Q5NUL3 · FFAR4_HUMAN
- ProteinFree fatty acid receptor 4
- GeneFFAR4
- StatusUniProtKB reviewed (Swiss-Prot)
- Organism
- Amino acids361 (go to sequence)
- Protein existenceEvidence at protein level
- Annotation score5/5
Function
function
Isoform 2
G-protein-coupled receptor for long-chain fatty acids (LCFAs) with a major role in adipogenesis, energy metabolism and inflammation. Signals via G-protein and beta-arrestin pathways (PubMed:22282525, PubMed:22343897, PubMed:24742677, PubMed:24817122, PubMed:27852822).
LCFAs sensing initiates activation of phosphoinositidase C-linked G proteins GNAQ and GNA11 (G(q)/G11), inducing a variety of cellular responses via second messenger pathways such as intracellular calcium mobilization, modulation of cyclic adenosine monophosphate (cAMP) production, and mitogen-activated protein kinases (MAPKs) (PubMed:22282525, PubMed:22343897, PubMed:24742677, PubMed:27852822).
After LCFAs binding, associates with beta-arrestin ARRB2 that acts as an adapter protein coupling the receptor to specific downstream signaling pathways, as well as mediating receptor endocytosis (PubMed:22282525, PubMed:24817122).
In response to dietary fats, plays an important role in the regulation of adipocyte proliferation and differentiation (By similarity).
Acts as a receptor for omega-3 polyunsaturated fatty acids (PUFAs) at primary cilium of perivascular preadipocytes, initiating an adipogenic program via cAMP and CTCF-dependent chromatin remodeling that ultimately results in transcriptional activation of adipogenic genes and cell cycle entry (By similarity).
Induces differentiation of brown adipocytes probably via autocrine and endocrine functions of FGF21 hormone (By similarity).
Activates brown adipocytes by initiating intracellular calcium signaling that leads to mitochondrial depolarization and fission, and overall increased mitochondrial respiration (By similarity).
Consequently stimulates fatty acid uptake and oxidation in mitochondria together with UCP1-mediated thermogenic respiration, eventually reducing fat mass (By similarity).
Regulates bi-potential differentiation of bone marrow mesenchymal stem cells toward osteoblasts or adipocytes likely by up-regulating distinct integrins (By similarity).
In response to dietary fats regulates hormone secretion and appetite (By similarity).
Stimulates GIP and GLP1 secretion from enteroendocrine cells as well as GCG secretion in pancreatic alpha cells, thereby playing a role in the regulation of blood glucose levels (By similarity).
Negatively regulates glucose-induced SST secretion in pancreatic delta cells (By similarity).
Mediates LCFAs inhibition of GHRL secretion, an appetite-controlling hormone (By similarity).
In taste buds, contributes to sensing of dietary fatty acids by the gustatory system (By similarity).
During the inflammatory response, promotes anti-inflammatory M2 macrophage differentiation in adipose tissue (By similarity).
Mediates the anti-inflammatory effects of omega-3 PUFAs via inhibition of NLRP3 inflammasome activation (PubMed:23809162).
In this pathway, interacts with adapter protein ARRB2 and inhibits the priming step triggered by Toll-like receptors (TLRs) at the level of TAK1 and TAB1 (By similarity).
Further inhibits the activation step when ARRB2 directly associates with NLRP3, leading to inhibition of pro-inflammatory cytokine release (PubMed:23809162).
Mediates LCFAs anti-apoptotic effects (By similarity).
LCFAs sensing initiates activation of phosphoinositidase C-linked G proteins GNAQ and GNA11 (G(q)/G11), inducing a variety of cellular responses via second messenger pathways such as intracellular calcium mobilization, modulation of cyclic adenosine monophosphate (cAMP) production, and mitogen-activated protein kinases (MAPKs) (PubMed:22282525, PubMed:22343897, PubMed:24742677, PubMed:27852822).
After LCFAs binding, associates with beta-arrestin ARRB2 that acts as an adapter protein coupling the receptor to specific downstream signaling pathways, as well as mediating receptor endocytosis (PubMed:22282525, PubMed:24817122).
In response to dietary fats, plays an important role in the regulation of adipocyte proliferation and differentiation (By similarity).
Acts as a receptor for omega-3 polyunsaturated fatty acids (PUFAs) at primary cilium of perivascular preadipocytes, initiating an adipogenic program via cAMP and CTCF-dependent chromatin remodeling that ultimately results in transcriptional activation of adipogenic genes and cell cycle entry (By similarity).
Induces differentiation of brown adipocytes probably via autocrine and endocrine functions of FGF21 hormone (By similarity).
Activates brown adipocytes by initiating intracellular calcium signaling that leads to mitochondrial depolarization and fission, and overall increased mitochondrial respiration (By similarity).
Consequently stimulates fatty acid uptake and oxidation in mitochondria together with UCP1-mediated thermogenic respiration, eventually reducing fat mass (By similarity).
Regulates bi-potential differentiation of bone marrow mesenchymal stem cells toward osteoblasts or adipocytes likely by up-regulating distinct integrins (By similarity).
In response to dietary fats regulates hormone secretion and appetite (By similarity).
Stimulates GIP and GLP1 secretion from enteroendocrine cells as well as GCG secretion in pancreatic alpha cells, thereby playing a role in the regulation of blood glucose levels (By similarity).
Negatively regulates glucose-induced SST secretion in pancreatic delta cells (By similarity).
Mediates LCFAs inhibition of GHRL secretion, an appetite-controlling hormone (By similarity).
In taste buds, contributes to sensing of dietary fatty acids by the gustatory system (By similarity).
During the inflammatory response, promotes anti-inflammatory M2 macrophage differentiation in adipose tissue (By similarity).
Mediates the anti-inflammatory effects of omega-3 PUFAs via inhibition of NLRP3 inflammasome activation (PubMed:23809162).
In this pathway, interacts with adapter protein ARRB2 and inhibits the priming step triggered by Toll-like receptors (TLRs) at the level of TAK1 and TAB1 (By similarity).
Further inhibits the activation step when ARRB2 directly associates with NLRP3, leading to inhibition of pro-inflammatory cytokine release (PubMed:23809162).
Mediates LCFAs anti-apoptotic effects (By similarity).
Isoform 1
Receptor for LCFAs decoupled from G-protein signaling. May signal through beta-arrestin pathway. After LCFAs binding, associates with beta-arrestin ARRB2 that may act as an adapter protein coupling the receptor to specific downstream signaling pathways, as well as mediating receptor endocytosis.
GO annotations
Keywords
- Molecular function
- Biological process
- Ligand
Enzyme and pathway databases
Protein family/group databases
Chemistry
Names & Taxonomy
Protein names
- Recommended nameFree fatty acid receptor 4
- Alternative names
Gene names
Organism names
- Organism
- Taxonomic lineageEukaryota > Metazoa > Chordata > Craniata > Vertebrata > Euteleostomi > Mammalia > Eutheria > Euarchontoglires > Primates > Haplorrhini > Catarrhini > Hominidae > Homo
Accessions
- Primary accessionQ5NUL3
- Secondary accessions
Proteomes
Organism-specific databases
Subcellular Location
UniProt Annotation
GO Annotation
Isoform 1
Cell membrane ; Multi-pass membrane protein
Endosome membrane ; Multi-pass membrane protein
Lysosome membrane ; Multi-pass membrane protein
Note: Sorted to late endosome/lysosome compartments upon internalization.
Isoform 2
Cell membrane ; Multi-pass membrane protein
Endosome membrane ; Multi-pass membrane protein
Lysosome membrane ; Multi-pass membrane protein
Cell projection, cilium membrane ; Multi-pass membrane protein
Note: Sorted to late endosome/lysosome compartments upon internalization (PubMed:22282525).
Specifically localizes to the primary cilium of undifferentiated adipocytes. Ciliary trafficking is TULP3-dependent. As the cilium is lost during adipogenesis, moves to the plasma membrane (Probable)
Specifically localizes to the primary cilium of undifferentiated adipocytes. Ciliary trafficking is TULP3-dependent. As the cilium is lost during adipogenesis, moves to the plasma membrane (Probable)
Features
Showing features for topological domain, transmembrane.
Type | ID | Position(s) | Description | |||
---|---|---|---|---|---|---|
Topological domain | 1-45 | Extracellular | ||||
Sequence: MSPECARAAGDAPLRSLEQANRTRFPFFSDVKGDHRLVLAAVETT | ||||||
Transmembrane | 46-66 | Helical; Name=1 | ||||
Sequence: VLVLIFAVSLLGNVCALVLVA | ||||||
Topological domain | 67-77 | Cytoplasmic | ||||
Sequence: RRRRRGATACL | ||||||
Transmembrane | 78-98 | Helical; Name=2 | ||||
Sequence: VLNLFCADLLFISAIPLVLAV | ||||||
Topological domain | 99-112 | Extracellular | ||||
Sequence: RWTEAWLLGPVACH | ||||||
Transmembrane | 113-133 | Helical; Name=3 | ||||
Sequence: LLFYVMTLSGSVTILTLAAVS | ||||||
Topological domain | 134-156 | Cytoplasmic | ||||
Sequence: LERMVCIVHLQRGVRGPGRRARA | ||||||
Transmembrane | 157-177 | Helical; Name=4 | ||||
Sequence: VLLALIWGYSAVAALPLCVFF | ||||||
Topological domain | 178-204 | Extracellular | ||||
Sequence: RVVPQRLPGADQEISICTLIWPTIPGE | ||||||
Transmembrane | 205-225 | Helical; Name=5 | ||||
Sequence: ISWDVSFVTLNFLVPGLVIVI | ||||||
Topological domain | 226-268 | Cytoplasmic | ||||
Sequence: SYSKILQITKASRKRLTVSLAYSESHQIRVSQQDFRLFRTLFL | ||||||
Transmembrane | 269-289 | Helical; Name=6 | ||||
Sequence: LMVSFFIMWSPIIITILLILI | ||||||
Topological domain | 290-295 | Extracellular | ||||
Sequence: QNFKQD | ||||||
Transmembrane | 296-316 | Helical; Name=7 | ||||
Sequence: LVIWPSLFFWVVAFTFANSAL | ||||||
Topological domain | 317-361 | Cytoplasmic | ||||
Sequence: NPILYNMTLCRNEWKKIFCCFWFPEKGAILTDTSVKRNDLSIISG |
Keywords
- Cellular component
Disease & Variants
Features
Showing features for natural variant, mutagenesis.
Type | ID | Position(s) | Description | |||
---|---|---|---|---|---|---|
Natural variant | VAR_067799 | 67 | in dbSNP:rs61866610 | |||
Sequence: R → C | ||||||
Mutagenesis | 99 | Impairs LCFA-induced intracellular calcium release. | ||||
Sequence: R → A | ||||||
Mutagenesis | 178 | Has no effect on LCFA-induced intracellular calcium release. | ||||
Sequence: R → A | ||||||
Natural variant | VAR_067800 | 254 | probable risk factor for obesity; significantly decreases LCFA-induced intracellular calcium release; dbSNP:rs116454156 | |||
Sequence: R → H | ||||||
Mutagenesis | 347-360 | Impairs LCFA-mediated phosphorylation and interaction with ARRB2. | ||||
Sequence: TDTSVKRNDLSIIS → AAAAVKRNALAIIA |
Variants
We now provide the "Disease & Variants" viewer in its own tab.
The viewer provides 453 variants from UniProt as well as other sources including ClinVar and dbSNP.
Organism-specific databases
Miscellaneous
Chemistry
Genetic variation databases
PTM/Processing
Features
Showing features for chain, glycosylation, disulfide bond, modified residue, modified residue (large scale data).
Type | ID | Position(s) | Source | Description | |||
---|---|---|---|---|---|---|---|
Chain | PRO_0000069610 | 1-361 | UniProt | Free fatty acid receptor 4 | |||
Sequence: MSPECARAAGDAPLRSLEQANRTRFPFFSDVKGDHRLVLAAVETTVLVLIFAVSLLGNVCALVLVARRRRRGATACLVLNLFCADLLFISAIPLVLAVRWTEAWLLGPVACHLLFYVMTLSGSVTILTLAAVSLERMVCIVHLQRGVRGPGRRARAVLLALIWGYSAVAALPLCVFFRVVPQRLPGADQEISICTLIWPTIPGEISWDVSFVTLNFLVPGLVIVISYSKILQITKASRKRLTVSLAYSESHQIRVSQQDFRLFRTLFLLMVSFFIMWSPIIITILLILIQNFKQDLVIWPSLFFWVVAFTFANSALNPILYNMTLCRNEWKKIFCCFWFPEKGAILTDTSVKRNDLSIISG | |||||||
Glycosylation | 21 | UniProt | N-linked (GlcNAc...) asparagine | ||||
Sequence: N | |||||||
Disulfide bond | 111↔194 | UniProt | |||||
Sequence: CHLLFYVMTLSGSVTILTLAAVSLERMVCIVHLQRGVRGPGRRARAVLLALIWGYSAVAALPLCVFFRVVPQRLPGADQEISIC | |||||||
Modified residue | 347 | UniProt | Phosphothreonine | ||||
Sequence: T | |||||||
Modified residue | 349 | UniProt | Phosphothreonine | ||||
Sequence: T | |||||||
Modified residue | 350 | UniProt | Phosphoserine | ||||
Sequence: S | |||||||
Modified residue (large scale data) | 350 | PRIDE | Phosphoserine | ||||
Sequence: S | |||||||
Modified residue | 357 | UniProt | Phosphoserine | ||||
Sequence: S | |||||||
Modified residue | 360 | UniProt | Phosphoserine | ||||
Sequence: S |
Post-translational modification
Phosphorylated at two clusters of Ser and Thr residues located in the intracellular C-terminus, a prerequisite for FFAR4 internalization via an ARRB2-dependent pathway.
Keywords
- PTM
Proteomic databases
PTM databases
Expression
Tissue specificity
Isoform 2
The predominant isoform in human tissues. Expressed in adipose tissue, pancreatic islets, lung and brain. Expressed in alpha cells of pancreatic islets (PubMed:24742677).
Expressed in primary cilia of perivascular preadipocytes of white adipose tissue (at protein level) (PubMed:31761534).
Expressed in primary cilia of perivascular preadipocytes of white adipose tissue (at protein level) (PubMed:31761534).
Abundant expression in the intestinal tract. Expressed in colonic intraepithelial neuroendocrine cells.
Developmental stage
Isoform 2
Low expression is detected in preadipocytes, mainly localized in primary cilium.
Gene expression databases
Organism-specific databases
Structure
Sequence & Isoform
- Sequence statusComplete
This entry describes 2 isoforms produced by Alternative splicing.
Q5NUL3-2
This isoform has been chosen as the canonical sequence. All positional information in this entry refers to it. This is also the sequence that appears in the downloadable versions of the entry.
- Name2
- Length361
- Mass (Da)40,494
- Last updated2020-04-22 v3
- ChecksumE90BD5D64D9E6E78
Q5NUL3-1
- Name1
- Differences from canonical
- 232-232: Q → QTSEHLLDARAVVTHSE
Computationally mapped potential isoform sequences
There is 1 potential isoform mapped to this entry
Entry | Entry name | Gene name | Length | ||
---|---|---|---|---|---|
S4R3L2 | S4R3L2_HUMAN | FFAR4 | 236 |
Features
Showing features for sequence conflict, alternative sequence.
Type | ID | Position(s) | Description | |||
---|---|---|---|---|---|---|
Sequence conflict | 67 | in Ref. 1; AAP72126 | ||||
Sequence: Missing | ||||||
Alternative sequence | VSP_060543 | 232 | in isoform 1 | |||
Sequence: Q → QTSEHLLDARAVVTHSE | ||||||
Sequence conflict | 258 | in Ref. 2; BAD83368 | ||||
Sequence: Q → H | ||||||
Sequence conflict | 281 | in Ref. 2; BAD83368 | ||||
Sequence: I → T |
Polymorphism
Genetic variations in FFAR4 define the body mass index quantitative trait locus 10 (BMIQ10) [MIM:607514]. Variance in body mass index is a susceptibility factor for obesity.
Keywords
- Coding sequence diversity
- Technical term
Sequence databases
Nucleotide Sequence | Protein Sequence | Molecule Type | Status | |
---|---|---|---|---|
AY288417 EMBL· GenBank· DDBJ | AAP72126.1 EMBL· GenBank· DDBJ | mRNA | ||
AB115768 EMBL· GenBank· DDBJ | BAD83368.1 EMBL· GenBank· DDBJ | mRNA | ||
AL356214 EMBL· GenBank· DDBJ | - | Genomic DNA | No translation available. | |
CH471066 EMBL· GenBank· DDBJ | EAW50069.1 EMBL· GenBank· DDBJ | Genomic DNA | ||
BC101175 EMBL· GenBank· DDBJ | AAI01176.1 EMBL· GenBank· DDBJ | mRNA | ||
AY255573 EMBL· GenBank· DDBJ | AAO85085.1 EMBL· GenBank· DDBJ | mRNA |