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   24-JAN-2024, entry version 184.
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; Mammalia;
OC   Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae;
OC   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., Stark K.L.;
RT   "Hypothalamic expression of ART, a novel gene related to agouti, is up-
RT   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 project:
RT   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., Zeni L.,
RA   Rosenfeld R.D., Stark K.L., Haniu M.;
RT   "Determination of disulfide structure in agouti-related protein (AGRP) by
RT   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., Kent S.B.,
RA   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 MUTAGENESIS OF
RP   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., Lawrence C.B.,
RA   Luckman S.M., Schmitz C.A., Davies R.A., Brennand J.C., White A.;
RT   "Agouti-related protein is posttranslationally cleaved by proprotein
RT   convertase 1 to generate agouti-related protein (AGRP)83-132: interaction
RT   between AGRP83-132 and melanocortin receptors cannot be influenced by
RT   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 BONDS,
RP   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 melanocortin
RT   receptor binding domain AGRP(87-132) of the agouti-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., Gantz I.,
RA   Barsh G.S., Millhauser G.L.;
RT   "Design, pharmacology, and NMR structure of a minimized cystine knot with
RT   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 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., Douglas N.R.,
RA   Kas M.J., Millhauser G.L., Adan R.A.;
RT   "Functional analysis of the Ala67Thr polymorphism in agouti related protein
RT   associated with anorexia nervosa and leanness.";
RL   Biochem. Pharmacol. 70:308-316(2005).
CC   -!- FUNCTION: Plays a role in weight homeostasis. Involved in the control
CC       of feeding behavior through the central melanocortin system. Acts as
CC       alpha melanocyte-stimulating hormone antagonist by inhibiting cAMP
CC       production mediated by stimulation of melanocortin receptors within the
CC       hypothalamus and adrenal gland. Has very low activity with MC5R (By
CC       similarity). Is an inverse agonist for MC3R and MC4R being able to
CC       suppress their constitutive activity. It promotes MC3R and MC4R
CC       endocytosis in an arrestin-dependent manner. {ECO:0000250,
CC       ECO:0000269|PubMed:10371151, ECO:0000269|PubMed:11145747,
CC       ECO:0000269|PubMed:15927146, ECO:0000269|PubMed:17041250,
CC       ECO:0000269|PubMed:9892020}.
CC   -!- SUBUNIT: Interacts with melanocortin receptors MC3R, MC4R and MC5R.
CC       {ECO:0000269|PubMed:9892020}.
CC   -!- SUBCELLULAR LOCATION: Secreted {ECO:0000269|PubMed:15927146}. Golgi
CC       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 expression
CC       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 by
CC       an increase of body weight beyond the limitation of skeletal and
CC       physical requirements, as the result of excessive accumulation of body
CC       fat. Note=Disease susceptibility is associated with variants affecting
CC       the gene represented in this entry.
CC   -!- WEB RESOURCE: Name=SeattleSNPs;
CC       URL="http://pga.gs.washington.edu/data/agrp/";
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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   PDBsum; 1HYK; -.
DR   PDBsum; 1MR0; -.
DR   AlphaFoldDB; O00253; -.
DR   SMR; O00253; -.
DR   BioGRID; 106688; 12.
DR   IntAct; O00253; 8.
DR   STRING; 9606.ENSP00000290953; -.
DR   BioMuta; AGRP; -.
DR   MassIVE; O00253; -.
DR   PaxDb; 9606-ENSP00000290953; -.
DR   PeptideAtlas; O00253; -.
DR   ProteomicsDB; 47806; -.
DR   Antibodypedia; 29554; 345 antibodies from 32 providers.
DR   DNASU; 181; -.
DR   Ensembl; ENST00000290953.3; ENSP00000290953.3; ENSG00000159723.5.
DR   GeneID; 181; -.
DR   KEGG; hsa:181; -.
DR   MANE-Select; ENST00000290953.3; ENSP00000290953.3; NM_001138.2; NP_001129.1.
DR   UCSC; uc002etg.1; human.
DR   AGR; HGNC:330; -.
DR   CTD; 181; -.
DR   DisGeNET; 181; -.
DR   GeneCards; AGRP; -.
DR   HGNC; HGNC:330; AGRP.
DR   HPA; ENSG00000159723; Group enriched (adrenal gland, brain, epididymis).
DR   MalaCards; AGRP; -.
DR   MIM; 601665; phenotype.
DR   MIM; 602311; gene.
DR   neXtProt; NX_O00253; -.
DR   OpenTargets; ENSG00000159723; -.
DR   PharmGKB; PA24627; -.
DR   VEuPathDB; HostDB:ENSG00000159723; -.
DR   eggNOG; ENOG502S7K0; Eukaryota.
DR   GeneTree; ENSGT00940000154258; -.
DR   HOGENOM; CLU_103790_0_0_1; -.
DR   InParanoid; O00253; -.
DR   OMA; SWAMLQG; -.
DR   OrthoDB; 4017051at2759; -.
DR   PhylomeDB; O00253; -.
DR   TreeFam; TF330729; -.
DR   PathwayCommons; O00253; -.
DR   Reactome; R-HSA-9615017; FOXO-mediated transcription of oxidative stress, metabolic and neuronal genes.
DR   SignaLink; O00253; -.
DR   SIGNOR; O00253; -.
DR   BioGRID-ORCS; 181; 14 hits in 1140 CRISPR screens.
DR   EvolutionaryTrace; O00253; -.
DR   GeneWiki; Agouti-related_peptide; -.
DR   GenomeRNAi; 181; -.
DR   Pharos; O00253; Tbio.
DR   PRO; PR:O00253; -.
DR   Proteomes; UP000005640; Chromosome 16.
DR   RNAct; O00253; Protein.
DR   Bgee; ENSG00000159723; Expressed in left adrenal gland and 116 other cell types or tissues.
DR   ExpressionAtlas; O00253; baseline and differential.
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:0070996; F:type 1 melanocortin receptor binding; IBA:GO_Central.
DR   GO; GO:0008343; P:adult feeding behavior; IBA:GO_Central.
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; IBA:GO_Central.
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; Agouti domain; 1.
DR   InterPro; IPR007733; Agouti.
DR   InterPro; IPR027300; Agouti_dom.
DR   InterPro; IPR036836; Agouti_dom_sf.
DR   PANTHER; PTHR16551; AGOUTI RELATED; 1.
DR   PANTHER; PTHR16551:SF4; AGOUTI-RELATED PROTEIN; 1.
DR   Pfam; PF05039; Agouti; 1.
DR   SMART; SM00792; Agouti; 1.
DR   SUPFAM; SSF57055; Agouti-related protein; 1.
DR   PROSITE; PS60024; AGOUTI_1; 1.
DR   PROSITE; PS51150; AGOUTI_2; 1.
DR   Genevisible; O00253; HS.
PE   1: Evidence at protein level;
KW   3D-structure; Disease variant; Disulfide bond; Golgi apparatus; Knottin;
KW   Obesity; Reference proteome; Secreted; Signal.
FT   SIGNAL          1..20
FT                   /evidence="ECO:0000255"
FT   PROPEP          21..82
FT                   /evidence="ECO:0000269|PubMed:16384863,
FT                   ECO:0000269|PubMed:17185225"
FT                   /id="PRO_0000434044"
FT   CHAIN           83..132
FT                   /note="Agouti-related protein"
FT                   /id="PRO_0000001034"
FT   DOMAIN          87..129
FT                   /note="Agouti"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00494"
FT   REGION          111..113
FT                   /note="Interaction with melanocortin receptors"
FT   SITE            82..83
FT                   /note="Cleavage; by PCSK1"
FT                   /evidence="ECO:0000269|PubMed:16384863"
FT   DISULFID        87..102
FT                   /evidence="ECO:0000269|PubMed:10371151,
FT                   ECO:0000269|PubMed:11747427, ECO:0000269|PubMed:9724530"
FT   DISULFID        94..108
FT                   /evidence="ECO:0000269|PubMed:10371151,
FT                   ECO:0000269|PubMed:11747427, ECO:0000269|PubMed:9724530"
FT   DISULFID        101..119
FT                   /evidence="ECO:0000269|PubMed:10371151,
FT                   ECO:0000269|PubMed:11747427, ECO:0000269|PubMed:9724530"
FT   DISULFID        105..129
FT                   /evidence="ECO:0000269|PubMed:10371151,
FT                   ECO:0000269|PubMed:11747427, ECO:0000269|PubMed:9724530"
FT   DISULFID        110..117
FT                   /evidence="ECO:0000269|PubMed:10371151,
FT                   ECO:0000269|PubMed:11747427, ECO:0000269|PubMed:9724530"
FT   VARIANT         67
FT                   /note="A -> T (may play a role in obesity in an
FT                   age-dependent manner; apparently no effect on activity;
FT                   dbSNP:rs5030980)"
FT                   /evidence="ECO:0000269|PubMed:11602360,
FT                   ECO:0000269|PubMed:12213871, ECO:0000269|PubMed:15927146"
FT                   /id="VAR_015385"
FT   MUTAGEN         79..82
FT                   /note="REPR->AEPA: Cleavage is blocked."
FT                   /evidence="ECO:0000269|PubMed:16384863"
FT   MUTAGEN         85..86
FT                   /note="RR->AA: No effect on cleavage."
FT                   /evidence="ECO:0000269|PubMed:16384863"
FT   MUTAGEN         86..89
FT                   /note="RCVR->ACVA: No effect on cleavage."
FT                   /evidence="ECO:0000269|PubMed:16384863"
FT   MUTAGEN         111
FT                   /note="R->A: Abolishes inhibition of cAMP production in
FT                   response to melanocortin receptor stimulation."
FT                   /evidence="ECO:0000269|PubMed:10371151"
FT   CONFLICT        6
FT                   /note="V -> L (in Ref. 2; AAB68621)"
FT                   /evidence="ECO:0000305"
FT   STRAND          95..97
FT                   /evidence="ECO:0007829|PDB:1HYK"
FT   STRAND          101..103
FT                   /evidence="ECO:0007829|PDB:1HYK"
FT   STRAND          107..115
FT                   /evidence="ECO:0007829|PDB:1HYK"
FT   STRAND          117..120
FT                   /evidence="ECO:0007829|PDB:1HYK"
FT   STRAND          125..127
FT                   /evidence="ECO:0007829|PDB:1HYK"
SQ   SEQUENCE   132 AA;  14440 MW;  1CCBE112C3EB10F5 CRC64;
     MLTAAVLSCA LLLALPATRG AQMGLAPMEG IRRPDQALLP ELPGLGLRAP LKKTTAEQAE
     EDLLQEAQAL AEVLDLQDRE PRSSRRCVRL HESCLGQQVP CCDPCATCYC RFFNAFCYCR
     KLGTAMNPCS RT
//