O00253 (AGRP_HUMAN) Reviewed, UniProtKB/Swiss-Prot

Names and origin

Protein names

Recommended name:
Agouti-related protein

Gene names

Name:	AGRP
Synonyms:	AGRT, ART

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	132 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	Plays a role in weight homeostasis. Involved in the control of feeding behavior through the central melanocortin system. Acts as alpha melanocyte-stimulating hormone antagonist by inhibiting cAMP production mediated by stimulation of melanocortin receptors within the hypothalamus and adrenal gland. Has very low activity with MC5R By similarity. Is an inverse agonist for MC3R and MC4R being able to suppress their constitutive activity. It promotes MC3R and MC4R endocytosis in an arrestin-dependent manner. Ref.8 Ref.9 Ref.10 Ref.11 Ref.15
Subunit structure	Interacts with melanocortin receptors MC3R, MC4R and MC5R. Ref.8
Subcellular location	Secreted. Golgi apparatus lumen Ref.15.
Tissue specificity	Expressed primarily in the adrenal gland, subthalamic nucleus, and hypothalamus, with a lower level of expression occurring in testis, lung, and kidney.
Domain	The presence of a 'disulfide through disulfide knot' structurally defines this protein as a knottin. Ref.12
Involvement in disease	Obesity (OBESITY) [MIM:601665]: A condition characterized by an increase of body weight beyond the limitation of skeletal and physical requirements, as the result of excessive accumulation of body fat. Note: Disease susceptibility is associated with variations affecting the gene represented in this entry. Ref.14
Sequence similarities	Contains 1 agouti domain.

Ontologies

Keywords
Cellular component	Golgi apparatus Secreted
Disease	Disease mutation Obesity
Domain	Knottin Signal
PTM	Disulfide bond
Technical term	3D-structure Complete proteome Reference proteome
Gene Ontology (GO)
Biological_process	adult feeding behavior Inferred from electronic annotation. Source: Compara feeding behavior Traceable author statement PubMed 9751529. Source: ProtInc hormone-mediated signaling pathway Inferred from electronic annotation. Source: InterPro neuropeptide signaling pathway Inferred from direct assay Ref.15. Source: UniProtKB regulation of feeding behavior Inferred from direct assay Ref.15. Source: UniProtKB
Cellular_component	Golgi lumen Inferred from direct assay Ref.15. Source: UniProtKB extracellular space Inferred from direct assay Ref.15. Source: UniProtKB
Molecular_function	neuropeptide hormone activity Inferred from direct assay Ref.15. Source: UniProtKB
Complete GO annotation...

Sequence annotation (Features)

Feature key

Position(s)

Length

Description

Graphical view

Feature identifier

Molecule processing

Signal peptide

1 – 20

20

Potential

Chain

21 – 132

112

Agouti-related protein

PRO_0000001034

Regions

Domain

87 – 129

43

Agouti

Region

111 – 113

3

Interaction with melanocortin receptors

Amino acid modifications

Disulfide bond

87 ↔ 102

Ref.7 Ref.11 Ref.12

Disulfide bond

94 ↔ 108

Ref.7 Ref.11 Ref.12

Disulfide bond

101 ↔ 119

Ref.7 Ref.11 Ref.12

Disulfide bond

105 ↔ 129

Ref.7 Ref.11 Ref.12

Disulfide bond

110 ↔ 117

Ref.7 Ref.11 Ref.12

Natural variations

Natural variant

67

1

A → T Polymorphism that may play a role in obesity in an age-dependent manner; apparently no effect on activity. Ref.3 Ref.14 Ref.15
Corresponds to variant rs5030980 [ dbSNP | Ensembl ].

VAR_015385

Experimental info

Mutagenesis

111

1

R → A: Abolishes inhibition of cAMP production in response to melanocortin receptor stimulation. Ref.11

Sequence conflict

6

1

V → L in AAB68621. Ref.2

Secondary structure

1

.

.

.

.

.

.

.

.

.

.

.

132

Helix Strand Turn

Details...

Beta strand

95 – 97

3

Beta strand

101 – 103

3

Beta strand

107 – 115

9

Beta strand

117 – 120

4

Beta strand

125 – 127

3

Sequences

	Sequence		Length	Mass (Da)
	O00253 [UniParc]. Last modified July 1, 1997. Version 1. Checksum: 1CCBE112C3EB10F5	FASTA	132	14,440
	10 20 30 40 50 60 MLTAAVLSCA LLLALPATRG AQMGLAPMEG IRRPDQALLP ELPGLGLRAP LKKTTAEQAE 70 80 90 100 110 120 EDLLQEAQAL AEVLDLQDRE PRSSRRCVRL HESCLGQQVP CCDPCATCYC RFFNAFCYCR 130 KLGTAMNPCS RT

References

	« Hide 'large scale' referencesShow 'large scale' references »
[1]	"Hypothalamic expression of ART, a novel gene related to agouti, is up-regulated in obese and diabetic mutant mice." Shutter J.R., Graham M., Kinsey A.C., Scully S., Luethy R., Stark K.L. Genes Dev. 11:593-602(1997) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA].
[2]	"Antagonism of central melanocortin receptors in vitro and in vivo by agouti-related protein." Ollmann M.M., Wilson B.D., Yang Y.K., Kerns J.A., Chen Y., Gantz I., Barsh G.S. Science 278:135-138(1997) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA]. Tissue: Adrenal gland.
[3]	"The gene structure and minimal promoter of the human agouti related protein." Brown A.M., Mayfield D.K., Volaufova J., Argyropoulos G. Gene 277:231-238(2001) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA], VARIANT THR-67.
[4]	"Association between an agouti-related protein gene polymorphism and anorexia nervosa." Vink T., Hinney A., van Elburg A.A., van Goozen S.H., Sandkuijl L.A., Sinke R.J., Herpertz-Dahlmann B.M., Hebebrand J., Remschmidt H., van Engeland H., Adan R.A. Mol. Psychiatry 6:325-328(2001) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA].
[5]	SeattleSNPs variation discovery resource Submitted (JAN-2006) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [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].
[7]	"Determination of disulfide structure in agouti-related protein (AGRP) by stepwise reduction and alkylation." Bures E.J., Hui J.O., Young Y., Chow D.T., Katta V., Rohde M.F., Zeni L., Rosenfeld R.D., Stark K.L., Haniu M. Biochemistry 37:12172-12177(1998) [PubMed] [Europe PMC] [Abstract] Cited for: DISULFIDE BONDS.
[8]	"Characterization of Agouti-related protein binding to melanocortin receptors." Yang Y.K., Thompson D.A., Dickinson C.J., Wilken J., Barsh G.S., Kent S.B., Gantz I. Mol. Endocrinol. 13:148-155(1999) [PubMed] [Europe PMC] [Abstract] Cited for: FUNCTION, INTERACTION WITH MC3R; MC4R AND MC5R.
[9]	"AgRP(83-132) acts as an inverse agonist on the human-melanocortin-4 receptor." Nijenhuis W.A., Oosterom J., Adan R.A. Mol. Endocrinol. 15:164-171(2001) [PubMed] [Europe PMC] [Abstract] Cited for: FUNCTION AS INVERSE AGONIST FOR MC3R AND MC4R.
[10]	"The natural inverse agonist agouti-related protein induces arrestin-mediated endocytosis of melanocortin-3 and -4 receptors." Breit A., Wolff K., Kalwa H., Jarry H., Buch T., Gudermann T. J. Biol. Chem. 281:37447-37456(2006) [PubMed] [Europe PMC] [Abstract] Cited for: FUNCTION IN MC3R AND MC4R ENDOCYTOSIS.
[11]	"NMR structure of a minimized human agouti related protein prepared by total chemical synthesis." Bolin K.A., Anderson D.J., Trulson J.A., Thompson D.A., Wilken J., Kent S.B.H., Gantz I., Millhauser G.L. FEBS Lett. 451:125-131(1999) [PubMed] [Europe PMC] [Abstract] Cited for: STRUCTURE BY NMR OF 87-132, FUNCTION, CIRCULAR DICHROISM, DISULFIDE BONDS, MUTAGENESIS OF ARG-111.
[12]	"High-resolution NMR structure of the chemically-synthesized melanocortin receptor binding domain AGRP(87-132) of the agouti-related protein." McNulty J.C., Thompson D.A., Bolin K.A., Wilken J., Barsh G.S., Millhauser G.L. Biochemistry 40:15520-15527(2001) [PubMed] [Europe PMC] [Abstract] Cited for: STRUCTURE BY NMR OF 87-132, DOMAIN, DISULFIDE BONDS.
[13]	"Design, pharmacology, and NMR structure of a minimized cystine knot with agouti-related protein activity." Jackson P.J., McNulty J.C., Yang Y.K., Thompson D.A., Chai B., Gantz I., Barsh G.S., Millhauser G.L. Biochemistry 41:7565-7572(2002) [PubMed] [Europe PMC] [Abstract] Cited for: STRUCTURE BY NMR OF 87-120.
[14]	"A polymorphism in the human agouti-related protein is associated with late-onset obesity." Argyropoulos G., Rankinen T., Neufeld D.R., Rice T., Province M.A., Leon A.S., Skinner J.S., Wilmore J.H., Rao D.C., Bouchard C. J. Clin. Endocrinol. Metab. 87:4198-4202(2002) [PubMed] [Europe PMC] [Abstract] Cited for: VARIANT THR-67, POSSIBLE ASSOCIATION WITH OBESITY.
[15]	"Functional analysis of the Ala67Thr polymorphism in agouti related protein associated with anorexia nervosa and leanness." de Rijke C.E., Jackson P.J., Garner K.M., van Rozen R.J., Douglas N.R., Kas M.J., Millhauser G.L., Adan R.A. Biochem. Pharmacol. 70:308-316(2005) [PubMed] [Europe PMC] [Abstract] Cited for: CHARACTERIZATION OF VARIANT THR-67, SUBCELLULAR LOCATION, FUNCTION.
+	Additional computationally mapped references.

Web resources

SeattleSNPs

Cross-references

Sequence databases

EMBL
GenBank
DDBJ

U88063 mRNA. Translation: AAB52240.1.
U89485 mRNA. Translation: AAB68621.1.
AF314194 Genomic DNA. Translation: AAL09457.1.
AF281309 Genomic DNA. Translation: AAK96256.1.
DQ374394 Genomic DNA. Translation: ABC88473.1.
BC110443 mRNA. Translation: AAI10444.1.

IPI

IPI00010869.

RefSeq

NP_001129.1. NM_001138.1.

UniGene

Hs.104633.

3D structure databases

PDBe
RCSB PDB
PDBj

Entry	Method	Resolution (Å)	Chain	Positions	PDBsum
1HYK	NMR	-	A	87-132	[»]
1MR0	NMR	-	A	87-120	[»]
2IQV	model	-	B	87-132	[»]

ProteinModelPortal

O00253.

ModBase

Search...

Protein-protein interaction databases

STRING

9606.ENSP00000290953.

Proteomic databases

PaxDb

O00253.

PRIDE

O00253.

Protocols and materials databases

StructuralBiologyKnowledgebase

Search...

Genome annotation databases

Ensembl

ENST00000290953; ENSP00000290953; ENSG00000159723.

GeneID

181.

KEGG

hsa:181.

UCSC

uc002etg.1. human.

Organism-specific databases

CTD

181.

GeneCards

GC16M067516.

HGNC

HGNC:330. AGRP.

HPA

HPA041017.

MIM

601665. phenotype.
602311. gene.

neXtProt

NX_O00253.

PharmGKB

PA24627.

GenAtlas

Search...

Phylogenomic databases

eggNOG

NOG44906.

HOGENOM

HOG000033861.

HOVERGEN

HBG050467.

InParanoid

O00253.

KO

K05231.

OMA

QMGLAPL.

OrthoDB

EOG4X3H2X.

PhylomeDB

O00253.

Enzyme and pathway databases

Pathway_Interaction_DB

syndecan_3_pathway. Syndecan-3-mediated signaling events.

Gene expression databases

ArrayExpress

O00253.

Bgee

O00253.

CleanEx

HS_AGRP.

Genevestigator

O00253.

GermOnline

ENSG00000159723. Homo sapiens.

Family and domain databases

Gene3D

4.10.760.10. 1 hit.

InterPro

IPR007733. Agouti.
IPR027300. Agouti_dom.
[Graphical view]

PANTHER

PTHR16551. PTHR16551. 1 hit.

Pfam

PF05039. Agouti. 1 hit.
[Graphical view]

SMART

SM00792. Agouti. 1 hit.
[Graphical view]

SUPFAM

SSF57055. Agouti. 1 hit.

PROSITE

PS60024. AGOUTI_1. 1 hit.
PS51150. AGOUTI_2. 1 hit.
[Graphical view]

ProtoNet

Search...

Other

EvolutionaryTrace

O00253.

GenomeRNAi

181.

NextBio

738.

SOURCE

Search...

Entry information

Entry name

AGRP_HUMAN

Accession

Primary (citable) accession number: O00253
Secondary accession number(s): O15459, Q2TBD9

Entry history

Integrated into UniProtKB/Swiss-Prot:	November 1, 1997
Last sequence update:	July 1, 1997
Last modified:	May 1, 2013
This is version 122 of the entry and version 1 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.