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O14843

- FFAR3_HUMAN

UniProt

O14843 - FFAR3_HUMAN

Protein

Free fatty acid receptor 3

Gene

FFAR3

Organism
Homo sapiens (Human)
Status
Reviewed - Annotation score: 5 out of 5- Experimental evidence at protein leveli
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    • History
      Entry version 116 (01 Oct 2014)
      Sequence version 1 (01 Jan 1998)
      Previous versions | rss
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    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. mucosal immune response Source: UniProtKB
    5. negative regulation of blood pressure Source: UniProtKB
    6. positive regulation of acute inflammatory response to non-antigenic stimulus Source: UniProtKB
    7. positive regulation of chemokine production Source: UniProtKB
    8. positive regulation of cytokine production involved in immune response Source: UniProtKB
    9. positive regulation of glucose import in response to insulin stimulus Source: UniProtKB
    10. regulation of hormone biosynthetic process Source: UniProtKB
    11. regulation of norepinephrine secretion Source: UniProtKB
    12. regulation of peptide hormone secretion Source: UniProtKB

    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: Chromosome 19

    Organism-specific databases

    HGNCiHGNC:4499. FFAR3.

    Subcellular locationi

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

    GO - Cellular componenti

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

    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.

    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 6-295.
    ModBaseiSearch...
    MobiDBiSearch...

    Topological domain

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Topological domaini1 – 1919ExtracellularSequence AnalysisAdd
    BLAST
    Topological domaini41 – 477Cytoplasmic
    Topological domaini69 – 8820ExtracellularSequence AnalysisAdd
    BLAST
    Topological domaini112 – 13221CytoplasmicSequence AnalysisAdd
    BLAST
    Topological domaini154 – 17825ExtracellularSequence AnalysisAdd
    BLAST
    Topological domaini200 – 22223CytoplasmicSequence AnalysisAdd
    BLAST
    Topological domaini244 – 25815ExtracellularSequence AnalysisAdd
    BLAST
    Topological domaini280 – 34667CytoplasmicSequence AnalysisAdd
    BLAST

    Transmembrane

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Transmembranei20 – 4021Helical; Name=1Sequence AnalysisAdd
    BLAST
    Transmembranei48 – 6821Helical; Name=2Sequence AnalysisAdd
    BLAST
    Transmembranei89 – 11123Helical; Name=3Sequence AnalysisAdd
    BLAST
    Transmembranei133 – 15321Helical; Name=4Sequence AnalysisAdd
    BLAST
    Transmembranei179 – 19921Helical; Name=5Sequence AnalysisAdd
    BLAST
    Transmembranei223 – 24321Helical; Name=6Sequence AnalysisAdd
    BLAST
    Transmembranei259 – 27921Helical; Name=7Sequence AnalysisAdd
    BLAST

    Family & Domainsi

    Sequence similaritiesi

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

    Keywords - Domaini

    Transmembrane, Transmembrane helix

    Phylogenomic databases

    eggNOGiNOG47521.
    HOGENOMiHOG000026778.
    HOVERGENiHBG051811.
    InParanoidiO14843.
    KOiK04326.
    OMAiYVMEFSG.
    OrthoDBiEOG7SFHXH.
    PhylomeDBiO14843.
    TreeFamiTF350010.

    Family and domain databases

    Gene3Di1.20.1070.10. 1 hit.
    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

    MDTGPDQSYF SGNHWFVFSV YLLTFLVGLP LNLLALVVFV GKLQRRPVAV    50
    DVLLLNLTAS DLLLLLFLPF RMVEAANGMH WPLPFILCPL SGFIFFTTIY 100
    LTALFLAAVS IERFLSVAHP LWYKTRPRLG QAGLVSVACW LLASAHCSVV 150
    YVIEFSGDIS HSQGTNGTCY LEFRKDQLAI LLPVRLEMAV VLFVVPLIIT 200
    SYCYSRLVWI LGRGGSHRRQ RRVAGLLAAT LLNFLVCFGP YNVSHVVGYI 250
    CGESPAWRIY VTLLSTLNSC VDPFVYYFSS SGFQADFHEL LRRLCGLWGQ 300
    WQQESSMELK EQKGGEEQRA DRPAERKTSE HSQGCGTGGQ VACAES 346
    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. 1 Publication
    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:
    EMBL
    GenBank
    DDBJ
    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.

    Keywords - Coding sequence diversityi

    Polymorphism

    Cross-referencesi

    Sequence databases

    Select the link destinations:
    EMBL
    GenBank
    DDBJ
    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 .
    CCDSi CCDS12459.1.
    PIRi JC5715.
    RefSeqi NP_005295.1. NM_005304.3.
    UniGenei Hs.248055.

    3D structure databases

    ProteinModelPortali O14843.
    SMRi O14843. Positions 6-295.
    ModBasei Search...
    MobiDBi Search...

    Protein-protein interaction databases

    STRINGi 9606.ENSP00000246538.

    Chemistry

    ChEMBLi CHEMBL5201.
    GuidetoPHARMACOLOGYi 227.

    Protein family/group databases

    GPCRDBi Search...

    Proteomic databases

    PaxDbi O14843.
    PRIDEi O14843.

    Protocols and materials databases

    DNASUi 2865.
    Structural Biology Knowledgebase Search...

    Genome annotation databases

    Ensembli ENST00000327809 ; ENSP00000328230 ; ENSG00000185897 .
    ENST00000594310 ; ENSP00000469522 ; ENSG00000185897 .
    GeneIDi 2865.
    KEGGi hsa:2865.
    UCSCi uc002nzd.3. human.

    Organism-specific databases

    CTDi 2865.
    GeneCardsi GC19P035851.
    HGNCi HGNC:4499. FFAR3.
    HPAi HPA044681.
    MIMi 603821. gene.
    neXtProti NX_O14843.
    PharmGKBi PA28888.
    GenAtlasi Search...

    Phylogenomic databases

    eggNOGi NOG47521.
    HOGENOMi HOG000026778.
    HOVERGENi HBG051811.
    InParanoidi O14843.
    KOi K04326.
    OMAi YVMEFSG.
    OrthoDBi EOG7SFHXH.
    PhylomeDBi O14843.
    TreeFami TF350010.

    Enzyme and pathway databases

    Reactomei REACT_18283. G alpha (q) signalling events.
    REACT_21268. Free fatty acid receptors.

    Miscellaneous databases

    GeneWikii Free_fatty_acid_receptor_3.
    GenomeRNAii 2865.
    NextBioi 11297.
    PROi O14843.
    SOURCEi Search...

    Gene expression databases

    Bgeei O14843.
    CleanExi HS_FFAR3.
    Genevestigatori O14843.

    Family and domain databases

    Gene3Di 1.20.1070.10. 1 hit.
    InterProi IPR000276. GPCR_Rhodpsn.
    IPR017452. GPCR_Rhodpsn_7TM.
    IPR013312. GPR40-rel_orph.
    [Graphical view ]
    Pfami PF00001. 7tm_1. 1 hit.
    [Graphical view ]
    PRINTSi PR00237. GPCRRHODOPSN.
    PR01904. GPR40FAMILY.
    PROSITEi PS00237. G_PROTEIN_RECEP_F1_1. 1 hit.
    PS50262. G_PROTEIN_RECEP_F1_2. 1 hit.
    [Graphical view ]
    ProtoNeti Search...

    Publicationsi

    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: October 1, 2014
    This is version 116 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