ID ASIP_HUMAN Reviewed; 132 AA. AC P42127; Q3SXL2; DT 01-NOV-1995, integrated into UniProtKB/Swiss-Prot. DT 01-NOV-1995, sequence version 1. DT 24-JAN-2024, entry version 185. DE RecName: Full=Agouti-signaling protein; DE Short=ASP; DE AltName: Full=Agouti switch protein; DE Flags: Precursor; GN Name=ASIP; Synonyms=AGTI, AGTIL, ASP; 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 [GENOMIC DNA], AND TISSUE SPECIFICITY. RX PubMed=7937887; DOI=10.1073/pnas.91.21.9760; RA Kwon H.-Y., Bultman S.J., Loeffler C., Chen W.-J., Furdon P.J., RA Powell J.G., Usala A.-L., Wilkison W., Hansmann I., Woychik R.P.; RT "Molecular structure and chromosomal mapping of the human homolog of the RT agouti gene."; RL Proc. Natl. Acad. Sci. U.S.A. 91:9760-9764(1994). RN [2] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA], AND TISSUE SPECIFICITY. RX PubMed=7757071; DOI=10.1093/hmg/4.2.223; RA Wilson B.D., Ollmann M.M., Kang L., Stoffel M., Bell G.I., Barsh G.S.; RT "Structure and function of ASP, the human homolog of the mouse agouti RT gene."; RL Hum. Mol. Genet. 4:223-230(1995). RN [3] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RX PubMed=11780052; DOI=10.1038/414865a; RA Deloukas P., Matthews L.H., Ashurst J.L., Burton J., Gilbert J.G.R., RA Jones M., Stavrides G., Almeida J.P., Babbage A.K., Bagguley C.L., RA Bailey J., Barlow K.F., Bates K.N., Beard L.M., Beare D.M., Beasley O.P., RA Bird C.P., Blakey S.E., Bridgeman A.M., Brown A.J., Buck D., Burrill W.D., RA Butler A.P., Carder C., Carter N.P., Chapman J.C., Clamp M., Clark G., RA Clark L.N., Clark S.Y., Clee C.M., Clegg S., Cobley V.E., Collier R.E., RA Connor R.E., Corby N.R., Coulson A., Coville G.J., Deadman R., Dhami P.D., RA Dunn M., Ellington A.G., Frankland J.A., Fraser A., French L., Garner P., RA Grafham D.V., Griffiths C., Griffiths M.N.D., Gwilliam R., Hall R.E., RA Hammond S., Harley J.L., Heath P.D., Ho S., Holden J.L., Howden P.J., RA Huckle E., Hunt A.R., Hunt S.E., Jekosch K., Johnson C.M., Johnson D., RA Kay M.P., Kimberley A.M., King A., Knights A., Laird G.K., Lawlor S., RA Lehvaeslaiho M.H., Leversha M.A., Lloyd C., Lloyd D.M., Lovell J.D., RA Marsh V.L., Martin S.L., McConnachie L.J., McLay K., McMurray A.A., RA Milne S.A., Mistry D., Moore M.J.F., Mullikin J.C., Nickerson T., RA Oliver K., Parker A., Patel R., Pearce T.A.V., Peck A.I., RA Phillimore B.J.C.T., Prathalingam S.R., Plumb R.W., Ramsay H., Rice C.M., RA Ross M.T., Scott C.E., Sehra H.K., Shownkeen R., Sims S., Skuce C.D., RA Smith M.L., Soderlund C., Steward C.A., Sulston J.E., Swann R.M., RA Sycamore N., Taylor R., Tee L., Thomas D.W., Thorpe A., Tracey A., RA Tromans A.C., Vaudin M., Wall M., Wallis J.M., Whitehead S.L., RA Whittaker P., Willey D.L., Williams L., Williams S.A., Wilming L., RA Wray P.W., Hubbard T., Durbin R.M., Bentley D.R., Beck S., Rogers J.; RT "The DNA sequence and comparative analysis of human chromosome 20."; RL Nature 414:865-871(2001). RN [4] 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 [5] RP STRUCTURE BY NMR OF 80-132, AND DISULFIDE BONDS. RX PubMed=15701517; DOI=10.1016/j.jmb.2004.12.030; RA McNulty J.C., Jackson P.J., Thompson D.A., Chai B., Gantz I., Barsh G.S., RA Dawson P.E., Millhauser G.L.; RT "Structures of the agouti signaling protein."; RL J. Mol. Biol. 346:1059-1070(2005). RN [6] RP INVOLVEMENT IN SHEP9. RX PubMed=11833005; DOI=10.1086/339076; RA Kanetsky P.A., Swoyer J., Panossian S., Holmes R., Guerry D., Rebbeck T.R.; RT "A polymorphism in the agouti signaling protein gene is associated with RT human pigmentation."; RL Am. J. Hum. Genet. 70:770-775(2002). RN [7] RP INVOLVEMENT IN OBHP, SUBCELLULAR LOCATION, AND TISSUE SPECIFICITY. RX PubMed=36536132; DOI=10.1038/s42255-022-00703-9; RA Kempf E., Landgraf K., Stein R., Hanschkow M., Hilbert A., Abou Jamra R., RA Boczki P., Herberth G., Kuehnapfel A., Tseng Y.H., Staeubert C., RA Schoeneberg T., Kuehnen P., Rayner N.W., Zeggini E., Kiess W., Blueher M., RA Koerner A.; RT "Aberrant expression of agouti signaling protein (ASIP) as a cause of RT monogenic severe childhood obesity."; RL Nat. Metab. 4:1697-1712(2022). CC -!- FUNCTION: Involved in the regulation of melanogenesis. The binding of CC ASP to MC1R precludes alpha-MSH initiated signaling and thus blocks CC production of cAMP, leading to a down-regulation of eumelanogenesis CC (brown/black pigment) and thus increasing synthesis of pheomelanin CC (yellow/red pigment). In higher primates, agouti may affect the quality CC of hair pigmentation rather than its pattern of deposition. Could well CC play a role in neuroendocrine aspects of melanocortin action. May have CC some functional role in regulating the lipid metabolism with CC adipocytes. {ECO:0000250|UniProtKB:Q03288}. CC -!- SUBCELLULAR LOCATION: Secreted {ECO:0000269|PubMed:36536132}. CC -!- TISSUE SPECIFICITY: Widely expressed at low levels. Highly expressed in CC the skin. Expressed in adipose tissue. {ECO:0000269|PubMed:36536132, CC ECO:0000269|PubMed:7757071, ECO:0000269|PubMed:7937887}. CC -!- DOMAIN: The presence of a 'disulfide through disulfide knot' CC structurally defines this protein as a knottin. CC -!- POLYMORPHISM: Genetic variants in ASIP define the skin/hair/eye CC pigmentation variation locus 9 (SHEP9) [MIM:611742]. Hair, eye and skin CC pigmentation are among the most visible examples of human phenotypic CC variation, with a broad normal range that is subject to substantial CC geographic stratification. In the case of skin, individuals tend to CC have lighter pigmentation with increasing distance from the equator. By CC contrast, the majority of variation in human eye and hair color is CC found among individuals of European ancestry, with most other human CC populations fixed for brown eyes and black hair. CC {ECO:0000269|PubMed:11833005}. CC -!- DISEASE: Obesity and hypopigmentation (OBHP) [MIM:620195]: An autosomal CC dominant disorder characterized by early-onset obesity, overgrowth, CC hyperinsulinemia, and hypopigmentation of the skin. Some affected CC individuals experience hyperphagia and exhibit reduced energy CC expenditure. {ECO:0000269|PubMed:36536132}. Note=The gene represented CC in this entry is involved in disease pathogenesis. A tandem duplication CC on chromosome 20 encompassing the neighboring genes ASIP and ITCH CC creates an ITCH-ASIP transcript consisting of the first two non-coding CC ITCH exons fused to the ASIP coding exons. This results in ASIP ectopic CC overexpression controlled by the ubiquitously active ITCH promoter. CC Ectopically expressed ASIP may antagonize MC4R signaling in the CC hypothalamus and may affect processes related to eating behavior and CC energy expenditure. {ECO:0000269|PubMed:36536132}. 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; U12775; AAB61247.1; -; Genomic_DNA. DR EMBL; U12770; AAB61247.1; JOINED; Genomic_DNA. DR EMBL; U12774; AAB61247.1; JOINED; Genomic_DNA. DR EMBL; L37019; AAA89208.1; -; Genomic_DNA. DR EMBL; AL035458; -; NOT_ANNOTATED_CDS; Genomic_DNA. DR EMBL; BC104238; AAI04239.1; -; mRNA. DR EMBL; BC104239; AAI04240.1; -; mRNA. DR CCDS; CCDS13232.1; -. DR PIR; I37143; I37143. DR RefSeq; NP_001663.2; NM_001672.2. DR RefSeq; XP_011527122.1; XM_011528820.2. DR RefSeq; XP_011527123.1; XM_011528821.1. DR PDB; 1Y7J; NMR; -; A=80-132. DR PDB; 1Y7K; NMR; -; A=80-132. DR PDB; 2KZA; NMR; -; A=80-132. DR PDB; 2L1J; NMR; -; A=93-126. DR PDBsum; 1Y7J; -. DR PDBsum; 1Y7K; -. DR PDBsum; 2KZA; -. DR PDBsum; 2L1J; -. DR AlphaFoldDB; P42127; -. DR SMR; P42127; -. DR BioGRID; 106926; 19. DR STRING; 9606.ENSP00000454804; -. DR GlyCosmos; P42127; 1 site, No reported glycans. DR GlyGen; P42127; 1 site. DR iPTMnet; P42127; -. DR PhosphoSitePlus; P42127; -. DR BioMuta; ASIP; -. DR DMDM; 1168389; -. DR MassIVE; P42127; -. DR PaxDb; 9606-ENSP00000454804; -. DR PeptideAtlas; P42127; -. DR ProteomicsDB; 55487; -. DR Antibodypedia; 25783; 92 antibodies from 15 providers. DR DNASU; 434; -. DR Ensembl; ENST00000374954.4; ENSP00000364092.3; ENSG00000101440.10. DR Ensembl; ENST00000568305.5; ENSP00000454804.1; ENSG00000101440.10. DR GeneID; 434; -. DR KEGG; hsa:434; -. DR MANE-Select; ENST00000374954.4; ENSP00000364092.3; NM_001672.3; NP_001663.2. DR UCSC; uc002xah.2; human. DR AGR; HGNC:745; -. DR CTD; 434; -. DR DisGeNET; 434; -. DR GeneCards; ASIP; -. DR HGNC; HGNC:745; ASIP. DR HPA; ENSG00000101440; Group enriched (epididymis, heart muscle, ovary). DR MalaCards; ASIP; -. DR MIM; 600201; gene. DR MIM; 611742; phenotype. DR MIM; 620195; phenotype. DR neXtProt; NX_P42127; -. DR OpenTargets; ENSG00000101440; -. DR PharmGKB; PA25045; -. DR VEuPathDB; HostDB:ENSG00000101440; -. DR eggNOG; ENOG502S5XF; Eukaryota. DR GeneTree; ENSGT00940000154258; -. DR HOGENOM; CLU_138633_0_0_1; -. DR InParanoid; P42127; -. DR OMA; CHCRFFR; -. DR PhylomeDB; P42127; -. DR TreeFam; TF330729; -. DR PathwayCommons; P42127; -. DR SignaLink; P42127; -. DR SIGNOR; P42127; -. DR BioGRID-ORCS; 434; 17 hits in 1144 CRISPR screens. DR ChiTaRS; ASIP; human. DR EvolutionaryTrace; P42127; -. DR GenomeRNAi; 434; -. DR Pharos; P42127; Tbio. DR PRO; PR:P42127; -. DR Proteomes; UP000005640; Chromosome 20. DR RNAct; P42127; Protein. DR Bgee; ENSG00000101440; Expressed in apex of heart and 97 other cell types or tissues. DR GO; GO:0005615; C:extracellular space; IDA:UniProtKB. DR GO; GO:0031779; F:melanocortin receptor binding; IBA:GO_Central. DR GO; GO:0005184; F:neuropeptide hormone activity; IBA:GO_Central. DR GO; GO:0005102; F:signaling receptor binding; TAS:ProtInc. DR GO; GO:0031781; F:type 3 melanocortin receptor binding; IEA:Ensembl. DR GO; GO:0031782; F:type 4 melanocortin receptor binding; IEA:Ensembl. DR GO; GO:0008343; P:adult feeding behavior; IEA:Ensembl. DR GO; GO:0007267; P:cell-cell signaling; TAS:ProtInc. DR GO; GO:0044725; P:epigenetic programming in the zygotic pronuclei; IEA:Ensembl. DR GO; GO:0006091; P:generation of precursor metabolites and energy; TAS:ProtInc. DR GO; GO:0009755; P:hormone-mediated signaling pathway; IEA:InterPro. DR GO; GO:0042438; P:melanin biosynthetic process; ISS:UniProtKB. DR GO; GO:0032438; P:melanosome organization; IBA:GO_Central. DR GO; GO:0032402; P:melanosome transport; IEA:Ensembl. DR GO; GO:0048023; P:positive regulation of melanin biosynthetic process; IBA:GO_Central. DR GO; GO:0007165; P:signal transduction; TAS:ProtInc. 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:SF1; AGOUTI-SIGNALING 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; P42127; HS. PE 1: Evidence at protein level; KW 3D-structure; Chromosomal rearrangement; Disulfide bond; Glycoprotein; KW Knottin; Obesity; Reference proteome; Secreted; Signal. FT SIGNAL 1..22 FT /evidence="ECO:0000255" FT CHAIN 23..132 FT /note="Agouti-signaling protein" FT /id="PRO_0000001028" FT DOMAIN 93..132 FT /note="Agouti" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00494" FT REGION 62..85 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT CARBOHYD 39 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000255" FT DISULFID 93..108 FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00494, FT ECO:0000269|PubMed:15701517" FT DISULFID 100..114 FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00494, FT ECO:0000269|PubMed:15701517" FT DISULFID 107..125 FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00494, FT ECO:0000269|PubMed:15701517" FT DISULFID 111..132 FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00494, FT ECO:0000269|PubMed:15701517" FT DISULFID 116..123 FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00494, FT ECO:0000269|PubMed:15701517" FT VARIANT 13 FT /note="V -> A (in dbSNP:rs2296151)" FT /id="VAR_022125" FT VARIANT 61 FT /note="Q -> P (in dbSNP:rs1129414)" FT /id="VAR_005003" FT STRAND 96..98 FT /evidence="ECO:0007829|PDB:2KZA" FT STRAND 102..105 FT /evidence="ECO:0007829|PDB:1Y7J" FT STRAND 113..116 FT /evidence="ECO:0007829|PDB:1Y7J" FT STRAND 123..126 FT /evidence="ECO:0007829|PDB:1Y7J" SQ SEQUENCE 132 AA; 14515 MW; AF82CC3C747F2BE6 CRC64; MDVTRLLLAT LLVFLCFFTA NSHLPPEEKL RDDRSLRSNS SVNLLDVPSV SIVALNKKSK QIGRKAAEKK RSSKKEASMK KVVRPRTPLS APCVATRNSC KPPAPACCDP CASCQCRFFR SACSCRVLSL NC //