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Protein

Proteinase-activated receptor 2

Gene

F2RL1

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

Functioni

Receptor for trypsin and trypsin-like enzymes coupled to G proteins (PubMed:28445455). Its function is mediated through the activation of several signaling pathways including phospholipase C (PLC), intracellular calcium, mitogen-activated protein kinase (MAPK), I-kappaB kinase/NF-kappaB and Rho (PubMed:28445455). Can also be transactivated by cleaved F2R/PAR1. Involved in modulation of inflammatory responses and regulation of innate and adaptive immunity, and acts as a sensor for proteolytic enzymes generated during infection. Generally is promoting inflammation. Can signal synergistically with TLR4 and probably TLR2 in inflammatory responses and modulates TLR3 signaling. Has a protective role in establishing the endothelial barrier; the activity involves coagulation factor X. Regulates endothelial cell barrier integrity during neutrophil extravasation, probably following proteolytic cleavage by PRTN3 (PubMed:23202369). Proposed to have a bronchoprotective role in airway epithelium, but also shown to compromise the airway epithelial barrier by interrupting E-cadherin adhesion (PubMed:10086357). Involved in the regulation of vascular tone; activation results in hypotension presumably mediated by vasodilation. Associates with a subset of G proteins alpha subunits such as GNAQ, GNA11, GNA14, GNA12 and GNA13, but probably not with G(o) alpha, G(i) subunit alpha-1 and G(i) subunit alpha-2. However, according to PubMed:21627585 can signal through G(i) subunit alpha. Believed to be a class B receptor which internalizes as a complex with arrestin and traffic with it to endosomal vesicles, presumably as desensitized receptor, for extended periods of time. Mediates inhibition of TNF-alpha stimulated JNK phosphorylation via coupling to GNAQ and GNA11; the function involves dissociation of RIPK1 and TRADD from TNFR1. Mediates phosphorylation of nuclear factor NF-kappa-B RELA subunit at 'Ser-536'; the function involves IKBKB and is predominantly independent of G proteins. Involved in cellular migration. Involved in cytoskeletal rearrangement and chemotaxis through beta-arrestin-promoted scaffolds; the function is independent of GNAQ and GNA11 and involves promotion of cofilin dephosphorylation and actin filament severing. Induces redistribution of COPS5 from the plasma membrane to the cytosol and activation of the JNK cascade is mediated by COPS5. Involved in the recruitment of leukocytes to the sites of inflammation and is the major PAR receptor capable of modulating eosinophil function such as proinflammatory cytokine secretion, superoxide production and degranulation. During inflammation promotes dendritic cell maturation, trafficking to the lymph nodes and subsequent T-cell activation. Involved in antimicrobial response of innate immnune cells; activation enhances phagocytosis of Gram-positive and killing of Gram-negative bacteria. Acts synergistically with interferon-gamma in enhancing antiviral responses. Implicated in a number of acute and chronic inflammatory diseases such as of the joints, lungs, brain, gastrointestinal tract, periodontium, skin, and vascular systems, and in autoimmune disorders.26 Publications

Miscellaneous

Synthetic PAR agonist peptides (APs) that mimic the first six amino acids of the newly formed N-terminus activate the native, uncleaved receptor nonenzymatically by binding directly to the corresponding second extracellular loop to mediate signaling.

GO - Molecular functioni

  • G-protein alpha-subunit binding Source: UniProtKB
  • G-protein beta-subunit binding Source: UniProtKB
  • G-protein coupled receptor activity Source: UniProtKB
  • receptor activity Source: ProtInc
  • receptor binding Source: ProtInc
  • thrombin-activated receptor activity Source: InterPro

GO - Biological processi

  • blood coagulation Source: InterPro
  • cell-cell junction maintenance Source: UniProtKB
  • chemokine (C-C motif) ligand 2 secretion Source: UniProtKB
  • chemokine secretion Source: UniProtKB
  • defense response to virus Source: UniProtKB
  • establishment of endothelial barrier Source: UniProtKB
  • G-protein coupled receptor signaling pathway Source: UniProtKB
  • inflammatory response Source: UniProtKB-KW
  • innate immune response Source: UniProtKB-KW
  • interferon-gamma secretion Source: UniProtKB
  • interleukin-10 secretion Source: UniProtKB
  • interleukin-1 beta secretion Source: UniProtKB
  • leukocyte migration Source: UniProtKB
  • leukocyte proliferation Source: UniProtKB
  • mature conventional dendritic cell differentiation Source: UniProtKB
  • negative regulation of chemokine secretion Source: UniProtKB
  • negative regulation of JNK cascade Source: UniProtKB
  • negative regulation of toll-like receptor 3 signaling pathway Source: UniProtKB
  • negative regulation of tumor necrosis factor-mediated signaling pathway Source: UniProtKB
  • neutrophil activation Source: UniProtKB
  • positive regulation of actin filament depolymerization Source: UniProtKB
  • positive regulation of blood vessel diameter Source: UniProtKB
  • positive regulation of cell migration Source: UniProtKB
  • positive regulation of chemotaxis Source: UniProtKB
  • positive regulation of cytokine secretion involved in immune response Source: UniProtKB
  • positive regulation of cytosolic calcium ion concentration Source: UniProtKB
  • positive regulation of cytosolic calcium ion concentration involved in phospholipase C-activating G-protein coupled signaling pathway Source: GO_Central
  • positive regulation of eosinophil degranulation Source: UniProtKB
  • positive regulation of ERK1 and ERK2 cascade Source: UniProtKB
  • positive regulation of glomerular filtration Source: UniProtKB
  • positive regulation of GTPase activity Source: UniProtKB
  • positive regulation of I-kappaB kinase/NF-kappaB signaling Source: UniProtKB
  • positive regulation of interleukin-6 secretion Source: UniProtKB
  • positive regulation of interleukin-8 secretion Source: UniProtKB
  • positive regulation of JNK cascade Source: UniProtKB
  • positive regulation of leukocyte chemotaxis Source: BHF-UCL
  • positive regulation of neutrophil mediated killing of gram-negative bacterium Source: UniProtKB
  • positive regulation of phagocytosis, engulfment Source: UniProtKB
  • positive regulation of phosphatidylinositol 3-kinase signaling Source: UniProtKB
  • positive regulation of positive chemotaxis Source: BHF-UCL
  • positive regulation of pseudopodium assembly Source: UniProtKB
  • positive regulation of renin secretion into blood stream Source: UniProtKB
  • positive regulation of Rho protein signal transduction Source: UniProtKB
  • positive regulation of superoxide anion generation Source: UniProtKB
  • positive regulation of toll-like receptor 2 signaling pathway Source: UniProtKB
  • positive regulation of toll-like receptor 3 signaling pathway Source: UniProtKB
  • positive regulation of toll-like receptor 4 signaling pathway Source: UniProtKB
  • positive regulation of transcription from RNA polymerase II promoter Source: UniProtKB
  • regulation of blood coagulation Source: BHF-UCL
  • regulation of I-kappaB kinase/NF-kappaB signaling Source: UniProtKB
  • regulation of JNK cascade Source: UniProtKB
  • T cell activation involved in immune response Source: UniProtKB

Keywordsi

Molecular functionG-protein coupled receptor, Receptor, Transducer
Biological processImmunity, Inflammatory response, Innate immunity

Enzyme and pathway databases

ReactomeiR-HSA-375276. Peptide ligand-binding receptors.
R-HSA-416476. G alpha (q) signalling events.
SIGNORiP55085.

Protein family/group databases

TCDBi9.A.14.13.12. the g-protein-coupled receptor (gpcr) family.

Names & Taxonomyi

Protein namesi
Recommended name:
Proteinase-activated receptor 2
Short name:
PAR-2
Alternative name(s):
Coagulation factor II receptor-like 1
G-protein coupled receptor 11
Thrombin receptor-like 1
Cleaved into the following 2 chains:
Gene namesi
Name:F2RL1
Synonyms:GPR11, PAR2
OrganismiHomo sapiens (Human)
Taxonomic identifieri9606 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo
Proteomesi
  • UP000005640 Componenti: Chromosome 5

Organism-specific databases

EuPathDBiHostDB:ENSG00000164251.4.
HGNCiHGNC:3538. F2RL1.
MIMi600933. gene.
neXtProtiNX_P55085.

Subcellular locationi

Extracellular region or secreted Cytosol Plasma membrane Cytoskeleton Lysosome Endosome Peroxisome ER Golgi apparatus Nucleus Mitochondrion Manual annotation Automatic computational assertionGraphics by Christian Stolte; Source: COMPARTMENTS

Topology

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Topological domaini37 – 71Extracellular1 PublicationAdd BLAST35
Transmembranei72 – 101Helical; Name=11 PublicationAdd BLAST30
Topological domaini102 – 108Cytoplasmic1 Publication7
Transmembranei109 – 137Helical; Name=21 PublicationAdd BLAST29
Topological domaini138 – 149Extracellular1 PublicationAdd BLAST12
Transmembranei150 – 177Helical; Name=31 PublicationAdd BLAST28
Topological domaini178 – 183Cytoplasmic1 Publication6
Transmembranei184 – 211Helical; Name=41 PublicationAdd BLAST28
Topological domaini212 – 235Extracellular1 PublicationAdd BLAST24
Transmembranei236 – 269Helical; Name=51 PublicationAdd BLAST34
Topological domaini270 – 277Cytoplasmic1 Publication8
Transmembranei278 – 317Helical; Name=61 PublicationAdd BLAST40
Topological domaini318 – 323Extracellular1 Publication6
Transmembranei324 – 347Helical; Name=71 PublicationAdd BLAST24
Topological domaini348 – 397Cytoplasmic1 PublicationAdd BLAST50

Keywords - Cellular componenti

Cell membrane, Membrane

Pathology & Biotechi

Mutagenesis

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Mutagenesisi30N → A: Decreases cell surface expression; when associate with A-222. 1 Publication1
Mutagenesisi30N → A: Increase of sensitivity towards tryptase. 1 Publication1
Mutagenesisi135H → Y: Slight reduction in ligand-mediated receptor activation. 1 Publication1
Mutagenesisi154F → A: Severe reduction in ligand-mediated receptor activation. 1 Publication1
Mutagenesisi157G → C or M: Severe reduction in ligand-mediated receptor activation. 1 Publication1
Mutagenesisi210Y → L: No defect in ligand-mediated receptor activation. 1 Publication1
Mutagenesisi222N → A: Decreases cell surface expression; when associated with A-30. Loss of sensitivity towards all tested proteases. 1 Publication1
Mutagenesisi222N → Q: No defect in ligand-mediated receptor activation. 1 Publication1
Mutagenesisi227H → A: No defect in ligand-mediated receptor activation. 1 Publication1
Mutagenesisi227H → Q: Slight reduction in ligand-mediated receptor activation. 1 Publication1
Mutagenesisi228D → A or N: Severe reduction in ligand-mediated receptor activation. 1 Publication1
Mutagenesisi327I → L: Slight reduction in ligand-mediated receptor activation. 1 Publication1
Mutagenesisi355 – 363Missing : Abolishes signaling through accumulation of intracellular calcium and phosphoinositide; no effect in signaling through MAPK. 1 Publication9
Mutagenesisi361C → A: Loss of palmitoylation; increases surface expression and internalization following trypsin activation, decreases sensitivity and intracellular calcium signaling, increases ERK activation through G(i) subunit alpha. 1
Mutagenesisi363S → A: Reduces receptor desensitization and internalization, activates ERK1/2; when associated with A-366. 1 Publication1
Mutagenesisi366T → A: Reduces receptor desensitization and internalization, activates ERK1/2; when associated with A-363. 1 Publication1

Organism-specific databases

DisGeNETi2150.
PharmGKBiPA27947.

Chemistry databases

ChEMBLiCHEMBL5963.
GuidetoPHARMACOLOGYi348.

Polymorphism and mutation databases

BioMutaiF2RL1.
DMDMi1709580.

PTM / Processingi

Molecule processing

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Signal peptidei1 – 25Sequence analysisAdd BLAST25
PropeptideiPRO_000001275026 – 36Removed for receptor activationAdd BLAST11
ChainiPRO_000041295437 – 397Proteinase-activated receptor 2Add BLAST361
ChainiPRO_000041295638 – 397Proteinase-activated receptor 2, alternate cleaved 1Add BLAST360
ChainiPRO_000001275139 – 397Proteinase-activated receptor 2, alternate cleaved 2Add BLAST359

Amino acid modifications

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Glycosylationi30N-linked (GlcNAc...) asparagine1 Publication1
Disulfide bondi148 ↔ 226PROSITE-ProRule annotationCombined sources1 Publication
Glycosylationi222N-linked (GlcNAc...) asparagine1 Publication1
Lipidationi361S-palmitoyl cysteine1 Publication1

Post-translational modificationi

A proteolytic cleavage generates a new N-terminus that functions as a tethered ligand (PubMed:10831593, PubMed:19864598, PubMed:9020112, PubMed:10805786, PubMed:16478888). Activating serine proteases include trypsin, mast cell tryptase, coagulation factors VII and Xa, myeloblastin/PRTN3 and membrane-type serine protease 1/ST14 (PubMed:10831593, PubMed:19864598, PubMed:9020112, PubMed:10805786, PubMed:16478888, PubMed:23202369). Subsequent cleavage by serine proteases, including neutrophil elastase and cathepsin G, leads to receptor deactivation (PubMed:12594060). At least in part, implicated proteases are also shown to activate the receptor; the glycosylation status of the receptor is thought to contribute to the difference (PubMed:12171601). In addition to conventional trypsin-like proteases activated by other proteases and glycosidases derived from bacteria, fungi and insects (PubMed:11447194, PubMed:11441110, PubMed:17404307, PubMed:18474671, PubMed:19864598). Activated by serine protease allergens such as dust mite Der p3 and Der p9 and mold Pen c13 (PubMed:11441110, PubMed:17404307). Activated by P.gingivalis arginine-specific (trypsin-like) cysteine proteinases called gingipains (PubMed:11447194). Activated by S.griseus exogenous chitinase (PubMed:18474671). Activated by A.alternata aspartate protease; the cleavage generates non-conventional processed forms (PubMed:19864598).12 Publications
N-glycosylated and sialylated.1 Publication
Multiple phosphorylated on serine and threonine residues in the cytoplasmic region upon receptor activation; required for receptor desensitization and recruitment of beta-arrestin.1 Publication
Monoubiquitinated by CBL at the plasma membrane and in early endosomes; not required for receptor endocytosis but for translocation to late endosomes or lysosomes. Deubiquitination involves STAMBP and USP8; required for lysosomal trafficking and receptor degradation.

Sites

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Sitei36 – 37Cleavage; by trypsin2

Keywords - PTMi

Disulfide bond, Glycoprotein, Lipoprotein, Palmitate, Phosphoprotein, Ubl conjugation

Proteomic databases

MaxQBiP55085.
PaxDbiP55085.
PeptideAtlasiP55085.
PRIDEiP55085.

PTM databases

iPTMnetiP55085.
PhosphoSitePlusiP55085.
SwissPalmiP55085.

Miscellaneous databases

PMAP-CutDBiP55085.

Expressioni

Tissue specificityi

Widely expressed in tissues with especially high levels in pancreas, liver, kidney, small intestine, and colon (PubMed:7556175, PubMed:8615752). Moderate expression is detected in many organs, but none in brain or skeletal muscle (PubMed:7556175, PubMed:8615752). Expressed in endothelial cells (PubMed:23202369).3 Publications

Gene expression databases

BgeeiENSG00000164251.
CleanExiHS_F2RL1.
ExpressionAtlasiP55085. baseline and differential.
GenevisibleiP55085. HS.

Organism-specific databases

HPAiCAB012989.
HPA014091.

Interactioni

Subunit structurei

Interacts with TLR4, COPS5 and TMED2. Interacts with GNAQ, GNA11, GNA12, GNA13 and GNA14 (By similarity).By similarity

Binary interactionsi

Show more details

GO - Molecular functioni

  • G-protein alpha-subunit binding Source: UniProtKB
  • G-protein beta-subunit binding Source: UniProtKB
  • receptor binding Source: ProtInc

Protein-protein interaction databases

BioGridi108449. 14 interactors.
DIPiDIP-42044N.
IntActiP55085. 7 interactors.
MINTiMINT-1326650.
STRINGi9606.ENSP00000296677.

Chemistry databases

BindingDBiP55085.

Structurei

Secondary structure

1397
Legend: HelixTurnBeta strandPDB Structure known for this area
Show more details
Feature keyPosition(s)DescriptionActionsGraphical viewLength
Helixi63 – 68Combined sources6
Helixi72 – 75Combined sources4
Helixi77 – 102Combined sources26
Helixi109 – 125Combined sources17
Helixi128 – 136Combined sources9
Helixi145 – 178Combined sources34
Helixi186 – 205Combined sources20
Helixi207 – 210Combined sources4
Beta strandi215 – 218Combined sources4
Turni219 – 222Combined sources4
Beta strandi223 – 229Combined sources7
Helixi233 – 235Combined sources3
Helixi236 – 249Combined sources14
Helixi252 – 269Combined sources18
Helixi279 – 298Combined sources20
Helixi301 – 316Combined sources16
Helixi323 – 332Combined sources10
Helixi333 – 335Combined sources3
Helixi336 – 347Combined sources12
Helixi349 – 358Combined sources10

3D structure databases

Select the link destinations:
PDBei
RCSB PDBi
PDBji
Links Updated
PDB entryMethodResolution (Å)ChainPositionsPDBsum
5NDDX-ray2.80A59-269[»]
A276-377[»]
5NDZX-ray3.60A59-269[»]
A276-377[»]
5NJ6X-ray4.00A55-269[»]
A276-377[»]
ProteinModelPortaliP55085.
SMRiP55085.
ModBaseiSearch...
MobiDBiSearch...

Family & Domainsi

Compositional bias

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Compositional biasi383 – 390Poly-Ser8

Sequence similaritiesi

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

Keywords - Domaini

Signal, Transmembrane, Transmembrane helix

Phylogenomic databases

eggNOGiENOG410IGEM. Eukaryota.
ENOG4111CWR. LUCA.
HOGENOMiHOG000116291.
HOVERGENiHBG105658.
InParanoidiP55085.
KOiK04234.
OrthoDBiEOG091G0C2F.
PhylomeDBiP55085.
TreeFamiTF330775.

Family and domain databases

InterProiView protein in InterPro
IPR000276. GPCR_Rhodpsn.
IPR017452. GPCR_Rhodpsn_7TM.
IPR002281. Pro_rcpt_2.
IPR003912. Protea_act_rcpt.
PfamiView protein in Pfam
PF00001. 7tm_1. 1 hit.
PRINTSiPR00237. GPCRRHODOPSN.
PR01428. PROTEASEAR.
PR01152. PROTEASEAR2.
PROSITEiView protein in PROSITE
PS50262. G_PROTEIN_RECEP_F1_2. 1 hit.

Sequencei

Sequence statusi: Complete.

Sequence processingi: The displayed sequence is further processed into a mature form.

P55085-1 [UniParc]FASTAAdd to basket

« Hide

        10         20         30         40         50
MRSPSAAWLL GAAILLAASL SCSGTIQGTN RSSKGRSLIG KVDGTSHVTG
60 70 80 90 100
KGVTVETVFS VDEFSASVLT GKLTTVFLPI VYTIVFVVGL PSNGMALWVF
110 120 130 140 150
LFRTKKKHPA VIYMANLALA DLLSVIWFPL KIAYHIHGNN WIYGEALCNV
160 170 180 190 200
LIGFFYGNMY CSILFMTCLS VQRYWVIVNP MGHSRKKANI AIGISLAIWL
210 220 230 240 250
LILLVTIPLY VVKQTIFIPA LNITTCHDVL PEQLLVGDMF NYFLSLAIGV
260 270 280 290 300
FLFPAFLTAS AYVLMIRMLR SSAMDENSEK KRKRAIKLIV TVLAMYLICF
310 320 330 340 350
TPSNLLLVVH YFLIKSQGQS HVYALYIVAL CLSTLNSCID PFVYYFVSHD
360 370 380 390
FRDHAKNALL CRSVRTVKQM QVSLTSKKHS RKSSSYSSSS TTVKTSY
Length:397
Mass (Da):44,126
Last modified:October 1, 1996 - v1
Checksum:iF1A4E1D5AB9B362B
GO

Experimental Info

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Sequence conflicti138G → A in AAB47871 (PubMed:8615752).Curated1
Sequence conflicti291T → S in AAH18130 (PubMed:15489334).Curated1

Natural variant

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Natural variantiVAR_01284621S → F1 PublicationCorresponds to variant dbSNP:rs2243072Ensembl.1
Natural variantiVAR_04943530N → S. Corresponds to variant dbSNP:rs616235Ensembl.1
Natural variantiVAR_012847270R → Q1 PublicationCorresponds to variant dbSNP:rs2243062Ensembl.1
Natural variantiVAR_012848291T → A1 PublicationCorresponds to variant dbSNP:rs2243083Ensembl.1

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
Z49993, Z49994 Genomic DNA. Translation: CAA90290.1.
U34038 mRNA. Translation: AAB47871.1.
AY336105 mRNA. Translation: AAP97012.1.
AF400075 Genomic DNA. Translation: AAK77914.1.
BT009856 mRNA. Translation: AAP88858.1.
CH471084 Genomic DNA. Translation: EAW95782.1.
BC012453 mRNA. Translation: AAH12453.1.
BC018130 mRNA. Translation: AAH18130.1.
U36753 Genomic DNA. Translation: AAA90957.1.
CCDSiCCDS4033.1.
PIRiS66518.
RefSeqiNP_005233.3. NM_005242.5.
UniGeneiHs.744181.

Genome annotation databases

EnsembliENST00000296677; ENSP00000296677; ENSG00000164251.
GeneIDi2150.
KEGGihsa:2150.
UCSCiuc003keo.4. human.

Keywords - Coding sequence diversityi

Polymorphism

Similar proteinsi

Entry informationi

Entry nameiPAR2_HUMAN
AccessioniPrimary (citable) accession number: P55085
Secondary accession number(s): Q13317, Q13346, Q53XJ8
Entry historyiIntegrated into UniProtKB/Swiss-Prot: October 1, 1996
Last sequence update: October 1, 1996
Last modified: December 20, 2017
This is version 170 of the entry and version 1 of the sequence. See 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

3D-structure, Complete proteome, Reference proteome

Documents

  1. 7-transmembrane G-linked receptors
    List of 7-transmembrane G-linked receptor entries
  2. Human chromosome 5
    Human chromosome 5: 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. PDB cross-references
    Index of Protein Data Bank (PDB) cross-references
  7. SIMILARITY comments
    Index of protein domains and families