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Protein

Free fatty acid receptor 1

Gene

FFAR1

Organism
Homo sapiens (Human)
Status
Reviewed-Annotation score: Annotation score: 5 out of 5-Experimental evidence at protein leveli

Functioni

G-protein coupled receptor for medium and long chain saturated and unsaturated fatty acids that plays an important role in glucose homeostasis. Fatty acid binding increases glucose-stimulated insulin secretion, and may also enhance the secretion of glucagon-like peptide 1 (GLP-1). May also play a role in bone homeostasis; receptor signaling activates pathways that inhibit osteoclast differentiation (By similarity). Ligand binding leads to a conformation change that triggers signaling via G-proteins that activate phospholipase C, leading to an increase of the intracellular calcium concentration. Seems to act through a G(q) and G(i)-mediated pathway.By similarity3 Publications

Enzyme regulationi

The receptor is strongly activated by gamma-linolenic acid, while myristate gives a lower response. It is also activated by phytanic acid and pristanic acid (PubMed:21570468). Is also activated by synthetic agonists, such as TAK-875 (fasiglifam); this compound is a partial agonist and potentiates the activity of the endogenous ligand gamma-linolenic acid (PubMed:24130766).2 Publications

Sites

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Sitei145 – 1451Important for receptor activation1 Publication
Sitei172 – 1721Important for receptor activation1 Publication
Binding sitei183 – 1831Agonist1 Publication
Binding sitei240 – 2401Agonist1 Publication
Binding sitei258 – 2581Agonist1 Publication

GO - Molecular functioni

  1. bioactive lipid receptor activity Source: UniProtKB
  2. G-protein coupled receptor activity Source: ProtInc
  3. guanyl-nucleotide exchange factor activity Source: Reactome
  4. lipid binding Source: UniProtKB-KW

GO - Biological processi

  1. energy reserve metabolic process Source: Reactome
  2. glucose homeostasis Source: Ensembl
  3. G-protein coupled receptor signaling pathway Source: ProtInc
  4. insulin secretion Source: Ensembl
  5. positive regulation of calcium ion transport Source: UniProtKB
  6. positive regulation of GTPase activity Source: GOC
  7. regulation of insulin secretion Source: Reactome
  8. response to fatty acid Source: UniProtKB
  9. small molecule metabolic process Source: Reactome
Complete GO annotation...

Keywords - Molecular functioni

G-protein coupled receptor, Receptor, Transducer

Keywords - Ligandi

Lipid-binding

Enzyme and pathway databases

ReactomeiREACT_18283. G alpha (q) signalling events.
REACT_19193. Fatty Acids bound to GPR40 (FFAR1) regulate insulin secretion.
REACT_21268. Free fatty acid receptors.
REACT_23824. Synthesis, secretion, and inactivation of Glucose-dependent Insulinotropic Polypeptide (GIP).
REACT_24019. Synthesis, secretion, and inactivation of Glucagon-like Peptide-1 (GLP-1).

Names & Taxonomyi

Protein namesi
Recommended name:
Free fatty acid receptor 1
Alternative name(s):
G-protein coupled receptor 40
Gene namesi
Name:FFAR1
Synonyms:GPR40
OrganismiHomo sapiens (Human)
Taxonomic identifieri9606 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo
ProteomesiUP000005640 Componenti: Chromosome 19

Organism-specific databases

HGNCiHGNC:4498. FFAR1.

Subcellular locationi

Cell membrane 2 Publications; Multi-pass membrane protein 1 Publication

Topology

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Topological domaini1 – 88ExtracellularSequence Analysis1 Publication
Transmembranei9 – 3123Helical; Name=1Sequence Analysis1 PublicationAdd
BLAST
Topological domaini32 – 4110CytoplasmicSequence Analysis1 Publication
Transmembranei42 – 6423Helical; Name=2Sequence Analysis1 PublicationAdd
BLAST
Topological domaini65 – 7915ExtracellularSequence Analysis1 PublicationAdd
BLAST
Transmembranei80 – 10122Helical; Name=3Sequence Analysis1 PublicationAdd
BLAST
Topological domaini102 – 12120CytoplasmicSequence Analysis1 PublicationAdd
BLAST
Transmembranei122 – 14221Helical; Name=4Sequence Analysis1 PublicationAdd
BLAST
Topological domaini143 – 17836ExtracellularSequence Analysis1 PublicationAdd
BLAST
Transmembranei179 – 20022Helical; Name=5Sequence Analysis1 PublicationAdd
BLAST
Topological domaini201 – 22323CytoplasmicSequence Analysis1 PublicationAdd
BLAST
Transmembranei224 – 24825Helical; Name=6Sequence Analysis1 PublicationAdd
BLAST
Topological domaini249 – 2568ExtracellularSequence Analysis1 Publication
Transmembranei257 – 27923Helical; Name=7Sequence Analysis1 PublicationAdd
BLAST
Topological domaini280 – 30021CytoplasmicSequence Analysis1 PublicationAdd
BLAST

GO - Cellular componenti

  1. integral component of plasma membrane Source: UniProtKB
  2. plasma membrane Source: UniProtKB
Complete GO annotation...

Keywords - Cellular componenti

Cell membrane, Membrane

Pathology & Biotechi

Mutagenesis

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Mutagenesisi12 – 121Y → A: Reduces cell surface expression and response to linolenic acid and synthetic agonists. 1 Publication
Mutagenesisi91 – 911Y → A: Reduces response to linolenic acid. Reduces response to synthetic agonists. 2 Publications
Mutagenesisi137 – 1371H → A: Reduces response to linolenic acid. Reduces response to synthetic agonists. 2 Publications
Mutagenesisi145 – 1451E → A: Constitutive receptor signaling. 1 Publication
Mutagenesisi172 – 1721E → A: Constitutive receptor signaling. 1 Publication
Mutagenesisi183 – 1831R → A: Reduces response to linolenic acid. Strongly reduces response to synthetic agonists. 2 Publications
Mutagenesisi240 – 2401Y → A: Reduces response to linolenic acid. Reduces response to synthetic agonists. 2 Publications
Mutagenesisi244 – 2441N → A: Reduces response to linolenic acid. Reduces response to synthetic agonists. 2 Publications
Mutagenesisi258 – 2581R → A: Strongly reduces response to linolenic acid. Strongly reduces response to synthetic agonists. 2 Publications
Mutagenesisi258 – 2581R → K: Reduces response to linolenic acid. Strongly reduces response to synthetic agonists. 1 Publication

Organism-specific databases

PharmGKBiPA28887.

PTM / Processingi

Molecule processing

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Chaini1 – 300300Free fatty acid receptor 1PRO_0000069567Add
BLAST

Amino acid modifications

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Disulfide bondi79 ↔ 1701 Publication
Glycosylationi155 – 1551N-linked (GlcNAc...)Sequence Analysis

Keywords - PTMi

Disulfide bond, Glycoprotein

Proteomic databases

PaxDbiO14842.
PRIDEiO14842.

PTM databases

PhosphoSiteiO14842.

Expressioni

Tissue specificityi

Detected in brain and pancreas. Detected in pancreatic beta cells.2 Publications

Gene expression databases

BgeeiO14842.
CleanExiHS_FFAR1.
GenevestigatoriO14842.

Interactioni

Protein-protein interaction databases

STRINGi9606.ENSP00000246553.

Structurei

Secondary structure

1
300
Legend: HelixTurnBeta strand
Show more details
Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Helixi5 – 3632Combined sources
Helixi40 – 6728Combined sources
Turni68 – 703Combined sources
Helixi78 – 10932Combined sources
Helixi121 – 14525Combined sources
Beta strandi149 – 1513Combined sources
Beta strandi169 – 1713Combined sources
Helixi176 – 19015Combined sources
Helixi192 – 21019Combined sources
Helixi214 – 23522Combined sources
Helixi237 – 24913Combined sources
Helixi256 – 26611Combined sources
Helixi268 – 2758Combined sources

3D structure databases

Select the link destinations:
PDBei
RCSB PDBi
PDBji
Links Updated
EntryMethodResolution (Å)ChainPositionsPDBsum
4PHUX-ray2.33A1-211[»]
A214-300[»]
ProteinModelPortaliO14842.
SMRiO14842. Positions 1-280.
ModBaseiSearch...
MobiDBiSearch...

Family & Domainsi

Region

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Regioni87 – 915Agonist binding1 Publication

Sequence similaritiesi

Belongs to the G-protein coupled receptor 1 family.PROSITE-ProRule annotation

Keywords - Domaini

Transmembrane, Transmembrane helix

Phylogenomic databases

eggNOGiNOG150822.
GeneTreeiENSGT00760000119001.
HOGENOMiHOG000236290.
HOVERGENiHBG080696.
InParanoidiO14842.
KOiK04325.
OMAiLHLGCSD.
OrthoDBiEOG7GQXWF.
PhylomeDBiO14842.
TreeFamiTF350010.

Family and domain databases

InterProiIPR000276. GPCR_Rhodpsn.
IPR017452. GPCR_Rhodpsn_7TM.
IPR013312. GPR40-rel_orph.
IPR013313. GPR40_recept_FA.
[Graphical view]
PfamiPF00001. 7tm_1. 1 hit.
[Graphical view]
PRINTSiPR01905. FATTYACIDR.
PR00237. GPCRRHODOPSN.
PR01904. GPR40FAMILY.
PROSITEiPS50262. G_PROTEIN_RECEP_F1_2. 1 hit.
[Graphical view]

Sequencei

Sequence statusi: Complete.

O14842-1 [UniParc]FASTAAdd to basket

« Hide

        10         20         30         40         50
MDLPPQLSFG LYVAAFALGF PLNVLAIRGA TAHARLRLTP SLVYALNLGC
60 70 80 90 100
SDLLLTVSLP LKAVEALASG AWPLPASLCP VFAVAHFFPL YAGGGFLAAL
110 120 130 140 150
SAGRYLGAAF PLGYQAFRRP CYSWGVCAAI WALVLCHLGL VFGLEAPGGW
160 170 180 190 200
LDHSNTSLGI NTPVNGSPVC LEAWDPASAG PARFSLSLLL FFLPLAITAF
210 220 230 240 250
CYVGCLRALA RSGLTHRRKL RAAWVAGGAL LTLLLCVGPY NASNVASFLY
260 270 280 290 300
PNLGGSWRKL GLITGAWSVV LNPLVTGYLG RGPGLKTVCA ARTQGGKSQK
Length:300
Mass (Da):31,457
Last modified:December 31, 1997 - v1
Checksum:i77EF27DACD93E80B
GO

Experimental Info

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Sequence conflicti24 – 241V → A in AAH95536 (PubMed:15489334).Curated

Natural variant

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Natural varianti211 – 2111R → H.1 Publication
Corresponds to variant rs2301151 [ dbSNP | Ensembl ].
VAR_020076

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
AF024687 Genomic DNA. Translation: AAB86710.1.
BC095536 mRNA. Translation: AAH95536.1.
BC120944 mRNA. Translation: AAI20945.1.
CCDSiCCDS12458.1.
PIRiJC5714.
RefSeqiNP_005294.1. NM_005303.2.
UniGeneiHs.248127.

Genome annotation databases

EnsembliENST00000246553; ENSP00000246553; ENSG00000126266.
GeneIDi2864.
KEGGihsa:2864.
UCSCiuc002nzc.2. human.

Keywords - Coding sequence diversityi

Polymorphism

Cross-referencesi

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
AF024687 Genomic DNA. Translation: AAB86710.1.
BC095536 mRNA. Translation: AAH95536.1.
BC120944 mRNA. Translation: AAI20945.1.
CCDSiCCDS12458.1.
PIRiJC5714.
RefSeqiNP_005294.1. NM_005303.2.
UniGeneiHs.248127.

3D structure databases

Select the link destinations:
PDBei
RCSB PDBi
PDBji
Links Updated
EntryMethodResolution (Å)ChainPositionsPDBsum
4PHUX-ray2.33A1-211[»]
A214-300[»]
ProteinModelPortaliO14842.
SMRiO14842. Positions 1-280.
ModBaseiSearch...
MobiDBiSearch...

Protein-protein interaction databases

STRINGi9606.ENSP00000246553.

Chemistry

BindingDBiO14842.
ChEMBLiCHEMBL4422.
DrugBankiDB00159. Icosapent.
GuidetoPHARMACOLOGYi225.

Protein family/group databases

GPCRDBiSearch...

PTM databases

PhosphoSiteiO14842.

Proteomic databases

PaxDbiO14842.
PRIDEiO14842.

Protocols and materials databases

DNASUi2864.
Structural Biology KnowledgebaseSearch...

Genome annotation databases

EnsembliENST00000246553; ENSP00000246553; ENSG00000126266.
GeneIDi2864.
KEGGihsa:2864.
UCSCiuc002nzc.2. human.

Organism-specific databases

CTDi2864.
GeneCardsiGC19P035842.
HGNCiHGNC:4498. FFAR1.
MIMi603820. gene.
neXtProtiNX_O14842.
PharmGKBiPA28887.
GenAtlasiSearch...

Phylogenomic databases

eggNOGiNOG150822.
GeneTreeiENSGT00760000119001.
HOGENOMiHOG000236290.
HOVERGENiHBG080696.
InParanoidiO14842.
KOiK04325.
OMAiLHLGCSD.
OrthoDBiEOG7GQXWF.
PhylomeDBiO14842.
TreeFamiTF350010.

Enzyme and pathway databases

ReactomeiREACT_18283. G alpha (q) signalling events.
REACT_19193. Fatty Acids bound to GPR40 (FFAR1) regulate insulin secretion.
REACT_21268. Free fatty acid receptors.
REACT_23824. Synthesis, secretion, and inactivation of Glucose-dependent Insulinotropic Polypeptide (GIP).
REACT_24019. Synthesis, secretion, and inactivation of Glucagon-like Peptide-1 (GLP-1).

Miscellaneous databases

GeneWikiiFree_fatty_acid_receptor_1.
GenomeRNAii2864.
NextBioi11293.
PROiO14842.
SOURCEiSearch...

Gene expression databases

BgeeiO14842.
CleanExiHS_FFAR1.
GenevestigatoriO14842.

Family and domain databases

InterProiIPR000276. GPCR_Rhodpsn.
IPR017452. GPCR_Rhodpsn_7TM.
IPR013312. GPR40-rel_orph.
IPR013313. GPR40_recept_FA.
[Graphical view]
PfamiPF00001. 7tm_1. 1 hit.
[Graphical view]
PRINTSiPR01905. FATTYACIDR.
PR00237. GPCRRHODOPSN.
PR01904. GPR40FAMILY.
PROSITEiPS50262. G_PROTEIN_RECEP_F1_2. 1 hit.
[Graphical view]
ProtoNetiSearch...

Publicationsi

« Hide 'large scale' publications
  1. "A cluster of four novel human G protein-coupled receptor genes occurring in close proximity to CD22 gene on chromosome 19q13.1."
    Sawzdargo M., George S.R., Nguyen T., Xu S., Kolakowski L.F. Jr., O'Dowd B.F.
    Biochem. Biophys. Res. Commun. 239:543-547(1996) [PubMed] [Europe PMC] [Abstract]
    Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA].
  2. "The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC)."
    The MGC Project Team
    Genome Res. 14:2121-2127(2003) [PubMed] [Europe PMC] [Abstract]
    Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA], VARIANT HIS-211.
  3. Cited for: FUNCTION, TISSUE SPECIFICITY.
  4. Cited for: TISSUE SPECIFICITY.
  5. "Identification of residues important for agonist recognition and activation in GPR40."
    Sum C.S., Tikhonova I.G., Neumann S., Engel S., Raaka B.M., Costanzi S., Gershengorn M.C.
    J. Biol. Chem. 282:29248-29255(2006) [PubMed] [Europe PMC] [Abstract]
    Cited for: FUNCTION, SUBCELLULAR LOCATION, MUTAGENESIS OF TYR-12; TYR-91; HIS-137; ARG-183; TYR-240; ASN-244 AND ARG-258.
  6. "Two arginine-glutamate ionic locks near the extracellular surface of FFAR1 gate receptor activation."
    Sum C.S., Tikhonova I.G., Costanzi S., Gershengorn M.C.
    J. Biol. Chem. 284:3529-3536(2008) [PubMed] [Europe PMC] [Abstract]
    Cited for: FUNCTION, MUTAGENESIS OF GLU-145 AND GLU-172, SITE.
  7. "Phytanic acid and pristanic acid, branched-chain fatty acids associated with Refsum disease and other inherited peroxisomal disorders, mediate intracellular Ca2+ signaling through activation of free fatty acid receptor GPR40."
    Kruska N., Reiser G.
    Neurobiol. Dis. 43:465-472(2010) [PubMed] [Europe PMC] [Abstract]
    Cited for: FUNCTION, ENZYME REGULATION.
  8. "A novel antidiabetic drug, fasiglifam/TAK-875, acts as an ago-allosteric modulator of FFAR1."
    Yabuki C., Komatsu H., Tsujihata Y., Maeda R., Ito R., Matsuda-Nagasumi K., Sakuma K., Miyawaki K., Kikuchi N., Takeuchi K., Habata Y., Mori M.
    PLoS ONE 8:E76280-E76280(2012) [PubMed] [Europe PMC] [Abstract]
    Cited for: FUNCTION, ENZYME REGULATION.
  9. "High-resolution structure of the human GPR40 receptor bound to allosteric agonist TAK-875."
    Srivastava A., Yano J., Hirozane Y., Kefala G., Gruswitz F., Snell G., Lane W., Ivetac A., Aertgeerts K., Nguyen J., Jennings A., Okada K.
    Nature 513:124-127(2013) [PubMed] [Europe PMC] [Abstract]
    Cited for: X-RAY CRYSTALLOGRAPHY (2.33 ANGSTROMS) OF 1-211 AND 214-300 IN COMPLEX WITH THE AGONIST TAK-875, AGONIST BINDING SITES, SUBCELLULAR LOCATION, TOPOLOGY, DISULFIDE BOND, MUTAGENESIS OF TYR-91; ARG-183; TYR-240; ASN-244 AND ARG-258.

Entry informationi

Entry nameiFFAR1_HUMAN
AccessioniPrimary (citable) accession number: O14842
Secondary accession number(s): Q0VAS2, Q4VBL4
Entry historyi
Integrated into UniProtKB/Swiss-Prot: July 14, 1998
Last sequence update: December 31, 1997
Last modified: January 6, 2015
This is version 123 of the entry and version 1 of the sequence. [Complete history]
Entry statusiReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program
DisclaimerAny medical or genetic information present in this entry is provided for research, educational and informational purposes only. It is not in any way intended to be used as a substitute for professional medical advice, diagnosis, treatment or care.

Miscellaneousi

Keywords - Technical termi

3D-structure, Complete proteome, Reference proteome

Documents

  1. 7-transmembrane G-linked receptors
    List of 7-transmembrane G-linked receptor entries
  2. Human chromosome 19
    Human chromosome 19: entries, gene names and cross-references to MIM
  3. Human entries with polymorphisms or disease mutations
    List of human entries with polymorphisms or disease mutations
  4. Human polymorphisms and disease mutations
    Index of human polymorphisms and disease mutations
  5. MIM cross-references
    Online Mendelian Inheritance in Man (MIM) cross-references in UniProtKB/Swiss-Prot
  6. PDB cross-references
    Index of Protein Data Bank (PDB) cross-references
  7. SIMILARITY comments
    Index of protein domains and families

External Data

Dasty 3

Similar proteinsi

Links to similar proteins from the UniProt Reference Clusters (UniRef) at 100%, 90% and 50% sequence identity:
100%UniRef100 combines identical sequences and sub-fragments with 11 or more residues from any organism into Uniref entry.
90%UniRef90 is built by clustering UniRef100 sequences that have at least 90% sequence identity to, and 80% overlap with, the longest sequence (a.k.a seed sequence).
50%UniRef50 is built by clustering UniRef90 seed sequences that have at least 50% sequence identity to, and 80% overlap with, the longest sequence in the cluster.