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O15552

- FFAR2_HUMAN

UniProt

O15552 - FFAR2_HUMAN

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Protein

Free fatty acid receptor 2

Gene

FFAR2

Organism
Homo sapiens (Human)
Status
Reviewed - 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 but also to the Gq family (PubMed:12496283, PubMed:12711604, PubMed:23589301). 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. May play a role in glucose homeostasis by regulating the secretion of GLP-1, in response to short-chain fatty acids accumulating in the intestine. May also regulate the production of LEP/Leptin, a hormone acting on the central nervous system to inhibit food intake. Finally, may also regulate whole-body energy homeostasis through adipogenesis regulating both differentiation and lipid storage of adipocytes. In parallel to its role in energy homeostasis, may also mediate the activation of the inflammatory and immune responses by SCFA in the intestine, regulating the rapid production of chemokines and cytokines. May also play a role in the resolution of the inflammatory response and control chemotaxis in neutrophils. In addition to SCFAs, may also be activated by the extracellular lectin FCN1 in a process leading to activation of monocytes and inducing the secretion of interleukin-8/IL-8 in response to the presence of microbes (PubMed:21037097). Among SCFAs, the fatty acids containing less than 6 carbons, the most potent activators are probably acetate, propionate and butyrate (PubMed:12496283, PubMed:12711604). Exhibits a SCFA-independent constitutive G protein-coupled receptor activity (PubMed:23066016).7 Publications

GO - Molecular functioni

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

GO - Biological processi

  1. cell surface pattern recognition receptor signaling pathway Source: UniProtKB
  2. cellular response to fatty acid Source: UniProtKB
  3. fat cell differentiation Source: UniProtKB
  4. glucose homeostasis Source: UniProtKB
  5. G-protein coupled receptor signaling pathway Source: UniProtKB
  6. leukocyte chemotaxis involved in inflammatory response Source: UniProtKB
  7. lipid storage Source: UniProtKB
  8. mucosal immune response Source: UniProtKB
  9. positive regulation of acute inflammatory response to non-antigenic stimulus Source: UniProtKB
  10. positive regulation of chemokine production Source: UniProtKB
  11. positive regulation of cytokine production involved in immune response Source: UniProtKB
  12. positive regulation of interleukin-8 secretion Source: UniProtKB
  13. regulation of acute inflammatory response Source: UniProtKB
  14. 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 2
Alternative name(s):
G-protein coupled receptor 43
Gene namesi
Name:FFAR2
Synonyms:FFA2, GPCR43, GPR43
OrganismiHomo sapiens (Human)
Taxonomic identifieri9606 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo
ProteomesiUP000005640: Chromosome 19

Organism-specific databases

HGNCiHGNC:4501. FFAR2.

Subcellular locationi

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

Topology

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Topological domaini1 – 1212ExtracellularSequence AnalysisAdd
BLAST
Transmembranei13 – 3321Helical; Name=1Sequence AnalysisAdd
BLAST
Topological domaini34 – 418Cytoplasmic
Transmembranei42 – 6221Helical; Name=2Sequence AnalysisAdd
BLAST
Topological domaini63 – 8422ExtracellularSequence AnalysisAdd
BLAST
Transmembranei85 – 10521Helical; Name=3Sequence AnalysisAdd
BLAST
Topological domaini106 – 12621CytoplasmicSequence AnalysisAdd
BLAST
Transmembranei127 – 14721Helical; Name=4Sequence AnalysisAdd
BLAST
Topological domaini148 – 17326ExtracellularSequence AnalysisAdd
BLAST
Transmembranei174 – 19421Helical; Name=5Sequence AnalysisAdd
BLAST
Topological domaini195 – 21925CytoplasmicSequence AnalysisAdd
BLAST
Transmembranei220 – 24021Helical; Name=6Sequence AnalysisAdd
BLAST
Topological domaini241 – 25515ExtracellularSequence AnalysisAdd
BLAST
Transmembranei256 – 27621Helical; Name=7Sequence AnalysisAdd
BLAST
Topological domaini277 – 33054CytoplasmicSequence AnalysisAdd
BLAST

GO - Cellular componenti

  1. cell projection Source: Ensembl
  2. integral component of plasma membrane Source: ProtInc
  3. plasma membrane Source: UniProtKB
Complete GO annotation...

Keywords - Cellular componenti

Cell membrane, Membrane

Pathology & Biotechi

Mutagenesis

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Mutagenesisi90 – 901Y → A: Partial loss of propionate-induced G protein-coupled receptor activity. 2 Publications
Mutagenesisi90 – 901Y → W: Complete loss of acetate-induced G protein-coupled receptor activity. 2 Publications
Mutagenesisi106 – 1061E → A: Partial loss of SCFA-induced G protein-coupled receptor activity. 1 Publication
Mutagenesisi108 – 1081Y → A: Complete loss of SCFA-induced G protein-coupled receptor activity. 1 Publication
Mutagenesisi140 – 1401H → A: Partial loss of SCFA-induced G protein-coupled receptor activity. 2 Publications
Mutagenesisi148 – 1481Q → A: No effect on SCFA-induced G protein-coupled receptor activity. 1 Publication
Mutagenesisi148 – 1481Q → E: Partial loss of SCFA-induced G protein-coupled receptor activity. 1 Publication
Mutagenesisi159 – 1591G → E: Partial loss of SCFA-independent constitutive G protein-coupled receptor activity. 1 Publication
Mutagenesisi165 – 1651Y → A: Partial loss of propionate-induced G protein-coupled receptor activity. 1 Publication
Mutagenesisi180 – 1801R → A, K, L or S: Complete loss of SCFA-induced G protein-coupled receptor activity. 3 Publications
Mutagenesisi238 – 2381Y → A: Partial loss of propionate-induced G protein-coupled receptor activity. 1 Publication
Mutagenesisi239 – 2391N → A: Complete loss of acetate-induced G protein-coupled receptor activity. 1 Publication
Mutagenesisi242 – 2421H → A or F: Complete loss of SCFA-induced G protein-coupled receptor activity. 3 Publications
Mutagenesisi255 – 2551R → A: Complete loss of SCFA-induced G protein-coupled receptor activity. 3 Publications

Organism-specific databases

PharmGKBiPA28890.

PTM / Processingi

Molecule processing

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Chaini1 – 330330Free fatty acid receptor 2PRO_0000069571Add
BLAST

Amino acid modifications

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Glycosylationi151 – 1511N-linked (GlcNAc...)Sequence Analysis
Glycosylationi167 – 1671N-linked (GlcNAc...)Sequence Analysis

Keywords - PTMi

Glycoprotein

Proteomic databases

PaxDbiO15552.
PRIDEiO15552.

PTM databases

PhosphoSiteiO15552.

Expressioni

Tissue specificityi

Expressed at relatively high levels in peripheral blood leukocytes and, to lesser extent, in spleen.2 Publications

Gene expression databases

BgeeiO15552.
CleanExiHS_FFAR2.
ExpressionAtlasiO15552. baseline and differential.
GenevestigatoriO15552.

Organism-specific databases

HPAiHPA023985.

Interactioni

Subunit structurei

Interacts with FCN1 (via Fibrinogen C-terminal domain).1 Publication

Protein-protein interaction databases

BioGridi109125. 2 interactions.
IntActiO15552. 3 interactions.
STRINGi9606.ENSP00000246549.

Structurei

3D structure databases

ProteinModelPortaliO15552.
SMRiO15552. Positions 4-288.
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.
InParanoidiO15552.
KOiK04328.
OMAiTGFGFYS.
OrthoDBiEOG7SFHXH.
PhylomeDBiO15552.
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.

O15552-1 [UniParc]FASTAAdd to Basket

« Hide

        10         20         30         40         50
MLPDWKSSLI LMAYIIIFLT GLPANLLALR AFVGRIRQPQ PAPVHILLLS
60 70 80 90 100
LTLADLLLLL LLPFKIIEAA SNFRWYLPKV VCALTSFGFY SSIYCSTWLL
110 120 130 140 150
AGISIERYLG VAFPVQYKLS RRPLYGVIAA LVAWVMSFGH CTIVIIVQYL
160 170 180 190 200
NTTEQVRSGN EITCYENFTD NQLDVVLPVR LELCLVLFFI PMAVTIFCYW
210 220 230 240 250
RFVWIMLSQP LVGAQRRRRA VGLAVVTLLN FLVCFGPYNV SHLVGYHQRK
260 270 280 290 300
SPWWRSIAVV FSSLNASLDP LLFYFSSSVV RRAFGRGLQV LRNQGSSLLG
310 320 330
RRGKDTAEGT NEDRGVGQGE GMPSSDFTTE
Length:330
Mass (Da):37,144
Last modified:January 1, 1998 - v1
Checksum:iF4A8AC6AFBDF1E90
GO

Experimental Info

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Sequence conflicti227 – 2271T → M in AAH96201. (PubMed:15489334)Curated

Natural variant

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Natural varianti211 – 2111L → H.
Corresponds to variant rs409093 [ dbSNP | Ensembl ].
VAR_011861

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
AF024690 Genomic DNA. Translation: AAB86713.1.
AC002511 Genomic DNA. Translation: AAB67886.1.
EU432114 Genomic DNA. Translation: ABY87913.1.
BC095535 mRNA. Translation: AAH95535.1.
BC096198 mRNA. Translation: AAH96198.1.
BC096199 mRNA. Translation: AAH96199.1.
BC096200 mRNA. Translation: AAH96200.1.
BC096201 mRNA. Translation: AAH96201.1.
CCDSiCCDS12461.1.
PIRiJC5717.
RefSeqiNP_005297.1. NM_005306.2.
UniGeneiHs.248056.

Genome annotation databases

EnsembliENST00000246549; ENSP00000246549; ENSG00000126262.
ENST00000599180; ENSP00000473159; ENSG00000126262.
GeneIDi2867.
KEGGihsa:2867.
UCSCiuc002nzg.2. human.

Keywords - Coding sequence diversityi

Polymorphism

Cross-referencesi

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
AF024690 Genomic DNA. Translation: AAB86713.1 .
AC002511 Genomic DNA. Translation: AAB67886.1 .
EU432114 Genomic DNA. Translation: ABY87913.1 .
BC095535 mRNA. Translation: AAH95535.1 .
BC096198 mRNA. Translation: AAH96198.1 .
BC096199 mRNA. Translation: AAH96199.1 .
BC096200 mRNA. Translation: AAH96200.1 .
BC096201 mRNA. Translation: AAH96201.1 .
CCDSi CCDS12461.1.
PIRi JC5717.
RefSeqi NP_005297.1. NM_005306.2.
UniGenei Hs.248056.

3D structure databases

ProteinModelPortali O15552.
SMRi O15552. Positions 4-288.
ModBasei Search...
MobiDBi Search...

Protein-protein interaction databases

BioGridi 109125. 2 interactions.
IntActi O15552. 3 interactions.
STRINGi 9606.ENSP00000246549.

Chemistry

BindingDBi O15552.
ChEMBLi CHEMBL5493.
GuidetoPHARMACOLOGYi 226.

Protein family/group databases

GPCRDBi Search...

PTM databases

PhosphoSitei O15552.

Proteomic databases

PaxDbi O15552.
PRIDEi O15552.

Protocols and materials databases

DNASUi 2867.
Structural Biology Knowledgebase Search...

Genome annotation databases

Ensembli ENST00000246549 ; ENSP00000246549 ; ENSG00000126262 .
ENST00000599180 ; ENSP00000473159 ; ENSG00000126262 .
GeneIDi 2867.
KEGGi hsa:2867.
UCSCi uc002nzg.2. human.

Organism-specific databases

CTDi 2867.
GeneCardsi GC19P036042.
H-InvDB HIX0027605.
HGNCi HGNC:4501. FFAR2.
HPAi HPA023985.
MIMi 603823. gene.
neXtProti NX_O15552.
PharmGKBi PA28890.
GenAtlasi Search...

Phylogenomic databases

eggNOGi NOG47521.
GeneTreei ENSGT00760000119001.
HOGENOMi HOG000026778.
HOVERGENi HBG051811.
InParanoidi O15552.
KOi K04328.
OMAi TGFGFYS.
OrthoDBi EOG7SFHXH.
PhylomeDBi O15552.
TreeFami TF350010.

Enzyme and pathway databases

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

Miscellaneous databases

GenomeRNAii 2867.
NextBioi 11305.
PROi O15552.
SOURCEi Search...

Gene expression databases

Bgeei O15552.
CleanExi HS_FFAR2.
ExpressionAtlasi O15552. baseline and differential.
Genevestigatori O15552.

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

« 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. Kaighin V.A., Martin A.L., Aronstam R.S.
    Submitted (DEC-2007) to the EMBL/GenBank/DDBJ databases
    Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA].
  4. "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].
  5. "Identification of a free fatty acid receptor, FFA2R, expressed on leukocytes and activated by short-chain fatty acids."
    Nilsson N.E., Kotarsky K., Owman C., Olde B.
    Biochem. Biophys. Res. Commun. 303:1047-1052(2003) [PubMed] [Europe PMC] [Abstract]
    Cited for: FUNCTION, TISSUE SPECIFICITY.
  6. Cited for: FUNCTION, TISSUE SPECIFICITY.
  7. "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.
  8. "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-140; ARG-180; HIS-242 AND ARG-255.
  9. Cited for: MUTAGENESIS OF GLU-106; TYR-108; ARG-180 AND ARG-255.
  10. "Secreted M-ficolin anchors onto monocyte transmembrane G protein-coupled receptor 43 and cross talks with plasma C-reactive protein to mediate immune signaling and regulate host defense."
    Zhang J., Yang L., Ang Z., Yoong S.L., Tran T.T., Anand G.S., Tan N.S., Ho B., Ding J.L.
    J. Immunol. 185:6899-6910(2010) [PubMed] [Europe PMC] [Abstract]
    Cited for: FUNCTION, INTERACTION WITH FCN1.
  11. Cited for: MUTAGENESIS OF TYR-90; ASN-239 AND HIS-242.
  12. "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: MUTAGENESIS OF GLY-159.
  13. "Defining the molecular basis for the first potent and selective orthosteric agonists of the FFA2 free fatty acid receptor."
    Hudson B.D., Due-Hansen M.E., Christiansen E., Hansen A.M., Mackenzie A.E., Murdoch H., Pandey S.K., Ward R.J., Marquez R., Tikhonova I.G., Ulven T., Milligan G.
    J. Biol. Chem. 288:17296-17312(2013) [PubMed] [Europe PMC] [Abstract]
    Cited for: FUNCTION, MUTAGENESIS OF TYR-90; HIS-140; GLN-148; TYR-165; ARG-180; TYR-238; HIS-242 AND ARG-255.

Entry informationi

Entry nameiFFAR2_HUMAN
AccessioniPrimary (citable) accession number: O15552
Secondary accession number(s): B0M0J9
, Q4VAZ3, Q4VAZ5, Q4VBL5
Entry historyi
Integrated into UniProtKB/Swiss-Prot: July 15, 1998
Last sequence update: January 1, 1998
Last modified: October 29, 2014
This is version 118 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