FFAR1_HUMAN
ID FFAR1_HUMAN Reviewed; 300 AA.
AC O14842; Q0VAS2; Q4VBL4;
DT 15-JUL-1998, integrated into UniProtKB/Swiss-Prot.
DT 01-JAN-1998, sequence version 1.
DT 03-AUG-2022, entry version 165.
DE RecName: Full=Free fatty acid receptor 1;
DE AltName: Full=G-protein coupled receptor 40;
GN Name=FFAR1; Synonyms=GPR40;
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].
RX PubMed=9344866; DOI=10.1006/bbrc.1997.7513;
RA Sawzdargo M., George S.R., Nguyen T., Xu S., Kolakowski L.F. Jr.,
RA O'Dowd B.F.;
RT "A cluster of four novel human G protein-coupled receptor genes occurring
RT in close proximity to CD22 gene on chromosome 19q13.1.";
RL Biochem. Biophys. Res. Commun. 239:543-547(1997).
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA], AND VARIANT HIS-211.
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 [3]
RP FUNCTION, AND TISSUE SPECIFICITY.
RX PubMed=12496284; DOI=10.1074/jbc.m211495200;
RA Briscoe C.P., Tadayyon M., Andrews J.L., Benson W.G., Chambers J.K.,
RA Eilert M.M., Ellis C., Elshourbagy N.A., Goetz A.S., Minnick D.T.,
RA Murdock P.R., Sauls H.R. Jr., Shabon U., Spinage L.D., Strum J.C.,
RA Szekeres P.G., Tan K.B., Way J.M., Ignar D.M., Wilson S., Muir A.I.;
RT "The orphan G protein-coupled receptor GPR40 is activated by medium and
RT long-chain fatty acids.";
RL J. Biol. Chem. 278:11303-11311(2003).
RN [4]
RP TISSUE SPECIFICITY.
RX PubMed=16289108; DOI=10.1016/j.bbrc.2005.10.161;
RA Tomita T., Masuzaki H., Noguchi M., Iwakura H., Fujikura J., Tanaka T.,
RA Ebihara K., Kawamura J., Komoto I., Kawaguchi Y., Fujimoto K., Doi R.,
RA Shimada Y., Hosoda K., Imamura M., Nakao K.;
RT "GPR40 gene expression in human pancreas and insulinoma.";
RL Biochem. Biophys. Res. Commun. 338:1788-1790(2005).
RN [5]
RP FUNCTION, SUBCELLULAR LOCATION, AND MUTAGENESIS OF TYR-12; TYR-91; HIS-137;
RP ARG-183; TYR-240; ASN-244 AND ARG-258.
RX PubMed=17699519; DOI=10.1074/jbc.m705077200;
RA Sum C.S., Tikhonova I.G., Neumann S., Engel S., Raaka B.M., Costanzi S.,
RA Gershengorn M.C.;
RT "Identification of residues important for agonist recognition and
RT activation in GPR40.";
RL J. Biol. Chem. 282:29248-29255(2007).
RN [6]
RP FUNCTION, MUTAGENESIS OF GLU-145 AND GLU-172, AND SITE.
RX PubMed=19068482; DOI=10.1074/jbc.m806987200;
RA Sum C.S., Tikhonova I.G., Costanzi S., Gershengorn M.C.;
RT "Two arginine-glutamate ionic locks near the extracellular surface of FFAR1
RT gate receptor activation.";
RL J. Biol. Chem. 284:3529-3536(2009).
RN [7]
RP FUNCTION, AND ACTIVITY REGULATION.
RX PubMed=21570468; DOI=10.1016/j.nbd.2011.04.020;
RA Kruska N., Reiser G.;
RT "Phytanic acid and pristanic acid, branched-chain fatty acids associated
RT with Refsum disease and other inherited peroxisomal disorders, mediate
RT intracellular Ca2+ signaling through activation of free fatty acid receptor
RT GPR40.";
RL Neurobiol. Dis. 43:465-472(2011).
RN [8]
RP FUNCTION.
RX PubMed=23809162; DOI=10.1016/j.immuni.2013.05.015;
RA Yan Y., Jiang W., Spinetti T., Tardivel A., Castillo R., Bourquin C.,
RA Guarda G., Tian Z., Tschopp J., Zhou R.;
RT "Omega-3 fatty acids prevent inflammation and metabolic disorder through
RT inhibition of NLRP3 inflammasome activation.";
RL Immunity 38:1154-1163(2013).
RN [9]
RP FUNCTION, AND ACTIVITY REGULATION.
RX PubMed=24130766; DOI=10.1371/journal.pone.0076280;
RA Yabuki C., Komatsu H., Tsujihata Y., Maeda R., Ito R., Matsuda-Nagasumi K.,
RA Sakuma K., Miyawaki K., Kikuchi N., Takeuchi K., Habata Y., Mori M.;
RT "A novel antidiabetic drug, fasiglifam/TAK-875, acts as an ago-allosteric
RT modulator of FFAR1.";
RL PLoS ONE 8:E76280-E76280(2013).
RN [10]
RP FUNCTION.
RX PubMed=24742677; DOI=10.1074/jbc.m114.568683;
RA Suckow A.T., Polidori D., Yan W., Chon S., Ma J.Y., Leonard J.,
RA Briscoe C.P.;
RT "Alteration of the glucagon axis in GPR120 (FFAR4) knockout mice: a role
RT for GPR120 in glucagon secretion.";
RL J. Biol. Chem. 289:15751-15763(2014).
RN [11]
RP X-RAY CRYSTALLOGRAPHY (2.33 ANGSTROMS) OF 1-211 AND 214-300 IN COMPLEX WITH
RP THE AGONIST TAK-875, AGONIST BINDING SITES, SUBCELLULAR LOCATION, TOPOLOGY,
RP DISULFIDE BOND, AND MUTAGENESIS OF TYR-91; ARG-183; TYR-240; ASN-244 AND
RP ARG-258.
RX PubMed=25043059; DOI=10.1038/nature13494;
RA Srivastava A., Yano J., Hirozane Y., Kefala G., Gruswitz F., Snell G.,
RA Lane W., Ivetac A., Aertgeerts K., Nguyen J., Jennings A., Okada K.;
RT "High-resolution structure of the human GPR40 receptor bound to allosteric
RT agonist TAK-875.";
RL Nature 513:124-127(2014).
RN [12]
RP X-RAY CRYSTALLOGRAPHY (2.76 ANGSTROMS) OF 1-211 AND 214-300, AND
RP MUTAGENESIS OF TYR-44; TYR-114 AND SER-123.
RX PubMed=29695780; DOI=10.1038/s41467-017-01240-w;
RA Ho J.D., Chau B., Rodgers L., Lu F., Wilbur K.L., Otto K.A., Chen Y.,
RA Song M., Riley J.P., Yang H.C., Reynolds N.A., Kahl S.D., Lewis A.P.,
RA Groshong C., Madsen R.E., Conners K., Lineswala J.P., Gheyi T.,
RA Saflor M.D., Lee M.R., Benach J., Baker K.A., Montrose-Rafizadeh C.,
RA Genin M.J., Miller A.R., Hamdouchi C.;
RT "Structural basis for GPR40 allosteric agonism and incretin stimulation.";
RL Nat. Commun. 9:1645-1645(2018).
CC -!- FUNCTION: G-protein coupled receptor for medium and long chain
CC saturated and unsaturated fatty acids that plays an important role in
CC glucose homeostasis. Fatty acid binding increases glucose-stimulated
CC insulin secretion, and may also enhance the secretion of glucagon-like
CC peptide 1 (GLP-1). May also play a role in bone homeostasis; receptor
CC signaling activates pathways that inhibit osteoclast differentiation
CC (By similarity). Ligand binding leads to a conformation change that
CC triggers signaling via G-proteins that activate phospholipase C,
CC leading to an increase of the intracellular calcium concentration.
CC Seems to act through a G(q) and G(i)-mediated pathway. Mediates the
CC anti-inflammatory effects of omega-3 polyunsaturated fatty acids
CC (PUFAs) via inhibition of NLRP3 inflammasome activation.
CC {ECO:0000250|UniProtKB:Q76JU9, ECO:0000269|PubMed:12496284,
CC ECO:0000269|PubMed:17699519, ECO:0000269|PubMed:23809162,
CC ECO:0000269|PubMed:24130766, ECO:0000269|PubMed:24742677}.
CC -!- ACTIVITY REGULATION: The receptor is strongly activated by gamma-
CC linolenic acid, while myristate gives a lower response. It is also
CC activated by phytanic acid and pristanic acid (PubMed:21570468). Is
CC also activated by synthetic agonists, such as TAK-875 (fasiglifam);
CC this compound is a partial agonist and potentiates the activity of the
CC endogenous ligand gamma-linolenic acid (PubMed:24130766).
CC {ECO:0000269|PubMed:21570468, ECO:0000269|PubMed:24130766}.
CC -!- SUBCELLULAR LOCATION: Cell membrane {ECO:0000269|PubMed:17699519,
CC ECO:0000269|PubMed:25043059}; Multi-pass membrane protein
CC {ECO:0000269|PubMed:25043059}.
CC -!- TISSUE SPECIFICITY: Detected in brain and pancreas. Detected in
CC pancreatic beta cells. {ECO:0000269|PubMed:12496284,
CC ECO:0000269|PubMed:16289108}.
CC -!- SIMILARITY: Belongs to the G-protein coupled receptor 1 family.
CC {ECO:0000255|PROSITE-ProRule:PRU00521}.
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DR EMBL; AF024687; AAB86710.1; -; Genomic_DNA.
DR EMBL; BC095536; AAH95536.1; -; mRNA.
DR EMBL; BC120944; AAI20945.1; -; mRNA.
DR CCDS; CCDS12458.1; -.
DR PIR; JC5714; JC5714.
DR RefSeq; NP_005294.1; NM_005303.2.
DR PDB; 4PHU; X-ray; 2.33 A; A=1-211, A=214-300.
DR PDB; 5KW2; X-ray; 2.76 A; A=1-211, A=214-300.
DR PDB; 5TZR; X-ray; 2.20 A; A=1-211, A=214-300.
DR PDB; 5TZY; X-ray; 3.22 A; A=1-211, A=214-300.
DR PDBsum; 4PHU; -.
DR PDBsum; 5KW2; -.
DR PDBsum; 5TZR; -.
DR PDBsum; 5TZY; -.
DR AlphaFoldDB; O14842; -.
DR SMR; O14842; -.
DR BioGRID; 109122; 268.
DR STRING; 9606.ENSP00000246553; -.
DR BindingDB; O14842; -.
DR ChEMBL; CHEMBL4422; -.
DR DrugBank; DB00159; Icosapent.
DR DrugCentral; O14842; -.
DR GuidetoPHARMACOLOGY; 225; -.
DR SwissLipids; SLP:000001550; -.
DR TCDB; 9.A.14.13.30; the g-protein-coupled receptor (gpcr) family.
DR GlyGen; O14842; 1 site.
DR iPTMnet; O14842; -.
DR PhosphoSitePlus; O14842; -.
DR BioMuta; FFAR1; -.
DR PaxDb; O14842; -.
DR PeptideAtlas; O14842; -.
DR PRIDE; O14842; -.
DR ProteomicsDB; 48273; -.
DR TopDownProteomics; O14842; -.
DR Antibodypedia; 15908; 337 antibodies from 34 providers.
DR DNASU; 2864; -.
DR Ensembl; ENST00000246553.3; ENSP00000246553.2; ENSG00000126266.3.
DR GeneID; 2864; -.
DR KEGG; hsa:2864; -.
DR MANE-Select; ENST00000246553.4; ENSP00000246553.2; NM_005303.3; NP_005294.1.
DR UCSC; uc002nzc.3; human.
DR CTD; 2864; -.
DR DisGeNET; 2864; -.
DR GeneCards; FFAR1; -.
DR HGNC; HGNC:4498; FFAR1.
DR HPA; ENSG00000126266; Group enriched (bone marrow, brain, ovary, pancreas).
DR MIM; 603820; gene.
DR neXtProt; NX_O14842; -.
DR OpenTargets; ENSG00000126266; -.
DR PharmGKB; PA28887; -.
DR VEuPathDB; HostDB:ENSG00000126266; -.
DR eggNOG; ENOG502QVCS; Eukaryota.
DR GeneTree; ENSGT00990000203527; -.
DR HOGENOM; CLU_009579_8_4_1; -.
DR InParanoid; O14842; -.
DR OMA; CWRKLGL; -.
DR OrthoDB; 1074213at2759; -.
DR PhylomeDB; O14842; -.
DR TreeFam; TF350010; -.
DR PathwayCommons; O14842; -.
DR Reactome; R-HSA-381771; Synthesis, secretion, and inactivation of Glucagon-like Peptide-1 (GLP-1).
DR Reactome; R-HSA-400511; Synthesis, secretion, and inactivation of Glucose-dependent Insulinotropic Polypeptide (GIP).
DR Reactome; R-HSA-416476; G alpha (q) signalling events.
DR Reactome; R-HSA-434316; Fatty Acids bound to GPR40 (FFAR1) regulate insulin secretion.
DR Reactome; R-HSA-444209; Free fatty acid receptors.
DR SignaLink; O14842; -.
DR SIGNOR; O14842; -.
DR BioGRID-ORCS; 2864; 9 hits in 1068 CRISPR screens.
DR GeneWiki; Free_fatty_acid_receptor_1; -.
DR GenomeRNAi; 2864; -.
DR Pharos; O14842; Tchem.
DR PRO; PR:O14842; -.
DR Proteomes; UP000005640; Chromosome 19.
DR RNAct; O14842; protein.
DR Bgee; ENSG00000126266; Expressed in islet of Langerhans and 47 other tissues.
DR Genevisible; O14842; HS.
DR GO; GO:0005887; C:integral component of plasma membrane; IDA:UniProtKB.
DR GO; GO:0005886; C:plasma membrane; IDA:UniProtKB.
DR GO; GO:0045125; F:bioactive lipid receptor activity; IDA:UniProtKB.
DR GO; GO:0004930; F:G protein-coupled receptor activity; IBA:GO_Central.
DR GO; GO:0008289; F:lipid binding; IEA:UniProtKB-KW.
DR GO; GO:0007186; P:G protein-coupled receptor signaling pathway; IBA:GO_Central.
DR GO; GO:0042593; P:glucose homeostasis; IEA:Ensembl.
DR GO; GO:0030073; P:insulin secretion; IEA:Ensembl.
DR GO; GO:0032691; P:negative regulation of interleukin-1 beta production; IMP:UniProtKB.
DR GO; GO:0051928; P:positive regulation of calcium ion transport; IDA:UniProtKB.
DR GO; GO:0007204; P:positive regulation of cytosolic calcium ion concentration; IDA:UniProtKB.
DR GO; GO:0032024; P:positive regulation of insulin secretion; IBA:GO_Central.
DR GO; GO:0070542; P:response to fatty acid; IDA:UniProtKB.
DR InterPro; IPR000276; GPCR_Rhodpsn.
DR InterPro; IPR017452; GPCR_Rhodpsn_7TM.
DR InterPro; IPR013312; GPR40-rel_orph.
DR InterPro; IPR013313; GPR40_recept_FA.
DR Pfam; PF00001; 7tm_1; 1.
DR PRINTS; PR01905; FATTYACIDR.
DR PRINTS; PR00237; GPCRRHODOPSN.
DR PRINTS; PR01904; GPR40FAMILY.
DR PROSITE; PS50262; G_PROTEIN_RECEP_F1_2; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Cell membrane; Disulfide bond; G-protein coupled receptor;
KW Glycoprotein; Lipid-binding; Membrane; Receptor; Reference proteome;
KW Transducer; Transmembrane; Transmembrane helix.
FT CHAIN 1..300
FT /note="Free fatty acid receptor 1"
FT /id="PRO_0000069567"
FT TOPO_DOM 1..8
FT /note="Extracellular"
FT /evidence="ECO:0000255, ECO:0000269|PubMed:25043059"
FT TRANSMEM 9..31
FT /note="Helical; Name=1"
FT /evidence="ECO:0000255, ECO:0000269|PubMed:25043059"
FT TOPO_DOM 32..41
FT /note="Cytoplasmic"
FT /evidence="ECO:0000255, ECO:0000269|PubMed:25043059"
FT TRANSMEM 42..64
FT /note="Helical; Name=2"
FT /evidence="ECO:0000255, ECO:0000269|PubMed:25043059"
FT TOPO_DOM 65..79
FT /note="Extracellular"
FT /evidence="ECO:0000255, ECO:0000269|PubMed:25043059"
FT TRANSMEM 80..101
FT /note="Helical; Name=3"
FT /evidence="ECO:0000255, ECO:0000269|PubMed:25043059"
FT TOPO_DOM 102..121
FT /note="Cytoplasmic"
FT /evidence="ECO:0000255, ECO:0000269|PubMed:25043059"
FT TRANSMEM 122..142
FT /note="Helical; Name=4"
FT /evidence="ECO:0000255, ECO:0000269|PubMed:25043059"
FT TOPO_DOM 143..178
FT /note="Extracellular"
FT /evidence="ECO:0000255, ECO:0000269|PubMed:25043059"
FT TRANSMEM 179..200
FT /note="Helical; Name=5"
FT /evidence="ECO:0000255, ECO:0000269|PubMed:25043059"
FT TOPO_DOM 201..223
FT /note="Cytoplasmic"
FT /evidence="ECO:0000255, ECO:0000269|PubMed:25043059"
FT TRANSMEM 224..248
FT /note="Helical; Name=6"
FT /evidence="ECO:0000255, ECO:0000269|PubMed:25043059"
FT TOPO_DOM 249..256
FT /note="Extracellular"
FT /evidence="ECO:0000255, ECO:0000269|PubMed:25043059"
FT TRANSMEM 257..279
FT /note="Helical; Name=7"
FT /evidence="ECO:0000255, ECO:0000269|PubMed:25043059"
FT TOPO_DOM 280..300
FT /note="Cytoplasmic"
FT /evidence="ECO:0000255, ECO:0000269|PubMed:25043059"
FT SITE 145
FT /note="Important for receptor activation"
FT /evidence="ECO:0000269|PubMed:19068482"
FT SITE 172
FT /note="Important for receptor activation"
FT /evidence="ECO:0000269|PubMed:19068482"
FT CARBOHYD 155
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT DISULFID 79..170
FT /evidence="ECO:0000269|PubMed:25043059"
FT VARIANT 211
FT /note="R -> H (in dbSNP:rs2301151)"
FT /evidence="ECO:0000269|PubMed:15489334"
FT /id="VAR_020076"
FT MUTAGEN 12
FT /note="Y->A: Reduces cell surface expression and response
FT to linolenic acid and synthetic agonists."
FT /evidence="ECO:0000269|PubMed:17699519"
FT MUTAGEN 44
FT /note="Y->F: Reduces response to synthetic agonists."
FT /evidence="ECO:0000269|PubMed:29695780"
FT MUTAGEN 91
FT /note="Y->A: Reduces response to linolenic acid. Reduces
FT response to synthetic agonists."
FT /evidence="ECO:0000269|PubMed:17699519,
FT ECO:0000269|PubMed:25043059"
FT MUTAGEN 114
FT /note="Y->F: Reduces response to synthetic agonists."
FT /evidence="ECO:0000269|PubMed:29695780"
FT MUTAGEN 123
FT /note="S->A: Reduces response to synthetic agonists."
FT /evidence="ECO:0000269|PubMed:29695780"
FT MUTAGEN 137
FT /note="H->A: Reduces response to linolenic acid. Reduces
FT response to synthetic agonists."
FT /evidence="ECO:0000269|PubMed:17699519,
FT ECO:0000269|PubMed:25043059"
FT MUTAGEN 145
FT /note="E->A: Constitutive receptor signaling."
FT /evidence="ECO:0000269|PubMed:19068482"
FT MUTAGEN 172
FT /note="E->A: Constitutive receptor signaling."
FT /evidence="ECO:0000269|PubMed:19068482"
FT MUTAGEN 183
FT /note="R->A: Reduces response to linolenic acid. Strongly
FT reduces response to synthetic agonists."
FT /evidence="ECO:0000269|PubMed:17699519,
FT ECO:0000269|PubMed:25043059"
FT MUTAGEN 240
FT /note="Y->A: Reduces response to linolenic acid. Reduces
FT response to synthetic agonists."
FT /evidence="ECO:0000269|PubMed:17699519,
FT ECO:0000269|PubMed:25043059"
FT MUTAGEN 244
FT /note="N->A: Reduces response to linolenic acid. Reduces
FT response to synthetic agonists."
FT /evidence="ECO:0000269|PubMed:17699519,
FT ECO:0000269|PubMed:25043059"
FT MUTAGEN 258
FT /note="R->A: Strongly reduces response to linolenic acid.
FT Strongly reduces response to synthetic agonists."
FT /evidence="ECO:0000269|PubMed:17699519,
FT ECO:0000269|PubMed:25043059"
FT MUTAGEN 258
FT /note="R->K: Reduces response to linolenic acid. Strongly
FT reduces response to synthetic agonists."
FT /evidence="ECO:0000269|PubMed:17699519"
FT CONFLICT 24
FT /note="V -> A (in Ref. 2; AAH95536)"
FT /evidence="ECO:0000305"
FT HELIX 5..36
FT /evidence="ECO:0007829|PDB:5TZR"
FT HELIX 40..67
FT /evidence="ECO:0007829|PDB:5TZR"
FT TURN 68..70
FT /evidence="ECO:0007829|PDB:5TZR"
FT HELIX 76..78
FT /evidence="ECO:0007829|PDB:5TZR"
FT HELIX 79..109
FT /evidence="ECO:0007829|PDB:5TZR"
FT HELIX 111..117
FT /evidence="ECO:0007829|PDB:5KW2"
FT HELIX 121..145
FT /evidence="ECO:0007829|PDB:5TZR"
FT STRAND 149..151
FT /evidence="ECO:0007829|PDB:5TZR"
FT STRAND 169..171
FT /evidence="ECO:0007829|PDB:5TZR"
FT HELIX 176..190
FT /evidence="ECO:0007829|PDB:5TZR"
FT HELIX 192..211
FT /evidence="ECO:0007829|PDB:5TZR"
FT HELIX 214..235
FT /evidence="ECO:0007829|PDB:5TZR"
FT HELIX 237..249
FT /evidence="ECO:0007829|PDB:5TZR"
FT HELIX 256..266
FT /evidence="ECO:0007829|PDB:5TZR"
FT HELIX 268..275
FT /evidence="ECO:0007829|PDB:5TZR"
SQ SEQUENCE 300 AA; 31457 MW; 77EF27DACD93E80B CRC64;
MDLPPQLSFG LYVAAFALGF PLNVLAIRGA TAHARLRLTP SLVYALNLGC SDLLLTVSLP
LKAVEALASG AWPLPASLCP VFAVAHFFPL YAGGGFLAAL SAGRYLGAAF PLGYQAFRRP
CYSWGVCAAI WALVLCHLGL VFGLEAPGGW LDHSNTSLGI NTPVNGSPVC LEAWDPASAG
PARFSLSLLL FFLPLAITAF CYVGCLRALA RSGLTHRRKL RAAWVAGGAL LTLLLCVGPY
NASNVASFLY PNLGGSWRKL GLITGAWSVV LNPLVTGYLG RGPGLKTVCA ARTQGGKSQK
