

Turn

100 – 104

5

Helix

105 – 115

11

Helix

117 – 122

6

Turn

123 – 126

4

Sequences

	Sequence		Length	Mass (Da)
	P01275-1 [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: 2901414] [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: 3725587] [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: 6877358] [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: 15815621] [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: 15489334] [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: 11946536] [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: 2753890] [Abstract] Cited for: PROTEIN SEQUENCE OF 98-127.
[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: 8482423] [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: 14557443] [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: 14632334] [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: 9287128] [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: 12651102] [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: 14719035] [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: 12554744] [Abstract] Cited for: REVIEW.
[16]	"Glucagon and regulation of glucose metabolism." Jiang G., Zhang B.B. Am. J. Physiol. 284:E671-E678(2003) [PubMed: 12626323] [Abstract] Cited for: REVIEW.
[17]	"Glucagon-like peptide 2." Drucker D.J. Trends Endocrinol. Metab. 10:153-156(1999) [PubMed: 10322410] [Abstract] Cited for: REVIEW.
[18]	"The glucagon-like peptides." Kieffer T.J., Habener J.F. Endocr. Rev. 20:876-913(1999) [PubMed: 10605628] [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: 9667960] [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: 11943215] [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: 12627948] [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

EMBLGenBankDDBJ

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.

PIR

GCHU. A24377.

RefSeq

NP_002045.1.

UniGene

Hs.516494

3D structure databases

PDBMSD

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	[»]

ModBase

Search...

Genome annotation databases

Ensembl

ENSG00000115263. Homo sapiens. [Contig view]

GeneID

2641.

KEGG

hsa:2641.

Organism-specific databases

HGNC

HGNC:4191. GCG.

HPA

CAB000040.

MIM

138030. gene.

PharmGKB

PA28606.

GenAtlas

Search...

GeneCards

Search...

Phylogenomic databases

HOGENOM

P01275.

HOVERGEN

P01275.

Enzyme and pathway databases

Reactome

REACT_1505. Integration of energy metabolism.

Gene expression databases

ArrayExpress

P01275.

CleanEx

HS_GCG.

GermOnline

ENSG00000115263. Homo sapiens.

Family and domain databases

InterPro

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

PANTHER

PTHR11418. GLU. 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 Resources

DrugBank

DB01276. Exenatide.
DB00692. Phentolamine.

NextBio

10412.

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:	November 25, 2008
This is version 106 of the entry and version 3 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation project

HPI (Human Proteome Initiative)