Skip Header

You are using a version of browser that may not display all the features of this website. Please consider upgrading your browser.
Protein

Forkhead box protein P3

Gene

Foxp3

Organism
Mus musculus (Mouse)
Status
Reviewed-Annotation score: Annotation score: 5 out of 5-Experimental evidence at protein leveli

Functioni

Transcriptional regulator which is crucial for the development and inhibitory function of regulatory T-cells (Treg). Plays an essential role in maintaining homeostasis of the immune system by allowing the acquisition of full suppressive function and stability of the Treg lineage, and by directly modulating the expansion and function of conventional T-cells. Can act either as a transcriptional repressor or a transcriptional activator depending on its interactions with other transcription factors, histone acetylases and deacetylases. The suppressive activity of Treg involves the coordinate activation of many genes, including CTLA4 and TNFRSF18 by FOXP3 along with repression of genes encoding cytokines such as interleukin-2 (IL2) and interferon-gamma (IFNG). Inhibits cytokine production and T-cell effector function by repressing the activity of two key transcription factors, RELA and NFATC2 (PubMed:15790681). Mediates transcriptional repression of IL2 via its association with histone acetylase KAT5 and histone deacetylase HDAC7 (By similarity). Can activate the expression of TNFRSF18, IL2RA and CTLA4 and repress the expression of IL2 and IFNG via its association with transcription factor RUNX1 (PubMed:17377532). Inhibits the differentiation of IL17 producing helper T-cells (Th17) by antagonizing RORC function, leading to down-regulation of IL17 expression, favoring Treg development (PubMed:18368049). Inhibits the transcriptional activator activity of RORA (By similarity). Can repress the expression of IL2 and IFNG via its association with transcription factor IKZF4 (PubMed:19696312).By similarity4 Publications

Regions

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Zinc fingeri196 – 221C2H2-typeAdd BLAST26
DNA bindingi337 – 423Fork-headPROSITE-ProRule annotationAdd BLAST87

GO - Molecular functioni

GO - Biological processi

  • B cell homeostasis Source: MGI
  • CD4-positive, CD25-positive, alpha-beta regulatory T cell differentiation Source: MGI
  • CD4-positive, CD25-positive, alpha-beta regulatory T cell lineage commitment Source: UniProtKB
  • cytokine production Source: MGI
  • myeloid cell homeostasis Source: MGI
  • negative regulation of cell proliferation Source: UniProtKB
  • negative regulation of chronic inflammatory response Source: MGI
  • negative regulation of CREB transcription factor activity Source: UniProtKB
  • negative regulation of cytokine biosynthetic process Source: UniProtKB
  • negative regulation of cytokine secretion Source: UniProtKB
  • negative regulation of gene expression Source: MGI
  • negative regulation of histone acetylation Source: MGI
  • negative regulation of histone deacetylation Source: MGI
  • negative regulation of immune response Source: UniProtKB
  • negative regulation of inflammatory response Source: MGI
  • negative regulation of interferon-gamma biosynthetic process Source: MGI
  • negative regulation of interferon-gamma production Source: UniProtKB
  • negative regulation of interleukin-10 production Source: UniProtKB
  • negative regulation of interleukin-17 production Source: UniProtKB
  • negative regulation of interleukin-2 biosynthetic process Source: UniProtKB
  • negative regulation of interleukin-2 production Source: UniProtKB
  • negative regulation of interleukin-4 production Source: UniProtKB
  • negative regulation of interleukin-5 production Source: MGI
  • negative regulation of interleukin-6 production Source: MGI
  • negative regulation of isotype switching to IgE isotypes Source: MGI
  • negative regulation of lymphocyte proliferation Source: MGI
  • negative regulation of NF-kappaB transcription factor activity Source: UniProtKB
  • negative regulation of sequence-specific DNA binding transcription factor activity Source: UniProtKB
  • negative regulation of T cell cytokine production Source: UniProtKB
  • negative regulation of T cell proliferation Source: UniProtKB
  • negative regulation of T-helper 17 cell differentiation Source: UniProtKB
  • negative regulation of transcription, DNA-templated Source: UniProtKB
  • negative regulation of transcription from RNA polymerase II promoter Source: MGI
  • negative regulation of tumor necrosis factor production Source: MGI
  • positive regulation of CD4-positive, CD25-positive, alpha-beta regulatory T cell differentiation Source: UniProtKB
  • positive regulation of gene expression Source: MGI
  • positive regulation of histone acetylation Source: MGI
  • positive regulation of immature T cell proliferation in thymus Source: MGI
  • positive regulation of interleukin-4 production Source: MGI
  • positive regulation of peripheral T cell tolerance induction Source: MGI
  • positive regulation of regulatory T cell differentiation Source: MGI
  • positive regulation of T cell anergy Source: MGI
  • positive regulation of T cell tolerance induction Source: MGI
  • positive regulation of transcription, DNA-templated Source: UniProtKB
  • positive regulation of transcription from RNA polymerase II promoter Source: MGI
  • positive regulation of transforming growth factor beta1 production Source: MGI
  • regulation of immunoglobulin production Source: MGI
  • regulation of isotype switching to IgG isotypes Source: MGI
  • regulation of T cell anergy Source: UniProtKB
  • regulation of transcription from RNA polymerase II promoter Source: MGI
  • regulatory T cell differentiation Source: MGI
  • response to virus Source: Ensembl
  • T cell activation Source: UniProtKB
  • T cell mediated immunity Source: MGI
  • T cell receptor signaling pathway Source: MGI
  • tolerance induction Source: MGI
  • tolerance induction to self antigen Source: MGI
  • transcription, DNA-templated Source: UniProtKB-KW
Complete GO annotation...

Keywords - Molecular functioni

Activator, Repressor

Keywords - Biological processi

Transcription, Transcription regulation

Keywords - Ligandi

DNA-binding, Metal-binding, Zinc

Names & Taxonomyi

Protein namesi
Recommended name:
Forkhead box protein P3
Alternative name(s):
Scurfin
Cleaved into the following 2 chains:
Gene namesi
Name:Foxp3
OrganismiMus musculus (Mouse)
Taxonomic identifieri10090 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresGliresRodentiaSciurognathiMuroideaMuridaeMurinaeMusMus
Proteomesi
  • UP000000589 Componenti: Chromosome X

Organism-specific databases

MGIiMGI:1891436. Foxp3.

Subcellular locationi

GO - Cellular componenti

  • cytoplasm Source: MGI
  • intracellular Source: MGI
  • nucleus Source: UniProtKB
Complete GO annotation...

Keywords - Cellular componenti

Cytoplasm, Nucleus

Pathology & Biotechi

Involvement in diseasei

Defects in Foxp3 are the cause of the scurfy phenotype (sf). It results in a lethal disorder of immunoregulation, characterized by infections, diarrhea, anemia, thrombocytopenia, hypogonadism, gastrointestinal bleeding, lymphadenopathy and leukocytosis.

Mutagenesis

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Mutagenesisi19S → A: Loss of phosphorylation. Increase in protein stability, transcriptional activity and the ability to suppress the proliferation of conventional T-cells in vitro; when associated with A-88; A-114 and A-175. 1 Publication1
Mutagenesisi48 – 51RDLR → HDLH: Loss of proteolytic processing. 1 Publication4
Mutagenesisi88S → A: Increase in protein stability, transcriptional activity and the ability to suppress the proliferation of conventional T-cells in vitro; when associated with A-19; A-114 and A-175. 1 Publication1
Mutagenesisi114T → A: Increase in protein stability, transcriptional activity and the ability to suppress the proliferation of conventional T-cells in vitro; when associated with A-19; A-88 and A-175. 1 Publication1
Mutagenesisi175T → A: Increase in protein stability, transcriptional activity and the ability to suppress the proliferation of conventional T-cells in vitro; when associated with A-19; A-88 and A-114. 1 Publication1
Mutagenesisi250Missing : Loss of homodimerization, decrease in transcriptional repressor activity, elimination of its Treg suppressor activity, defects in Th1 and Th2 cytokine secretion and down-regulation of cell surface markers on regulatory T-cells. 1 Publication1
Mutagenesisi329 – 330DY → VH: Reduced interaction with RUNX1, decrease in its ability to regulate the expression of IL2, TNFRSF18, IL2RA and CTLA4 in a RUNX1-dependent manner. Loss of interaction with RUNX1 but no effect on interaction with NFATC2 and loss of its ability to regulate the expression of IL2, TNFRSF18, IL2RA and CTLA4 in a RUNX1-dependent manner; when associated with L-332. 1 Publication2
Mutagenesisi332K → L: Loss of interaction with RUNX1 but no effect on interaction with NFATC2 and loss of its ability to regulate the expression of IL2, TNFRSF18, IL2RA and CTLA4 in a RUNX1-dependent manner; when associated with 329-VH-330. 1 Publication1
Mutagenesisi414 – 417RKKR → PNNW: Loss of ability to suppress the proliferation of effector T-cells. 1 Publication4
Mutagenesisi414 – 417RKKR → QNKS: Loss of proteolytic processing. 1 Publication4

PTM / Processingi

Molecule processing

Feature keyPosition(s)DescriptionActionsGraphical viewLength
ChainiPRO_00000918881 – 429Forkhead box protein P3Add BLAST429
ChainiPRO_00004324361 – 417Forkhead box protein P3, C-terminally processed1 PublicationAdd BLAST417
ChainiPRO_000043243752 – 417Forkhead box protein P3 41 kDa form1 PublicationAdd BLAST366
PropeptideiPRO_0000432438418 – 4291 PublicationAdd BLAST12

Amino acid modifications

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Modified residuei19Phosphoserine; by CDK21 Publication1
Modified residuei31N6-acetyllysine1 Publication1
Modified residuei175Phosphothreonine; by CDK21 Publication1
Cross-linki249Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in ubiquitin)1 Publication
Cross-linki251Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in ubiquitin)1 Publication
Modified residuei262N6-acetyllysine; alternate1 Publication1
Cross-linki262Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in ubiquitin); alternate1 Publication
Modified residuei267N6-acetyllysine; alternate1 Publication1
Cross-linki267Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in ubiquitin); alternate1 Publication
Cross-linki393Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in ubiquitin)1 Publication
Modified residuei418PhosphoserineBy similarity1

Post-translational modificationi

Acetylation on lysine residues stabilizes FOXP3 and promotes differentiation of T-cells into induced regulatory T-cells (iTregs) associated with suppressive functions. Deacetylated by SIRT1.1 Publication
Polyubiquitinated, leading to its proteasomal degradation in regulatory T-cells (Treg) which is mediated by STUB1 in a HSPA1A/B-dependent manner. Deubiquitinated by USP7 leading to increase in protein stability.2 Publications
Phosphorylation at Ser-418 regulates its transcriptional repressor activity and consequently, regulatory T-cells (Treg) suppressive function (By similarity). Phosphorylation by CDK2 negatively regulates its transcriptional activity and protein stability.By similarity1 Publication
Undergoes proteolytic cleavage in activated regulatory T-cells (Treg), and can be cleaved at either the N- or C-terminal site, or at both sites. Treg expressing the form cleaved at C-terminal site or both N- and C-terminal sites exhibit an increased induction of IL10 and an increased capacity to suppress proliferation of conventional T-cells in vitro. Treg expressing the form cleaved at only the C-terminal site are highly effective at preventing experimental colitis in an in vivo model of inflammatory bowel disease.1 Publication

Sites

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Sitei51 – 52Cleavage1 Publication2
Sitei417 – 418Cleavage; by PCSK1 or PCSK21 Publication2

Keywords - PTMi

Acetylation, Isopeptide bond, Phosphoprotein, Ubl conjugation

Proteomic databases

PaxDbiQ99JB6.
PRIDEiQ99JB6.

PTM databases

iPTMnetiQ99JB6.
PhosphoSitePlusiQ99JB6.

Expressioni

Tissue specificityi

High level of expression in thymus and spleen.

Inductioni

By TGFB1 in T-cells. Down-regulated in regulatory T-cells (Treg) during inflammation.2 Publications

Gene expression databases

BgeeiENSMUSG00000039521.
CleanExiMM_FOXP3.
ExpressionAtlasiQ99JB6. baseline and differential.
GenevisibleiQ99JB6. MM.

Interactioni

Subunit structurei

Homodimer. Interacts with IKZF3 (By similarity). Interacts (via LXXLL motif) with isoform 4 of RORA (via AF-2 motif) (By similarity). Interacts with STUB1 and HSPA1A/B. Interacts with IKZF4, HDAC7 and KAT5. Interacts with RUNX1, RUNX2, RUNX3 and NFATC2. Interacts with RORC. Interacts with HDAC9 in the absence of T-cell stimulation (By similarity). Interacts with RELA, PPP1CA, PPP1CB, PPP1CG, HSPA8 and USP7 (By similarity).By similarity5 Publications

Binary interactionsi

WithEntry#Exp.IntActNotes
Runx1Q033475EBI-10956246,EBI-3863873

GO - Molecular functioni

Protein-protein interaction databases

BioGridi203183. 368 interactors.
DIPiDIP-59739N.
IntActiQ99JB6. 11 interactors.
STRINGi10090.ENSMUSP00000041953.

Structurei

Secondary structure

1429
Legend: HelixTurnBeta strandPDB Structure known for this area
Show more details
Feature keyPosition(s)DescriptionActionsGraphical viewLength
Turni204 – 207Combined sources4
Helixi208 – 257Combined sources50

3D structure databases

Select the link destinations:
PDBei
RCSB PDBi
PDBji
Links Updated
PDB entryMethodResolution (Å)ChainPositionsPDBsum
4I1LX-ray2.10A189-276[»]
ProteinModelPortaliQ99JB6.
SMRiQ99JB6.
ModBaseiSearch...
MobiDBiSearch...

Family & Domainsi

Region

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Regioni105 – 189Essential for transcriptional repressor activity and for interaction with KAT5 and HDAC7By similarityAdd BLAST85
Regioni148 – 198Interaction with IKZF41 PublicationAdd BLAST51
Regioni238 – 259Leucine-zipperAdd BLAST22
Regioni277 – 336Interaction with RUNX1By similarityAdd BLAST60

Motif

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Motifi67 – 75Nuclear export signalBy similarity9
Motifi91 – 95LXXLL motifBy similarity5
Motifi238 – 247Nuclear export signalBy similarity10
Motifi414 – 417Nuclear localization signalBy similarity4

Sequence similaritiesi

Contains 1 C2H2-type zinc finger.Curated
Contains 1 fork-head DNA-binding domain.PROSITE-ProRule annotation

Zinc finger

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Zinc fingeri196 – 221C2H2-typeAdd BLAST26

Keywords - Domaini

Zinc-finger

Phylogenomic databases

eggNOGiKOG4385. Eukaryota.
COG5025. LUCA.
GeneTreeiENSGT00800000124014.
HOGENOMiHOG000082490.
HOVERGENiHBG051656.
InParanoidiQ99JB6.
KOiK10163.
OMAiFKEPEDF.
OrthoDBiEOG091G08HY.
PhylomeDBiQ99JB6.
TreeFamiTF326978.

Family and domain databases

Gene3Di1.10.10.10. 1 hit.
3.30.160.60. 1 hit.
InterProiIPR001766. Fork_head_dom.
IPR032354. FOXP-CC.
IPR030456. TF_fork_head_CS_2.
IPR011991. WHTH_DNA-bd_dom.
IPR007087. Znf_C2H2.
IPR013087. Znf_C2H2/integrase_DNA-bd.
[Graphical view]
PfamiPF00250. Forkhead. 1 hit.
PF16159. FOXP-CC. 1 hit.
[Graphical view]
PRINTSiPR00053. FORKHEAD.
SMARTiSM00339. FH. 1 hit.
[Graphical view]
SUPFAMiSSF46785. SSF46785. 1 hit.
PROSITEiPS00658. FORK_HEAD_2. 1 hit.
PS50039. FORK_HEAD_3. 1 hit.
PS00028. ZINC_FINGER_C2H2_1. 1 hit.
[Graphical view]

Sequencei

Sequence statusi: Complete.

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

Q99JB6-1 [UniParc]FASTAAdd to basket

« Hide

        10         20         30         40         50
MPNPRPAKPM APSLALGPSP GVLPSWKTAP KGSELLGTRG SGGPFQGRDL
60 70 80 90 100
RSGAHTSSSL NPLPPSQLQL PTVPLVMVAP SGARLGPSPH LQALLQDRPH
110 120 130 140 150
FMHQLSTVDA HAQTPVLQVR PLDNPAMISL PPPSAATGVF SLKARPGLPP
160 170 180 190 200
GINVASLEWV SREPALLCTF PRSGTPRKDS NLLAAPQGSY PLLANGVCKW
210 220 230 240 250
PGCEKVFEEP EEFLKHCQAD HLLDEKGKAQ CLLQREVVQS LEQQLELEKE
260 270 280 290 300
KLGAMQAHLA GKMALAKAPS VASMDKSSCC IVATSTQGSV LPAWSAPREA
310 320 330 340 350
PDGGLFAVRR HLWGSHGNSS FPEFFHNMDY FKYHNMRPPF TYATLIRWAI
360 370 380 390 400
LEAPERQRTL NEIYHWFTRM FAYFRNHPAT WKNAIRHNLS LHKCFVRVES
410 420
EKGAVWTVDE FEFRKKRSQR PNKCSNPCP
Length:429
Mass (Da):47,346
Last modified:June 1, 2001 - v1
Checksum:i28D5B8E67891840C
GO

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
AF277994 Genomic DNA. Translation: AAG53608.1.
AF277991 mRNA. Translation: AAG53605.1.
AF277992 mRNA. Translation: AAG53606.1.
CCDSiCCDS29965.1.
RefSeqiNP_001186276.1. NM_001199347.1.
NP_001186277.1. NM_001199348.1.
NP_473380.1. NM_054039.2.
UniGeneiMm.182291.
Mm.288192.

Genome annotation databases

EnsembliENSMUST00000045566; ENSMUSP00000041953; ENSMUSG00000039521.
ENSMUST00000115738; ENSMUSP00000111403; ENSMUSG00000039521.
ENSMUST00000115739; ENSMUSP00000111404; ENSMUSG00000039521.
ENSMUST00000115740; ENSMUSP00000111405; ENSMUSG00000039521.
GeneIDi20371.
KEGGimmu:20371.
UCSCiuc009sll.2. mouse.

Cross-referencesi

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
AF277994 Genomic DNA. Translation: AAG53608.1.
AF277991 mRNA. Translation: AAG53605.1.
AF277992 mRNA. Translation: AAG53606.1.
CCDSiCCDS29965.1.
RefSeqiNP_001186276.1. NM_001199347.1.
NP_001186277.1. NM_001199348.1.
NP_473380.1. NM_054039.2.
UniGeneiMm.182291.
Mm.288192.

3D structure databases

Select the link destinations:
PDBei
RCSB PDBi
PDBji
Links Updated
PDB entryMethodResolution (Å)ChainPositionsPDBsum
4I1LX-ray2.10A189-276[»]
ProteinModelPortaliQ99JB6.
SMRiQ99JB6.
ModBaseiSearch...
MobiDBiSearch...

Protein-protein interaction databases

BioGridi203183. 368 interactors.
DIPiDIP-59739N.
IntActiQ99JB6. 11 interactors.
STRINGi10090.ENSMUSP00000041953.

PTM databases

iPTMnetiQ99JB6.
PhosphoSitePlusiQ99JB6.

Proteomic databases

PaxDbiQ99JB6.
PRIDEiQ99JB6.

Protocols and materials databases

Structural Biology KnowledgebaseSearch...

Genome annotation databases

EnsembliENSMUST00000045566; ENSMUSP00000041953; ENSMUSG00000039521.
ENSMUST00000115738; ENSMUSP00000111403; ENSMUSG00000039521.
ENSMUST00000115739; ENSMUSP00000111404; ENSMUSG00000039521.
ENSMUST00000115740; ENSMUSP00000111405; ENSMUSG00000039521.
GeneIDi20371.
KEGGimmu:20371.
UCSCiuc009sll.2. mouse.

Organism-specific databases

CTDi50943.
MGIiMGI:1891436. Foxp3.

Phylogenomic databases

eggNOGiKOG4385. Eukaryota.
COG5025. LUCA.
GeneTreeiENSGT00800000124014.
HOGENOMiHOG000082490.
HOVERGENiHBG051656.
InParanoidiQ99JB6.
KOiK10163.
OMAiFKEPEDF.
OrthoDBiEOG091G08HY.
PhylomeDBiQ99JB6.
TreeFamiTF326978.

Miscellaneous databases

PROiQ99JB6.
SOURCEiSearch...

Gene expression databases

BgeeiENSMUSG00000039521.
CleanExiMM_FOXP3.
ExpressionAtlasiQ99JB6. baseline and differential.
GenevisibleiQ99JB6. MM.

Family and domain databases

Gene3Di1.10.10.10. 1 hit.
3.30.160.60. 1 hit.
InterProiIPR001766. Fork_head_dom.
IPR032354. FOXP-CC.
IPR030456. TF_fork_head_CS_2.
IPR011991. WHTH_DNA-bd_dom.
IPR007087. Znf_C2H2.
IPR013087. Znf_C2H2/integrase_DNA-bd.
[Graphical view]
PfamiPF00250. Forkhead. 1 hit.
PF16159. FOXP-CC. 1 hit.
[Graphical view]
PRINTSiPR00053. FORKHEAD.
SMARTiSM00339. FH. 1 hit.
[Graphical view]
SUPFAMiSSF46785. SSF46785. 1 hit.
PROSITEiPS00658. FORK_HEAD_2. 1 hit.
PS50039. FORK_HEAD_3. 1 hit.
PS00028. ZINC_FINGER_C2H2_1. 1 hit.
[Graphical view]
ProtoNetiSearch...

Entry informationi

Entry nameiFOXP3_MOUSE
AccessioniPrimary (citable) accession number: Q99JB6
Entry historyi
Integrated into UniProtKB/Swiss-Prot: June 20, 2001
Last sequence update: June 1, 2001
Last modified: November 30, 2016
This is version 139 of the entry and version 1 of the sequence. [Complete history]
Entry statusiReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program

Miscellaneousi

Keywords - Technical termi

3D-structure, Complete proteome, Reference proteome

Documents

  1. MGD cross-references
    Mouse Genome Database (MGD) cross-references in UniProtKB/Swiss-Prot
  2. PDB cross-references
    Index of Protein Data Bank (PDB) cross-references
  3. SIMILARITY comments
    Index of protein domains and families

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 one 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.