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Forkhead box protein P3 [Cleaved into: Forkhead box protein P3, C-terminally processed; Forkhead box protein P3 41 kDa form]

 FOXP3_MACFA             Reviewed;         431 AA.
Q6U8D7;
12-APR-2005, integrated into UniProtKB/Swiss-Prot.
05-JUL-2004, sequence version 1.
31-JAN-2018, entry version 79.
RecName: Full=Forkhead box protein P3;
Contains:
RecName: Full=Forkhead box protein P3, C-terminally processed;
Contains:
RecName: Full=Forkhead box protein P3 41 kDa form;
Name=FOXP3;
Macaca fascicularis (Crab-eating macaque) (Cynomolgus monkey).
Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi;
Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini;
Catarrhini; Cercopithecidae; Cercopithecinae; Macaca.
NCBI_TaxID=9541;
[1]
NUCLEOTIDE SEQUENCE [MRNA].
Apoil P.-A., Tiraby G., Blancher A.;
"Transduction of macaque lymphocytes by Foxp3: in vitro functional
studies.";
Submitted (AUG-2003) to the EMBL/GenBank/DDBJ databases.
-!- FUNCTION: 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. Mediates transcriptional repression of
IL2 via its association with histone acetylase KAT5 and histone
deacetylase HDAC7. Can activate the expression of TNFRSF18, IL2RA
and CTLA4 and repress the expression of IL2 and IFNG via its
association with transcription factor RUNX1. Inhibits the
differentiation of IL17 producing helper T-cells (Th17) by
antagonizing RORC function, leading to down-regulation of IL17
expression, favoring Treg development. Inhibits the
transcriptional activator activity of RORA. Can repress the
expression of IL2 and IFNG via its association with transcription
factor IKZF4. {ECO:0000250|UniProtKB:Q99JB6,
ECO:0000250|UniProtKB:Q9BZS1}.
-!- SUBUNIT: Homodimer. Dimerization is essential for its
transcriptional regulator activity. Interacts with IKZF3.
Interacts (via LXXLL motif) with RORA (via AF-2 motif). Interacts
with HDAC9 in the absence of T-cell stimulation. Interacts with
PPP1CA, PPP1CB, PPP1CG, KAT5, HDAC7, HSPA8, USP7, STUB1, HSPA1A/B,
RUNX1, RUNX2, RUNX3, RELA, NFATC2, IKFZ4 and RORC.
{ECO:0000250|UniProtKB:Q99JB6, ECO:0000250|UniProtKB:Q9BZS1}.
-!- SUBCELLULAR LOCATION: Nucleus {ECO:0000250|UniProtKB:Q9BZS1,
ECO:0000255|PROSITE-ProRule:PRU00089}. Cytoplasm
{ECO:0000250|UniProtKB:Q9BZS1}. Note=Predominantly expressed in
the cytoplasm in activated conventional T-cells whereas
predominantly expressed in the nucleus in regulatory T-cells
(Treg). The 41 kDa form derived by proteolytic processing is found
exclusively in the chromatin fraction of activated Treg cells.
{ECO:0000250|UniProtKB:Q99JB6, ECO:0000250|UniProtKB:Q9BZS1}.
-!- DOMAIN: The fork-head DNA-binding domain is essential for its
dimerization and interaction with NFATC2.
{ECO:0000250|UniProtKB:Q9BZS1}.
-!- PTM: Phosphorylation at Ser-418 regulates its transcriptional
repressor activity and consequently, regulatory T-cells (Treg)
suppressive function. Phosphorylation by CDK2 negatively regulates
its transcriptional activity and protein stability.
{ECO:0000250|UniProtKB:Q99JB6, ECO:0000250|UniProtKB:Q9BZS1}.
-!- PTM: 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. {ECO:0000250|UniProtKB:Q9BZS1}.
-!- PTM: 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. {ECO:0000250|UniProtKB:Q9BZS1}.
-!- PTM: 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. {ECO:0000250|UniProtKB:Q99JB6}.
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EMBL; AY376065; AAQ82647.1; -; mRNA.
UniGene; Mfa.6265; -.
ProteinModelPortal; Q6U8D7; -.
SMR; Q6U8D7; -.
HOVERGEN; HBG051656; -.
GO; GO:0005737; C:cytoplasm; ISS:UniProtKB.
GO; GO:0005634; C:nucleus; ISS:UniProtKB.
GO; GO:0001047; F:core promoter binding; ISS:UniProtKB.
GO; GO:0003677; F:DNA binding; ISS:UniProtKB.
GO; GO:0003700; F:DNA binding transcription factor activity; ISS:UniProtKB.
GO; GO:0046872; F:metal ion binding; IEA:UniProtKB-KW.
GO; GO:0051525; F:NFAT protein binding; ISS:UniProtKB.
GO; GO:0042803; F:protein homodimerization activity; ISS:UniProtKB.
GO; GO:0043565; F:sequence-specific DNA binding; ISS:UniProtKB.
GO; GO:0008285; P:negative regulation of cell proliferation; ISS:UniProtKB.
GO; GO:0032792; P:negative regulation of CREB transcription factor activity; ISS:UniProtKB.
GO; GO:0042036; P:negative regulation of cytokine biosynthetic process; ISS:UniProtKB.
GO; GO:0050710; P:negative regulation of cytokine secretion; ISS:UniProtKB.
GO; GO:0043433; P:negative regulation of DNA binding transcription factor activity; ISS:UniProtKB.
GO; GO:0050777; P:negative regulation of immune response; ISS:UniProtKB.
GO; GO:0032689; P:negative regulation of interferon-gamma production; ISS:UniProtKB.
GO; GO:0032693; P:negative regulation of interleukin-10 production; ISS:UniProtKB.
GO; GO:0045085; P:negative regulation of interleukin-2 biosynthetic process; ISS:UniProtKB.
GO; GO:0032703; P:negative regulation of interleukin-2 production; ISS:UniProtKB.
GO; GO:0032713; P:negative regulation of interleukin-4 production; ISS:UniProtKB.
GO; GO:0032088; P:negative regulation of NF-kappaB transcription factor activity; ISS:UniProtKB.
GO; GO:0002725; P:negative regulation of T cell cytokine production; ISS:UniProtKB.
GO; GO:0042130; P:negative regulation of T cell proliferation; ISS:UniProtKB.
GO; GO:2000320; P:negative regulation of T-helper 17 cell differentiation; ISS:UniProtKB.
GO; GO:0045892; P:negative regulation of transcription, DNA-templated; ISS:UniProtKB.
GO; GO:0045893; P:positive regulation of transcription, DNA-templated; ISS:UniProtKB.
GO; GO:0002667; P:regulation of T cell anergy; ISS:UniProtKB.
GO; GO:0042110; P:T cell activation; ISS:UniProtKB.
GO; GO:0006351; P:transcription, DNA-templated; IEA:UniProtKB-KW.
CDD; cd00059; FH; 1.
Gene3D; 1.10.10.10; -; 1.
InterPro; IPR001766; Fork_head_dom.
InterPro; IPR032354; FOXP-CC.
InterPro; IPR030456; TF_fork_head_CS_2.
InterPro; IPR036388; WH-like_DNA-bd_sf.
InterPro; IPR036390; WH_DNA-bd_sf.
InterPro; IPR013087; Znf_C2H2_type.
Pfam; PF00250; Forkhead; 1.
Pfam; PF16159; FOXP-CC; 1.
PRINTS; PR00053; FORKHEAD.
SMART; SM00339; FH; 1.
SUPFAM; SSF46785; SSF46785; 1.
PROSITE; PS00658; FORK_HEAD_2; 1.
PROSITE; PS50039; FORK_HEAD_3; 1.
PROSITE; PS00028; ZINC_FINGER_C2H2_1; 1.
2: Evidence at transcript level;
Acetylation; Activator; Cytoplasm; DNA-binding; Isopeptide bond;
Metal-binding; Nucleus; Phosphoprotein; Repressor; Transcription;
Transcription regulation; Ubl conjugation; Zinc; Zinc-finger.
CHAIN 1 431 Forkhead box protein P3.
/FTId=PRO_0000091887.
CHAIN 1 417 Forkhead box protein P3, C-terminally
processed.
{ECO:0000250|UniProtKB:Q99JB6}.
/FTId=PRO_0000432433.
CHAIN 52 417 Forkhead box protein P3 41 kDa form.
{ECO:0000250|UniProtKB:Q99JB6}.
/FTId=PRO_0000432434.
PROPEP 418 431 {ECO:0000250|UniProtKB:Q99JB6}.
/FTId=PRO_0000432435.
ZN_FING 197 222 C2H2-type.
DNA_BIND 337 423 Fork-head. {ECO:0000255|PROSITE-
ProRule:PRU00089}.
REGION 106 190 Essential for transcriptional repressor
activity and for interaction with KAT5
and HDAC7.
{ECO:0000250|UniProtKB:Q9BZS1}.
REGION 149 199 Interaction with IKZF4.
{ECO:0000250|UniProtKB:Q99JB6}.
REGION 239 260 Leucine-zipper.
REGION 278 336 Interaction with RUNX1.
{ECO:0000250|UniProtKB:Q9BZS1}.
MOTIF 68 76 Nuclear export signal.
{ECO:0000250|UniProtKB:Q9BZS1}.
MOTIF 92 96 LXXLL motif.
{ECO:0000250|UniProtKB:Q9BZS1}.
MOTIF 239 248 Nuclear export signal.
{ECO:0000250|UniProtKB:Q9BZS1}.
MOTIF 414 417 Nuclear localization signal.
{ECO:0000250|UniProtKB:Q9BZS1}.
SITE 51 52 Cleavage. {ECO:0000250|UniProtKB:Q99JB6}.
SITE 417 418 Cleavage; by PCSK1 or PCSK2.
{ECO:0000250|UniProtKB:Q99JB6}.
MOD_RES 19 19 Phosphoserine; by CDK2.
{ECO:0000250|UniProtKB:Q99JB6}.
MOD_RES 31 31 N6-acetyllysine.
{ECO:0000250|UniProtKB:Q9BZS1}.
MOD_RES 263 263 N6-acetyllysine; alternate.
{ECO:0000250|UniProtKB:Q9BZS1}.
MOD_RES 268 268 N6-acetyllysine; alternate.
{ECO:0000250|UniProtKB:Q9BZS1}.
MOD_RES 418 418 Phosphoserine.
{ECO:0000250|UniProtKB:Q9BZS1}.
CROSSLNK 250 250 Glycyl lysine isopeptide (Lys-Gly)
(interchain with G-Cter in ubiquitin).
{ECO:0000250|UniProtKB:Q99JB6}.
CROSSLNK 252 252 Glycyl lysine isopeptide (Lys-Gly)
(interchain with G-Cter in ubiquitin).
{ECO:0000250|UniProtKB:Q99JB6}.
CROSSLNK 263 263 Glycyl lysine isopeptide (Lys-Gly)
(interchain with G-Cter in ubiquitin);
alternate.
{ECO:0000250|UniProtKB:Q99JB6}.
CROSSLNK 268 268 Glycyl lysine isopeptide (Lys-Gly)
(interchain with G-Cter in ubiquitin);
alternate.
{ECO:0000250|UniProtKB:Q99JB6}.
CROSSLNK 393 393 Glycyl lysine isopeptide (Lys-Gly)
(interchain with G-Cter in ubiquitin).
{ECO:0000250|UniProtKB:Q99JB6}.
SEQUENCE 431 AA; 47216 MW; 6C5F4AB342A9630F CRC64;
MPNPRPGKPS APSLALGPSP GASPSWRAAP KASDLLGARG PGGIFQGRDL RGGAHASSSS
LNPMPPSQLQ LPTLPLVMVA PSGARLGPLP HLQALLQDRP HFMHQLSTVD AHARTPVLQV
HPLESPAMIS LPPPTTATGV FSLKARPGLP PGINVASLEW VSREPALLCT FPNPGAPRKD
STLSAMPQSS YPLLANGVCK WPGCEKVFEE PEDFLKHCQA DHLLDEKGRA QCLLQREMVQ
SLEQQLVLEK EKLSAMQAHL AGKMALTKAS SVASSDKGSC CIVAAGSQGS AVPAWSGPRE
APDSLFAVRR HLWGSHGNST FPEFLHNMDY FKFHNMRPPF TYATLIRWAI LEAPEKQRTL
NEIYHWFTRM FAFFRNHPAT WKNAIRHNLS LHKCFVRVES EKGAVWTVDE LEFRKKRSQR
PSRCSNPTPG P


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