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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

  1. G-protein coupled receptor activity Source: UniProtKB
  2. lipid binding Source: UniProtKB-KW

GO - Biological processi

  1. adenylate cyclase-inhibiting G-protein coupled receptor signaling pathway Source: UniProtKB
  2. cellular response to fatty acid Source: UniProtKB
  3. G-protein coupled receptor signaling pathway Source: UniProtKB
  4. inflammatory response Source: UniProtKB-KW
  5. mucosal immune response Source: UniProtKB
  6. negative regulation of blood pressure Source: UniProtKB
  7. positive regulation of acute inflammatory response to non-antigenic stimulus Source: UniProtKB
  8. positive regulation of chemokine production Source: UniProtKB
  9. positive regulation of cytokine production involved in immune response Source: UniProtKB
  10. positive regulation of glucose import in response to insulin stimulus Source: UniProtKB
  11. regulation of hormone biosynthetic process Source: UniProtKB
  12. regulation of norepinephrine secretion Source: UniProtKB
  13. regulation of peptide hormone secretion Source: UniProtKB
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

ReactomeiREACT_18283. G alpha (q) signalling events.
REACT_21268. Free fatty acid receptors.

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
ProteomesiUP000005640 Componenti: Chromosome 19

Organism-specific databases

HGNCiHGNC:4499. FFAR3.

Subcellular locationi

  1. Cell membrane 1 Publication; Multi-pass membrane protein 1 Publication

Topology

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Topological domaini1 – 1919ExtracellularSequence AnalysisAdd
BLAST
Transmembranei20 – 4021Helical; Name=1Sequence AnalysisAdd
BLAST
Topological domaini41 – 477Cytoplasmic
Transmembranei48 – 6821Helical; Name=2Sequence AnalysisAdd
BLAST
Topological domaini69 – 8820ExtracellularSequence AnalysisAdd
BLAST
Transmembranei89 – 11123Helical; Name=3Sequence AnalysisAdd
BLAST
Topological domaini112 – 13221CytoplasmicSequence AnalysisAdd
BLAST
Transmembranei133 – 15321Helical; Name=4Sequence AnalysisAdd
BLAST
Topological domaini154 – 17825ExtracellularSequence AnalysisAdd
BLAST
Transmembranei179 – 19921Helical; Name=5Sequence AnalysisAdd
BLAST
Topological domaini200 – 22223CytoplasmicSequence AnalysisAdd
BLAST
Transmembranei223 – 24321Helical; Name=6Sequence AnalysisAdd
BLAST
Topological domaini244 – 25815ExtracellularSequence AnalysisAdd
BLAST
Transmembranei259 – 27921Helical; Name=7Sequence AnalysisAdd
BLAST
Topological domaini280 – 34667CytoplasmicSequence AnalysisAdd
BLAST

GO - Cellular componenti

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

Keywords - Cellular componenti

Cell membrane, Membrane

Pathology & Biotechi

Mutagenesis

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Mutagenesisi146 – 1461H → A: Partial loss of SCFA-induced G protein-coupled receptor activity. 1 Publication
Mutagenesisi158 – 1581D → N: Gain of SCFA-independent constitutive G protein-coupled receptor activity. 1 Publication
Mutagenesisi185 – 1851R → A: Loss of SCFA-induced G protein-coupled receptor activity. 1 Publication
Mutagenesisi245 – 2451H → A: Loss of SCFA-induced G protein-coupled receptor activity. 1 Publication
Mutagenesisi258 – 2581R → A: Loss of SCFA-induced G protein-coupled receptor activity. 1 Publication

Organism-specific databases

PharmGKBiPA28888.

Polymorphism and mutation databases

BioMutaiFFAR3.

PTM / Processingi

Molecule processing

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Chaini1 – 346346Free fatty acid receptor 3PRO_0000069569Add
BLAST

Amino acid modifications

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Disulfide bondi88 ↔ 169PROSITE-ProRule annotation
Glycosylationi166 – 1661N-linked (GlcNAc...)Sequence Analysis

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

BgeeiO14843.
CleanExiHS_FFAR3.
GenevestigatoriO14843.

Organism-specific databases

HPAiHPA044681.

Interactioni

Protein-protein interaction databases

STRINGi9606.ENSP00000246538.

Structurei

3D structure databases

ProteinModelPortaliO14843.
SMRiO14843. Positions 16-295.
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

eggNOGiNOG47521.
GeneTreeiENSGT00760000119001.
HOGENOMiHOG000026778.
HOVERGENiHBG051811.
InParanoidiO14843.
KOiK04326.
OMAiNSCVDPL.
OrthoDBiEOG7SFHXH.
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%.

Natural variant

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Natural varianti44 – 441Q → R.1 Publication
VAR_062854
Natural varianti45 – 451R → C.1 Publication
Corresponds to variant rs423385 [ dbSNP | Ensembl ].
VAR_062855
Natural varianti174 – 1741R → W Abolishes activation by propionate. 2 Publications
VAR_062856
Natural varianti227 – 2271L → V.1 Publication
Corresponds to variant rs403989 [ dbSNP | Ensembl ].
VAR_062857
Natural varianti256 – 2561A → V.1 Publication
Corresponds to variant rs424715 [ dbSNP | Ensembl ].
VAR_062858
Natural varianti346 – 3461S → N.1 Publication
VAR_062962

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.3. human.

Polymorphism and mutation databases

BioMutaiFFAR3.

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.
SMRiO14843. Positions 16-295.
ModBaseiSearch...
MobiDBiSearch...

Protein-protein interaction databases

STRINGi9606.ENSP00000246538.

Chemistry

BindingDBiO14843.
ChEMBLiCHEMBL5201.
GuidetoPHARMACOLOGYi227.

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.3. human.

Organism-specific databases

CTDi2865.
GeneCardsiGC19P035960.
HGNCiHGNC:4499. FFAR3.
HPAiHPA044681.
MIMi603821. gene.
neXtProtiNX_O14843.
PharmGKBiPA28888.
GenAtlasiSearch...

Phylogenomic databases

eggNOGiNOG47521.
GeneTreeiENSGT00760000119001.
HOGENOMiHOG000026778.
HOVERGENiHBG051811.
InParanoidiO14843.
KOiK04326.
OMAiNSCVDPL.
OrthoDBiEOG7SFHXH.
PhylomeDBiO14843.
TreeFamiTF350010.

Enzyme and pathway databases

ReactomeiREACT_18283. G alpha (q) signalling events.
REACT_21268. Free fatty acid receptors.

Miscellaneous databases

GeneWikiiFree_fatty_acid_receptor_3.
GenomeRNAii2865.
NextBioi11297.
PROiO14843.
SOURCEiSearch...

Gene expression databases

BgeeiO14843.
CleanExiHS_FFAR3.
GenevestigatoriO14843.

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...

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(1997) [PubMed] [Europe PMC] [Abstract]
    Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA].
  2. "The DNA sequence and biology of human chromosome 19."
    Grimwood J., Gordon L.A., Olsen A.S., Terry A., Schmutz J., Lamerdin J.E., Hellsten U., Goodstein D., Couronne O., Tran-Gyamfi M., Aerts A., Altherr M., Ashworth L., Bajorek E., Black S., Branscomb E., Caenepeel S., Carrano A.V.
    , Caoile C., Chan Y.M., Christensen M., Cleland C.A., Copeland A., Dalin E., Dehal P., Denys M., Detter J.C., Escobar J., Flowers D., Fotopulos D., Garcia C., Georgescu A.M., Glavina T., Gomez M., Gonzales E., Groza M., Hammon N., Hawkins T., Haydu L., Ho I., Huang W., Israni S., Jett J., Kadner K., Kimball H., Kobayashi A., Larionov V., Leem S.-H., Lopez F., Lou Y., Lowry S., Malfatti S., Martinez D., McCready P.M., Medina C., Morgan J., Nelson K., Nolan M., Ovcharenko I., Pitluck S., Pollard M., Popkie A.P., Predki P., Quan G., Ramirez L., Rash S., Retterer J., Rodriguez A., Rogers S., Salamov A., Salazar A., She X., Smith D., Slezak T., Solovyev V., Thayer N., Tice H., Tsai M., Ustaszewska A., Vo N., Wagner M., Wheeler J., Wu K., Xie G., Yang J., Dubchak I., Furey T.S., DeJong P., Dickson M., Gordon D., Eichler E.E., Pennacchio L.A., Richardson P., Stubbs L., Rokhsar D.S., Myers R.M., Rubin E.M., Lucas S.M.
    Nature 428:529-535(2004) [PubMed] [Europe PMC] [Abstract]
    Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
  3. "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(2004) [PubMed] [Europe PMC] [Abstract]
    Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
    Tissue: Brain and Ovary.
  4. Cited for: FUNCTION, CHARACTERIZATION OF VARIANT TRP-174, TISSUE SPECIFICITY.
  5. "Functional characterization of human receptors for short chain fatty acids and their role in polymorphonuclear cell activation."
    Le Poul E., Loison C., Struyf S., Springael J.Y., Lannoy V., Decobecq M.E., Brezillon S., Dupriez V., Vassart G., Van Damme J., Parmentier M., Detheux M.
    J. Biol. Chem. 278:25481-25489(2003) [PubMed] [Europe PMC] [Abstract]
    Cited for: FUNCTION, CHARACTERIZATION.
  6. "Conserved polar residues in transmembrane domains V, VI, and VII of free fatty acid receptor 2 and free fatty acid receptor 3 are required for the binding and function of short chain fatty acids."
    Stoddart L.A., Smith N.J., Jenkins L., Brown A.J., Milligan G.
    J. Biol. Chem. 283:32913-32924(2008) [PubMed] [Europe PMC] [Abstract]
    Cited for: FUNCTION, SUBCELLULAR LOCATION, MUTAGENESIS OF HIS-146; ARG-185; HIS-245 AND ARG-258.
  7. "Sequence polymorphisms provide a common consensus sequence for GPR41 and GPR42."
    Liaw C.W., Connolly D.T.
    DNA Cell Biol. 28:555-560(2009) [PubMed] [Europe PMC] [Abstract]
    Cited for: POLYMORPHISM, VARIANTS ARG-44; CYS-45; TRP-174; VAL-227; VAL-256 AND ASN-346.
  8. "Short-chain fatty acids and ketones directly regulate sympathetic nervous system via G protein-coupled receptor 41 (GPR41)."
    Kimura I., Inoue D., Maeda T., Hara T., Ichimura A., Miyauchi S., Kobayashi M., Hirasawa A., Tsujimoto G.
    Proc. Natl. Acad. Sci. U.S.A. 108:8030-8035(2011) [PubMed] [Europe PMC] [Abstract]
    Cited for: TISSUE SPECIFICITY.
  9. "Extracellular ionic locks determine variation in constitutive activity and ligand potency between species orthologs of the free fatty acid receptors FFA2 and FFA3."
    Hudson B.D., Tikhonova I.G., Pandey S.K., Ulven T., Milligan G.
    J. Biol. Chem. 287:41195-41209(2012) [PubMed] [Europe PMC] [Abstract]
    Cited for: FUNCTION, MUTAGENESIS OF ASP-158.

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: April 29, 2015
This is version 121 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

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.