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 16-OCT-2019, entry version 163. 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 PubMed=9119224; DOI=10.1101/gad.11.5.593; 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 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 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 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/mend.13.1.0223; 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 FUNCTION AS INVERSE AGONIST FOR MC3R AND MC4R. RX PubMed=11145747; DOI=10.1210/mend.15.1.0578; RA Nijenhuis W.A., Oosterom J., Adan R.A.; RT "AgRP(83-132) acts as an inverse agonist on the human-melanocortin-4 RT receptor."; RL Mol. Endocrinol. 15:164-171(2001). RN [10] RP IDENTIFICATION OF MATURE N-TERMINUS. RX PubMed=17185225; DOI=10.1016/j.chembiol.2006.10.006; RA Jackson P.J., Douglas N.R., Chai B., Binkley J., Sidow A., Barsh G.S., RA Millhauser G.L.; RT "Structural and molecular evolutionary analysis of Agouti and Agouti- RT related proteins."; RL Chem. Biol. 13:1297-1305(2006). RN [11] RP IDENTIFICATION OF MATURE N-TERMINUS, CLEAVAGE BY PCSK1, AND RP MUTAGENESIS OF 79-ARG--ARG-82; 85-ARG-ARG-86 AND 86-ARG--ARG-89. RX PubMed=16384863; DOI=10.1210/en.2005-1373; RA Creemers J.W., Pritchard L.E., Gyte A., Le Rouzic P., Meulemans S., RA Wardlaw S.L., Zhu X., Steiner D.F., Davies N., Armstrong D., RA Lawrence C.B., Luckman S.M., Schmitz C.A., Davies R.A., Brennand J.C., RA White A.; RT "Agouti-related protein is posttranslationally cleaved by proprotein RT convertase 1 to generate agouti-related protein (AGRP)83-132: RT interaction between AGRP83-132 and melanocortin receptors cannot be RT influenced by syndecan-3."; RL Endocrinology 147:1621-1631(2006). RN [12] RP FUNCTION IN MC3R AND MC4R ENDOCYTOSIS. RX PubMed=17041250; DOI=10.1074/jbc.m605982200; RA Breit A., Wolff K., Kalwa H., Jarry H., Buch T., Gudermann T.; RT "The natural inverse agonist agouti-related protein induces arrestin- RT mediated endocytosis of melanocortin-3 and -4 receptors."; RL J. Biol. Chem. 281:37447-37456(2006). RN [13] RP STRUCTURE BY NMR OF 87-132, FUNCTION, CIRCULAR DICHROISM, DISULFIDE RP BONDS, AND MUTAGENESIS OF ARG-111. RX 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 [14] 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 [15] RP STRUCTURE BY NMR OF 87-120. RX 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 [16] RP VARIANT THR-67, AND POSSIBLE ASSOCIATION WITH OBESITY. RX 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 [17] 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. Involved in the CC control of feeding behavior through the central melanocortin CC system. Acts as alpha melanocyte-stimulating hormone antagonist by CC inhibiting cAMP production mediated by stimulation of melanocortin CC receptors within the hypothalamus and adrenal gland. Has very low CC activity with MC5R (By similarity). Is an inverse agonist for MC3R CC and MC4R being able to suppress their constitutive activity. It CC promotes MC3R and MC4R endocytosis in an arrestin-dependent CC manner. {ECO:0000250, ECO:0000269|PubMed:10371151, CC ECO:0000269|PubMed:11145747, ECO:0000269|PubMed:15927146, CC ECO:0000269|PubMed:17041250, ECO:0000269|PubMed:9892020}. CC -!- SUBUNIT: Interacts with melanocortin receptors MC3R, MC4R and CC MC5R. {ECO:0000269|PubMed:9892020}. CC -!- SUBCELLULAR LOCATION: Secreted {ECO:0000269|PubMed:15927146}. CC Golgi apparatus lumen {ECO:0000269|PubMed:15927146}. 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 {ECO:0000269|PubMed:11747427}. CC -!- DISEASE: Obesity (OBESITY) [MIM:601665]: A condition characterized CC by an increase of body weight beyond the limitation of skeletal CC and physical requirements, as the result of excessive accumulation CC of body fat. Note=Disease susceptibility is associated with CC variations affecting the gene represented in this entry. CC -!- WEB RESOURCE: Name=SeattleSNPs; CC URL="http://pga.gs.washington.edu/data/agrp/"; CC ----------------------------------------------------------------------- CC Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms CC Distributed under the Creative Commons Attribution (CC BY 4.0) 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 CCDS; CCDS10839.1; -. DR RefSeq; NP_001129.1; NM_001138.1. 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 SMR; O00253; -. DR BioGrid; 106688; 9. DR IntAct; O00253; 8. DR STRING; 9606.ENSP00000290953; -. DR BioMuta; AGRP; -. DR MassIVE; O00253; -. DR PaxDb; O00253; -. DR PeptideAtlas; O00253; -. DR PRIDE; O00253; -. DR ProteomicsDB; 47806; -. DR Ensembl; ENST00000290953; ENSP00000290953; ENSG00000159723. DR GeneID; 181; -. DR KEGG; hsa:181; -. DR UCSC; uc002etg.1; human. DR CTD; 181; -. DR DisGeNET; 181; -. DR GeneCards; AGRP; -. DR HGNC; HGNC:330; AGRP. DR HPA; HPA041017; -. DR MalaCards; AGRP; -. DR MIM; 601665; phenotype. DR MIM; 602311; gene. DR neXtProt; NX_O00253; -. DR OpenTargets; ENSG00000159723; -. DR PharmGKB; PA24627; -. DR eggNOG; ENOG410J14P; Eukaryota. DR eggNOG; ENOG410Z66T; LUCA. DR GeneTree; ENSGT00940000154258; -. DR HOGENOM; HOG000033861; -. DR InParanoid; O00253; -. DR KO; K05231; -. DR OMA; TNPCSRT; -. DR OrthoDB; 1404700at2759; -. DR PhylomeDB; O00253; -. DR TreeFam; TF330729; -. DR Reactome; R-HSA-9615017; FOXO-mediated transcription of oxidative stress, metabolic and neuronal genes. DR SIGNOR; O00253; -. DR EvolutionaryTrace; O00253; -. DR GeneWiki; Agouti-related_peptide; -. DR GenomeRNAi; 181; -. DR Pharos; O00253; -. DR PRO; PR:O00253; -. DR Proteomes; UP000005640; Chromosome 16. DR Bgee; ENSG00000159723; Expressed in 66 organ(s), highest expression level in left adrenal gland. DR ExpressionAtlas; O00253; baseline and differential. DR Genevisible; O00253; HS. DR GO; GO:0005615; C:extracellular space; IDA:UniProtKB. DR GO; GO:0005796; C:Golgi lumen; IDA:UniProtKB. DR GO; GO:0043025; C:neuronal cell body; IEA:Ensembl. DR GO; GO:0005184; F:neuropeptide hormone activity; IDA:UniProtKB. DR GO; GO:0005102; F:signaling receptor binding; TAS:ProtInc. DR GO; GO:0008343; P:adult feeding behavior; IEA:Ensembl. DR GO; GO:0007623; P:circadian rhythm; IEA:Ensembl. DR GO; GO:0042755; P:eating behavior; IEA:Ensembl. DR GO; GO:0007631; P:feeding behavior; TAS:ProtInc. DR GO; GO:0009755; P:hormone-mediated signaling pathway; IEA:InterPro. DR GO; GO:0048571; P:long-day photoperiodism; IEA:Ensembl. DR GO; GO:0060135; P:maternal process involved in female pregnancy; IEA:Ensembl. DR GO; GO:0007218; P:neuropeptide signaling pathway; IDA:UniProtKB. DR GO; GO:2000253; P:positive regulation of feeding behavior; IEA:Ensembl. DR GO; GO:0060259; P:regulation of feeding behavior; IDA:UniProtKB. DR GO; GO:0032868; P:response to insulin; IEA:Ensembl. DR Gene3D; 4.10.760.10; -; 1. DR InterPro; IPR007733; Agouti. DR InterPro; IPR027300; Agouti_dom. DR InterPro; IPR036836; Agouti_dom_sf. DR PANTHER; PTHR16551; PTHR16551; 1. DR Pfam; PF05039; Agouti; 1. DR SMART; SM00792; Agouti; 1. DR SUPFAM; SSF57055; SSF57055; 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 {ECO:0000255}. FT PROPEP 21 82 {ECO:0000269|PubMed:16384863, FT ECO:0000269|PubMed:17185225}. FT /FTId=PRO_0000434044. FT CHAIN 83 132 Agouti-related protein. FT /FTId=PRO_0000001034. FT DOMAIN 87 129 Agouti. {ECO:0000255|PROSITE- FT ProRule:PRU00494}. FT REGION 111 113 Interaction with melanocortin receptors. FT SITE 82 83 Cleavage; by PCSK1. FT {ECO:0000269|PubMed:16384863}. FT DISULFID 87 102 {ECO:0000269|PubMed:10371151, FT ECO:0000269|PubMed:11747427, FT ECO:0000269|PubMed:9724530}. FT DISULFID 94 108 {ECO:0000269|PubMed:10371151, FT ECO:0000269|PubMed:11747427, FT ECO:0000269|PubMed:9724530}. FT DISULFID 101 119 {ECO:0000269|PubMed:10371151, FT ECO:0000269|PubMed:11747427, FT ECO:0000269|PubMed:9724530}. FT DISULFID 105 129 {ECO:0000269|PubMed:10371151, FT ECO:0000269|PubMed:11747427, FT ECO:0000269|PubMed:9724530}. FT DISULFID 110 117 {ECO:0000269|PubMed:10371151, FT ECO:0000269|PubMed:11747427, FT ECO:0000269|PubMed:9724530}. 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 {ECO:0000269|PubMed:11602360, FT ECO:0000269|PubMed:12213871, FT ECO:0000269|PubMed:15927146}. FT /FTId=VAR_015385. FT MUTAGEN 79 82 REPR->AEPA: Cleavage is blocked. FT {ECO:0000269|PubMed:16384863}. FT MUTAGEN 85 86 RR->AA: No effect on cleavage. FT {ECO:0000269|PubMed:16384863}. FT MUTAGEN 86 89 RCVR->ACVA: No effect on cleavage. FT {ECO:0000269|PubMed:16384863}. FT MUTAGEN 111 111 R->A: Abolishes inhibition of cAMP FT production in response to melanocortin FT receptor stimulation. FT {ECO:0000269|PubMed:10371151}. FT CONFLICT 6 6 V -> L (in Ref. 2; AAB68621). FT {ECO:0000305}. FT STRAND 95 97 {ECO:0000244|PDB:1HYK}. FT STRAND 101 103 {ECO:0000244|PDB:1HYK}. FT STRAND 107 115 {ECO:0000244|PDB:1HYK}. FT STRAND 117 120 {ECO:0000244|PDB:1HYK}. FT STRAND 125 127 {ECO:0000244|PDB:1HYK}. SQ SEQUENCE 132 AA; 14440 MW; 1CCBE112C3EB10F5 CRC64; MLTAAVLSCA LLLALPATRG AQMGLAPMEG IRRPDQALLP ELPGLGLRAP LKKTTAEQAE EDLLQEAQAL AEVLDLQDRE PRSSRRCVRL HESCLGQQVP CCDPCATCYC RFFNAFCYCR KLGTAMNPCS RT //