ID AGRP_HUMAN Reviewed; 132 AA. AC O00253; O15459; Q2TBD9; DT 01-NOV-1997, integrated into UniProtKB/Swiss-Prot. DT 01-JUL-1997, sequence version 1. DT 25-JAN-2012, entry version 109. DE RecName: Full=Agouti-related protein; DE Flags: Precursor; GN Name=AGRP; Synonyms=AGRT, ART; OS Homo sapiens (Human). OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; OC Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini; OC Catarrhini; Hominidae; Homo. OX NCBI_TaxID=9606; RN [1] RP NUCLEOTIDE SEQUENCE [MRNA]. RX MEDLINE=97230362; PubMed=9119224; RA Shutter J.R., Graham M., Kinsey A.C., Scully S., Luethy R., RA Stark K.L.; RT "Hypothalamic expression of ART, a novel gene related to agouti, is RT up-regulated in obese and diabetic mutant mice."; RL Genes Dev. 11:593-602(1997). RN [2] RP NUCLEOTIDE SEQUENCE [MRNA]. RC TISSUE=Adrenal gland; RX MEDLINE=97458244; PubMed=9311920; DOI=10.1126/science.278.5335.135; RA Ollmann M.M., Wilson B.D., Yang Y.K., Kerns J.A., Chen Y., Gantz I., RA Barsh G.S.; RT "Antagonism of central melanocortin receptors in vitro and in vivo by RT agouti-related protein."; RL Science 278:135-138(1997). RN [3] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA], AND VARIANT THR-67. RX MEDLINE=21488347; PubMed=11602360; DOI=10.1016/S0378-1119(01)00705-3; RA Brown A.M., Mayfield D.K., Volaufova J., Argyropoulos G.; RT "The gene structure and minimal promoter of the human agouti related RT protein."; RL Gene 277:231-238(2001). RN [4] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA]. RX PubMed=11326303; DOI=10.1038/sj.mp.4000854; RA Vink T., Hinney A., van Elburg A.A., van Goozen S.H., Sandkuijl L.A., RA Sinke R.J., Herpertz-Dahlmann B.M., Hebebrand J., Remschmidt H., RA van Engeland H., Adan R.A.; RT "Association between an agouti-related protein gene polymorphism and RT anorexia nervosa."; RL Mol. Psychiatry 6:325-328(2001). RN [5] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA]. RG SeattleSNPs variation discovery resource; RL Submitted (JAN-2006) to the EMBL/GenBank/DDBJ databases. RN [6] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA]. RX PubMed=15489334; DOI=10.1101/gr.2596504; RG The MGC Project Team; RT "The status, quality, and expansion of the NIH full-length cDNA RT project: the Mammalian Gene Collection (MGC)."; RL Genome Res. 14:2121-2127(2004). RN [7] RP DISULFIDE BONDS. RX MEDLINE=98393470; PubMed=9724530; DOI=10.1021/bi981082v; RA Bures E.J., Hui J.O., Young Y., Chow D.T., Katta V., Rohde M.F., RA Zeni L., Rosenfeld R.D., Stark K.L., Haniu M.; RT "Determination of disulfide structure in agouti-related protein (AGRP) RT by stepwise reduction and alkylation."; RL Biochemistry 37:12172-12177(1998). RN [8] RP FUNCTION, AND INTERACTION WITH MC3R; MC4R AND MC5R. RX PubMed=9892020; DOI=10.1210/me.13.1.148; RA Yang Y.K., Thompson D.A., Dickinson C.J., Wilken J., Barsh G.S., RA Kent S.B., Gantz I.; RT "Characterization of Agouti-related protein binding to melanocortin RT receptors."; RL Mol. Endocrinol. 13:148-155(1999). RN [9] RP STRUCTURE BY NMR OF 87-132, FUNCTION, CIRCULAR DICHROISM, DISULFIDE RP BONDS, AND MUTAGENESIS OF ARG-111. RX MEDLINE=99297561; PubMed=10371151; DOI=10.1016/S0014-5793(99)00553-0; RA Bolin K.A., Anderson D.J., Trulson J.A., Thompson D.A., Wilken J., RA Kent S.B.H., Gantz I., Millhauser G.L.; RT "NMR structure of a minimized human agouti related protein prepared by RT total chemical synthesis."; RL FEBS Lett. 451:125-131(1999). RN [10] RP STRUCTURE BY NMR OF 87-132, DOMAIN, AND DISULFIDE BONDS. RX PubMed=11747427; DOI=10.1021/bi0117192; RA McNulty J.C., Thompson D.A., Bolin K.A., Wilken J., Barsh G.S., RA Millhauser G.L.; RT "High-resolution NMR structure of the chemically-synthesized RT melanocortin receptor binding domain AGRP(87-132) of the agouti- RT related protein."; RL Biochemistry 40:15520-15527(2001). RN [11] RP STRUCTURE BY NMR OF 87-120. RX MEDLINE=22052396; PubMed=12056887; DOI=10.1021/bi012000x; RA Jackson P.J., McNulty J.C., Yang Y.K., Thompson D.A., Chai B., RA Gantz I., Barsh G.S., Millhauser G.L.; RT "Design, pharmacology, and NMR structure of a minimized cystine knot RT with agouti-related protein activity."; RL Biochemistry 41:7565-7572(2002). RN [12] RP VARIANT THR-67, AND POSSIBLE ASSOCIATION WITH OBESITY. RX MEDLINE=22202398; PubMed=12213871; DOI=10.1210/jc.2002-011834; RA Argyropoulos G., Rankinen T., Neufeld D.R., Rice T., Province M.A., RA Leon A.S., Skinner J.S., Wilmore J.H., Rao D.C., Bouchard C.; RT "A polymorphism in the human agouti-related protein is associated with RT late-onset obesity."; RL J. Clin. Endocrinol. Metab. 87:4198-4202(2002). RN [13] RP CHARACTERIZATION OF VARIANT THR-67, SUBCELLULAR LOCATION, AND RP FUNCTION. RX PubMed=15927146; DOI=10.1016/j.bcp.2005.04.033; RA de Rijke C.E., Jackson P.J., Garner K.M., van Rozen R.J., RA Douglas N.R., Kas M.J., Millhauser G.L., Adan R.A.; RT "Functional analysis of the Ala67Thr polymorphism in agouti related RT protein associated with anorexia nervosa and leanness."; RL Biochem. Pharmacol. 70:308-316(2005). CC -!- FUNCTION: Plays a role in weight homeostasis. Plays a role in the CC central control of feeding. Reduces food intake. Inhibits cAMP CC production mediated by stimulation of melanocortin receptors CC within the hypothalamus and adrenal gland. Acts primarily on MC3R CC and MC4R. Has very low activity with MC5R (By similarity). CC -!- SUBUNIT: Interacts with melanocortin receptors MC3R, MC4R and CC MC5R. CC -!- SUBCELLULAR LOCATION: Secreted. Golgi apparatus lumen. CC -!- TISSUE SPECIFICITY: Expressed primarily in the adrenal gland, CC subthalamic nucleus, and hypothalamus, with a lower level of CC expression occurring in testis, lung, and kidney. CC -!- DOMAIN: The presence of a 'disulfide through disulfide knot' CC structurally defines this protein as a knottin. CC -!- DISEASE: Genetic variations in AGRP may be a cause of obesity CC (OBESITY) [MIM:601665]. It is a condition characterized by an CC increase of body weight beyond the limitation of skeletal and CC physical requirements, as the result of excessive accumulation of CC body fat. CC -!- SIMILARITY: Contains 1 agouti domain. CC -!- WEB RESOURCE: Name=SeattleSNPs; CC URL="http://pga.gs.washington.edu/data/agrp/"; CC ----------------------------------------------------------------------- CC Copyrighted by the UniProt Consortium, see http://www.uniprot.org/terms CC Distributed under the Creative Commons Attribution-NoDerivs License CC ----------------------------------------------------------------------- DR EMBL; U88063; AAB52240.1; -; mRNA. DR EMBL; U89485; AAB68621.1; -; mRNA. DR EMBL; AF314194; AAL09457.1; -; Genomic_DNA. DR EMBL; AF281309; AAK96256.1; -; Genomic_DNA. DR EMBL; DQ374394; ABC88473.1; -; Genomic_DNA. DR EMBL; BC110443; AAI10444.1; -; mRNA. DR IPI; IPI00010869; -. DR RefSeq; NP_001129.1; NM_001138.1. DR UniGene; Hs.104633; -. DR PDB; 1HYK; NMR; -; A=87-132. DR PDB; 1MR0; NMR; -; A=87-120. DR PDB; 2IQV; Model; -; B=87-132. DR PDBsum; 1HYK; -. DR PDBsum; 1MR0; -. DR PDBsum; 2IQV; -. DR ProteinModelPortal; O00253; -. DR SMR; O00253; 87-132. DR STRING; O00253; -. DR PRIDE; O00253; -. DR Ensembl; ENST00000290953; ENSP00000290953; ENSG00000159723. DR Ensembl; ENST00000393941; ENSP00000377515; ENSG00000159723. DR GeneID; 181; -. DR KEGG; hsa:181; -. DR UCSC; uc002etg.1; human. DR CTD; 181; -. DR GeneCards; GC16M067516; -. DR H-InvDB; HIX0202329; -. DR HGNC; HGNC:330; AGRP. DR HPA; HPA041017; -. DR MIM; 601665; phenotype. DR MIM; 602311; gene. DR neXtProt; NX_O00253; -. DR eggNOG; prNOG20473; -. DR GeneTree; ENSGT00510000048590; -. DR HOGENOM; HBG126983; -. DR HOVERGEN; HBG050467; -. DR InParanoid; O00253; -. DR OMA; HESCLGH; -. DR OrthoDB; EOG4X3H2X; -. DR PhylomeDB; O00253; -. DR Pathway_Interaction_DB; syndecan_3_pathway; Syndecan-3-mediated signaling events. DR NextBio; 738; -. DR ArrayExpress; O00253; -. DR Bgee; O00253; -. DR CleanEx; HS_AGRP; -. DR Genevestigator; O00253; -. DR GermOnline; ENSG00000159723; Homo sapiens. DR GO; GO:0005615; C:extracellular space; IDA:UniProtKB. DR GO; GO:0005796; C:Golgi lumen; IDA:UniProtKB. DR GO; GO:0005184; F:neuropeptide hormone activity; IDA:UniProtKB. DR GO; GO:0009755; P:hormone-mediated signaling pathway; IEA:InterPro. DR GO; GO:0007218; P:neuropeptide signaling pathway; IDA:UniProtKB. DR GO; GO:0060259; P:regulation of feeding behavior; IDA:UniProtKB. DR InterPro; IPR007733; Agouti. DR Gene3D; G3DSA:4.10.760.10; Agouti; 1. DR KO; K05231; -. DR PANTHER; PTHR16551; Agouti; 1. DR Pfam; PF05039; Agouti; 1. DR SMART; SM00792; Agouti; 1. DR SUPFAM; SSF57055; Agouti; 1. DR PROSITE; PS60024; AGOUTI_1; 1. DR PROSITE; PS51150; AGOUTI_2; 1. PE 1: Evidence at protein level; KW 3D-structure; Complete proteome; Disease mutation; Disulfide bond; KW Golgi apparatus; Knottin; Obesity; Reference proteome; Secreted; KW Signal. FT SIGNAL 1 20 Potential. FT CHAIN 21 132 Agouti-related protein. FT /FTId=PRO_0000001034. FT DOMAIN 87 129 Agouti. FT REGION 111 113 Interaction with melanocortin receptors. FT DISULFID 87 102 FT DISULFID 94 108 FT DISULFID 101 119 FT DISULFID 105 129 FT DISULFID 110 117 FT VARIANT 67 67 A -> T (polymorphism that may play a role FT in obesity in an age-dependent manner; FT apparently no effect on activity; FT dbSNP:rs5030980). FT /FTId=VAR_015385. FT MUTAGEN 111 111 R->A: Abolishes inhibition of cAMP FT production in response to melanocortin FT receptor stimulation. FT CONFLICT 6 6 V -> L (in Ref. 2; AAB68621). FT STRAND 95 97 FT STRAND 101 103 FT STRAND 107 115 FT STRAND 117 120 FT STRAND 125 127 SQ SEQUENCE 132 AA; 14440 MW; 1CCBE112C3EB10F5 CRC64; MLTAAVLSCA LLLALPATRG AQMGLAPMEG IRRPDQALLP ELPGLGLRAP LKKTTAEQAE EDLLQEAQAL AEVLDLQDRE PRSSRRCVRL HESCLGQQVP CCDPCATCYC RFFNAFCYCR KLGTAMNPCS RT //