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Protein

Free fatty acid receptor 3

Gene

FFAR3

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

Functioni

G protein-coupled receptor that is activated by a major product of dietary fiber digestion, the short chain fatty acids (SCFAs), and that plays a role in the regulation of whole-body energy homeostasis and in intestinal immunity. In omnivorous mammals, the short chain fatty acids acetate, propionate and butyrate are produced primarily by the gut microbiome that metabolizes dietary fibers. SCFAs serve as a source of energy but also act as signaling molecules. That G protein-coupled receptor is probably coupled to the pertussis toxin-sensitive, G(i/o)-alpha family of G proteins. Its activation results in the formation of inositol 1,4,5-trisphosphate, the mobilization of intracellular calcium, the phosphorylation of the MAPK3/ERK1 and MAPK1/ERK2 kinases and the inhibition of intracellular cAMP accumulation (PubMed:12711604). Activated by SCFAs and by beta-hydroxybutyrate, a ketone body produced by the liver upon starvation, it inhibits N-type calcium channels and modulates the activity of sympathetic neurons through a signaling cascade involving the beta and gamma subunits of its coupled G protein, phospholipase C and MAP kinases. Thereby, it may regulate energy expenditure through the control of the sympathetic nervous system that controls for instance heart rate. Upon activation by SCFAs accumulating in the intestine, it may also signal to the brain via neural circuits which in turn would regulate intestinal gluconeogenesis. May also control the production of hormones involved in whole-body energy homeostasis. May for instance, regulate blood pressure through renin secretion. May also regulate secretion of the PYY peptide by enteroendocrine cells and control gut motility, intestinal transit rate, and the harvesting of energy from SCFAs produced by gut microbiota. May also indirectly regulate the production of LEP/Leptin, a hormone acting on the CNS to inhibit food intake, in response to the presence of short-chain fatty acids in the intestine. Finally, may also play a role in glucose homeostasis. Besides its role in energy homeostasis, may play a role in intestinal immunity. May mediate the activation of the inflammatory and immune response by SCFAs in the gut, regulating the rapid production of chemokines and cytokines by intestinal epithelial cells. Among SCFAs, the fatty acids containing less than 6 carbons, the most potent activators are probably propionate, butyrate and pentanoate while acetate is a poor activator (PubMed:12496283, PubMed:12711604).4 Publications

GO - Molecular functioni

  • G-protein coupled receptor activity Source: UniProtKB
  • lipid binding Source: UniProtKB-KW

GO - Biological processi

Complete GO annotation...

Keywords - Molecular functioni

G-protein coupled receptor, Receptor, Transducer

Keywords - Biological processi

Immunity, Inflammatory response

Keywords - Ligandi

Lipid-binding

Enzyme and pathway databases

BioCyciZFISH:G66-31670-MONOMER.
ReactomeiR-HSA-416476. G alpha (q) signalling events.
R-HSA-444209. Free fatty acid receptors.

Chemistry databases

SwissLipidsiSLP:000001557.

Names & Taxonomyi

Protein namesi
Recommended name:
Free fatty acid receptor 3
Alternative name(s):
G-protein coupled receptor 41
Gene namesi
Name:FFAR3
Synonyms:GPR41
OrganismiHomo sapiens (Human)
Taxonomic identifieri9606 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo
Proteomesi
  • UP000005640 Componenti: Chromosome 19

Organism-specific databases

HGNCiHGNC:4499. FFAR3.

Subcellular locationi

Topology

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Topological domaini1 – 19ExtracellularSequence analysisAdd BLAST19
Transmembranei20 – 40Helical; Name=1Sequence analysisAdd BLAST21
Topological domaini41 – 47Cytoplasmic7
Transmembranei48 – 68Helical; Name=2Sequence analysisAdd BLAST21
Topological domaini69 – 88ExtracellularSequence analysisAdd BLAST20
Transmembranei89 – 111Helical; Name=3Sequence analysisAdd BLAST23
Topological domaini112 – 132CytoplasmicSequence analysisAdd BLAST21
Transmembranei133 – 153Helical; Name=4Sequence analysisAdd BLAST21
Topological domaini154 – 178ExtracellularSequence analysisAdd BLAST25
Transmembranei179 – 199Helical; Name=5Sequence analysisAdd BLAST21
Topological domaini200 – 222CytoplasmicSequence analysisAdd BLAST23
Transmembranei223 – 243Helical; Name=6Sequence analysisAdd BLAST21
Topological domaini244 – 258ExtracellularSequence analysisAdd BLAST15
Transmembranei259 – 279Helical; Name=7Sequence analysisAdd BLAST21
Topological domaini280 – 346CytoplasmicSequence analysisAdd BLAST67

GO - Cellular componenti

  • integral component of plasma membrane Source: ProtInc
  • plasma membrane Source: UniProtKB
Complete GO annotation...

Keywords - Cellular componenti

Cell membrane, Membrane

Pathology & Biotechi

Mutagenesis

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Mutagenesisi146H → A: Partial loss of SCFA-induced G protein-coupled receptor activity. 1 Publication1
Mutagenesisi158D → N: Gain of SCFA-independent constitutive G protein-coupled receptor activity. 1 Publication1
Mutagenesisi185R → A: Loss of SCFA-induced G protein-coupled receptor activity. 1 Publication1
Mutagenesisi245H → A: Loss of SCFA-induced G protein-coupled receptor activity. 1 Publication1
Mutagenesisi258R → A: Loss of SCFA-induced G protein-coupled receptor activity. 1 Publication1

Organism-specific databases

DisGeNETi2865.
OpenTargetsiENSG00000185897.
PharmGKBiPA28888.

Chemistry databases

ChEMBLiCHEMBL5201.
GuidetoPHARMACOLOGYi227.

Polymorphism and mutation databases

BioMutaiFFAR3.

PTM / Processingi

Molecule processing

Feature keyPosition(s)DescriptionActionsGraphical viewLength
ChainiPRO_00000695691 – 346Free fatty acid receptor 3Add BLAST346

Amino acid modifications

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Disulfide bondi88 ↔ 169PROSITE-ProRule annotation
Glycosylationi166N-linked (GlcNAc...)Sequence analysis1

Keywords - PTMi

Disulfide bond, Glycoprotein

Proteomic databases

PaxDbiO14843.
PRIDEiO14843.

Expressioni

Tissue specificityi

Highest level in adipose tissue, and lower expression across all tissues tested. Expressed in sympathetic ganglia.2 Publications

Gene expression databases

BgeeiENSG00000185897.
CleanExiHS_FFAR3.
ExpressionAtlasiO14843. baseline and differential.
GenevisibleiO14843. HS.

Organism-specific databases

HPAiHPA044681.

Interactioni

Protein-protein interaction databases

STRINGi9606.ENSP00000328230.

Chemistry databases

BindingDBiO14843.

Structurei

3D structure databases

ProteinModelPortaliO14843.
ModBaseiSearch...
MobiDBiSearch...

Family & Domainsi

Sequence similaritiesi

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

Keywords - Domaini

Transmembrane, Transmembrane helix

Phylogenomic databases

eggNOGiENOG410IITC. Eukaryota.
ENOG4111Q82. LUCA.
GeneTreeiENSGT00760000119001.
HOGENOMiHOG000026778.
HOVERGENiHBG051811.
InParanoidiO14843.
KOiK04326.
OMAiNSCVDPL.
OrthoDBiEOG091G0EX2.
PhylomeDBiO14843.
TreeFamiTF350010.

Family and domain databases

InterProiIPR000276. GPCR_Rhodpsn.
IPR017452. GPCR_Rhodpsn_7TM.
IPR013312. GPR40-rel_orph.
[Graphical view]
PfamiPF00001. 7tm_1. 1 hit.
[Graphical view]
PRINTSiPR00237. GPCRRHODOPSN.
PR01904. GPR40FAMILY.
PROSITEiPS00237. G_PROTEIN_RECEP_F1_1. 1 hit.
PS50262. G_PROTEIN_RECEP_F1_2. 1 hit.
[Graphical view]

Sequencei

Sequence statusi: Complete.

O14843-1 [UniParc]FASTAAdd to basket

« Hide

        10         20         30         40         50
MDTGPDQSYF SGNHWFVFSV YLLTFLVGLP LNLLALVVFV GKLQRRPVAV
60 70 80 90 100
DVLLLNLTAS DLLLLLFLPF RMVEAANGMH WPLPFILCPL SGFIFFTTIY
110 120 130 140 150
LTALFLAAVS IERFLSVAHP LWYKTRPRLG QAGLVSVACW LLASAHCSVV
160 170 180 190 200
YVIEFSGDIS HSQGTNGTCY LEFRKDQLAI LLPVRLEMAV VLFVVPLIIT
210 220 230 240 250
SYCYSRLVWI LGRGGSHRRQ RRVAGLLAAT LLNFLVCFGP YNVSHVVGYI
260 270 280 290 300
CGESPAWRIY VTLLSTLNSC VDPFVYYFSS SGFQADFHEL LRRLCGLWGQ
310 320 330 340
WQQESSMELK EQKGGEEQRA DRPAERKTSE HSQGCGTGGQ VACAES
Length:346
Mass (Da):38,649
Last modified:January 1, 1998 - v1
Checksum:iB3B19D62D11B6BA1
GO

Polymorphismi

The 6 amino acid differences at positions 44, 45, 174, 227, 256 and 346 between GPR42 and FFAR3, are polymorphic in the human population. The frequency of the probable inactive allele of FFAR3, with a Trp at position 174 was estimated to 1%.1 Publication

Natural variant

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Natural variantiVAR_06285444Q → R.1 Publication1
Natural variantiVAR_06285545R → C.1 PublicationCorresponds to variant rs423385dbSNPEnsembl.1
Natural variantiVAR_062856174R → W Abolishes activation by propionate. 2 Publications1
Natural variantiVAR_062857227L → V.1 PublicationCorresponds to variant rs403989dbSNPEnsembl.1
Natural variantiVAR_062858256A → V.1 PublicationCorresponds to variant rs424715dbSNPEnsembl.1
Natural variantiVAR_062962346S → N.1 PublicationCorresponds to variant rs201080710dbSNPEnsembl.1

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
AF024688 Genomic DNA. Translation: AAB86711.1.
U62631 Genomic DNA. No translation available.
BC035657 mRNA. Translation: AAH35657.1.
BC113695 mRNA. Translation: AAI13696.1.
BC148269 mRNA. Translation: AAI48270.1.
CCDSiCCDS12459.1.
PIRiJC5715.
RefSeqiNP_005295.1. NM_005304.3.
UniGeneiHs.248055.

Genome annotation databases

EnsembliENST00000327809; ENSP00000328230; ENSG00000185897.
ENST00000594310; ENSP00000469522; ENSG00000185897.
GeneIDi2865.
KEGGihsa:2865.
UCSCiuc002nzd.4. human.

Keywords - Coding sequence diversityi

Polymorphism

Cross-referencesi

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
AF024688 Genomic DNA. Translation: AAB86711.1.
U62631 Genomic DNA. No translation available.
BC035657 mRNA. Translation: AAH35657.1.
BC113695 mRNA. Translation: AAI13696.1.
BC148269 mRNA. Translation: AAI48270.1.
CCDSiCCDS12459.1.
PIRiJC5715.
RefSeqiNP_005295.1. NM_005304.3.
UniGeneiHs.248055.

3D structure databases

ProteinModelPortaliO14843.
ModBaseiSearch...
MobiDBiSearch...

Protein-protein interaction databases

STRINGi9606.ENSP00000328230.

Chemistry databases

BindingDBiO14843.
ChEMBLiCHEMBL5201.
GuidetoPHARMACOLOGYi227.
SwissLipidsiSLP:000001557.

Protein family/group databases

GPCRDBiSearch...

Polymorphism and mutation databases

BioMutaiFFAR3.

Proteomic databases

PaxDbiO14843.
PRIDEiO14843.

Protocols and materials databases

DNASUi2865.
Structural Biology KnowledgebaseSearch...

Genome annotation databases

EnsembliENST00000327809; ENSP00000328230; ENSG00000185897.
ENST00000594310; ENSP00000469522; ENSG00000185897.
GeneIDi2865.
KEGGihsa:2865.
UCSCiuc002nzd.4. human.

Organism-specific databases

CTDi2865.
DisGeNETi2865.
GeneCardsiFFAR3.
HGNCiHGNC:4499. FFAR3.
HPAiHPA044681.
MIMi603821. gene.
neXtProtiNX_O14843.
OpenTargetsiENSG00000185897.
PharmGKBiPA28888.
GenAtlasiSearch...

Phylogenomic databases

eggNOGiENOG410IITC. Eukaryota.
ENOG4111Q82. LUCA.
GeneTreeiENSGT00760000119001.
HOGENOMiHOG000026778.
HOVERGENiHBG051811.
InParanoidiO14843.
KOiK04326.
OMAiNSCVDPL.
OrthoDBiEOG091G0EX2.
PhylomeDBiO14843.
TreeFamiTF350010.

Enzyme and pathway databases

BioCyciZFISH:G66-31670-MONOMER.
ReactomeiR-HSA-416476. G alpha (q) signalling events.
R-HSA-444209. Free fatty acid receptors.

Miscellaneous databases

GeneWikiiFree_fatty_acid_receptor_3.
GenomeRNAii2865.
PROiO14843.
SOURCEiSearch...

Gene expression databases

BgeeiENSG00000185897.
CleanExiHS_FFAR3.
ExpressionAtlasiO14843. baseline and differential.
GenevisibleiO14843. HS.

Family and domain databases

InterProiIPR000276. GPCR_Rhodpsn.
IPR017452. GPCR_Rhodpsn_7TM.
IPR013312. GPR40-rel_orph.
[Graphical view]
PfamiPF00001. 7tm_1. 1 hit.
[Graphical view]
PRINTSiPR00237. GPCRRHODOPSN.
PR01904. GPR40FAMILY.
PROSITEiPS00237. G_PROTEIN_RECEP_F1_1. 1 hit.
PS50262. G_PROTEIN_RECEP_F1_2. 1 hit.
[Graphical view]
ProtoNetiSearch...

Entry informationi

Entry nameiFFAR3_HUMAN
AccessioniPrimary (citable) accession number: O14843
Secondary accession number(s): B2RWM8, Q14CM7
Entry historyi
Integrated into UniProtKB/Swiss-Prot: July 15, 1998
Last sequence update: January 1, 1998
Last modified: November 2, 2016
This is version 133 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

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. SIMILARITY comments
    Index of protein domains and families

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 one 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.