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PR01789

Identifier
NUCFACTORATC  [View Relations]  [View Alignment]  
Accession
PR01789
No. of Motifs
4
Creation Date
04-MAR-2002
Title
Nuclear factor of activated T cells (NFAT) signature
Database References

PROSITE; PS01204 REL_1; PS50254 REL_2
PFAM; PF00554 RHD_1; PF01833 TIG_1
INTERPRO; IPR002909; IPR000451
PDB; 1A02; 1A66; 1IMH; 1NFA
SCOP; 1A02; 1A66; 1NFA
CATH; 1A02; 1A66; 1NFA
Literature References
1. MASUDA, E.S., NAITO, Y., TOKUMITSU, H., CAMPBELL, D., SAITO, F., 
HANNUM, C., ARAI, K.I. AND ARAI, N.
NFATx, a novel member of the nuclear factor of activated T cells family that 
is expressed predominately in the thymus.
MOL.CELL BIOL. 15 2697-2706 (1995).
 
2. PARK, J., TAKEUCHI, A. AND SHARMA, S.
Characterization of a new isoform of the NFAT (nuclear factor of activated T 
cells) gene family member NFATc.
J.BIOL.CHEM. 271 20914-20921 (1996).
 
3. IMAMURA, R., MASUDA, E.S., NAITO, Y., IMAI, S.I., FUJINO, T., TAKANO, T., 
ARAI, K.I. AND ARAI, N.
Carboxyl-terminal 15-amino acid sequence of NFATx1 is possibly created by 
tissue-specific splicing and is essential for transactivation activity in T 
cells.
J.IMMUNOL. 161 3455-3463 (1998).
 
4. RODRIGUEZ, C.L., ARAMBURU, J., RAKEMAN, A. AND RAO, A.
NFAT5, a constitutively nuclear NFAT5 protein that does not cooperate with 
Fos and Jun.
PROC.NATL.ACAD.SCI.U.S.A. 96 7214-7219 (1999).
 
5. PORTER, C.M., HAVENS, M.A. AND CLIPSTONE, N.A.
Identification of amino acid residues and protein kinases involved in the 
regulation of NFATc subcellular localization.
J.BIOL.CHEM. 275 3543-3551 (2000).

Documentation
Antigenic stimulation of T lymphocytes initiates a complex series of 
intracellular signal transduction pathways that leads to the expression of a 
panel of immunoregulatory genes, whose function is critical to the 
initiation and coordination of the immune response. The multi-subunit 
nuclear factor of activated T cells (NFAT) transcription factor family 
plays a pivotal role in this process and is involved in the expression of a 
number of immunologically important genes. These include the cytokines IL-2, 
IL-3, IL-4, IL-5, granulocyte-macrophage colony-stimulating factor, and 
tumour necrosis factor-alpha, as well as several cell-surface molecules, 
such as CD40L and FasL. Although originally described in T cells, it is now 
apparent that NFAT proteins are also expressed in other immune system cells,
including B cells, mast cells, basophils and natural killer cells, as well 
as in a variety of non-immune cell types and tissues, such as skeletal 
muscle, neurons, heart and adipocytes. However, although NFAT acts as a 
calcium-dependent transcription factor and serves to couple gene expression 
to changes in intracellular calcium levels in most cases, NFAT target genes 
have not been identified in these latter cell types [1-5].
 
NFAT proteins appear to be regulated primarily at the level of their  
subcellular localisation. They are found exclusively in the cytoplasm of 
resting T cells, and consist of 2 components: a pre-existing cytoplasmic 
component that translocates into the nucleus on calcium mobilisation, and an 
inducible nuclear component comprising members of the activating protein-1 
(AP-1) family of transcription factors. In response to antigen receptor 
signalling, the calcium-regulated phosphatase calcineurin acts directly to 
dephosphorylate NFAT proteins, causing their rapid translocation from the 
cytoplasm to the nucleus, where they cooperatively bind their target 
sequences together with AP-1 proteins, thereby initiating transcription. 
It is now apparent that regulation of NFAT subcellular localisation is a 
highly dynamic process, which greatly depends on quantitative changes in 
intracellular calcium concentration. The calcineurin-mediated 
dephosphorylation and nuclear translocation of NFAT proteins are 
counteracted by poorly defined NFAT kinase(s), which phosphorylate the 
proteins, thereby either antagonising their nuclear translocation or
promoting their export from the nucleus back to the cytoplasm. Thus, in the 
absence of sustained calcineurin activity, nuclear NFAT proteins are rapidly 
rephosphorylated and exported back into the cytoplasm [3,5].
 
The NFAT family of transcription factors contains 4 members: NFAT1 (NFATp),
NFAT2 (NFATc), NFAT3 and NFAT4 (NFATx), each expressed as several isoforms 
related by alternative splicing. These proteins share a highly conserved 
DNA-binding domain of ~270 amino acids. This domain, which is related to  
that of the Rel family of transcription factors, is required for cooperative 
interactions with AP-1 proteins, and contains one of 2 redundant nuclear 
localisation sequences (NLSs). Upstream of this region is a less well 
conserved regulatory domain of ~300 amino acids, characterised by the 
presence of repeated motifs rich in serine and proline residues 
(SPXXSPXXSPXXXXXX[D/E][D/E]). The N-terminal domain is both necessary and 
sufficient to confer calcinuerin-dependent nuclear localisation and 
recycling: it contains binding sites for calcineurin, as well as a second 
redundant NLS and a sequence motif involved in directing the nuclear export 
of NFAT proteins. Most, if not all, of the sites of regulatory 
phosphorylation are found within this domain. It has been proposed that the 
phophorylation status of these sites modifies the activity of the two 
redundant NFAT NLSs and so determines the subcellular distribution of NFAT 
proteins. By contrast, little is known about the C-terminal domain, which 
shares no significant sequence similarities with other proteins, and is 
absent in NFATc [2,3,5].
 
An additional member of the NFAT family, NFAT5, has a constitutive nuclear 
localisation that is not modified on cellular activation, implying that it 
is a target of signalling pathways distinct from those that regulate NFAT1-
4, and that it is likely to modulate cellular processes in a wide variety of 
cells [4].
 
The calcineurin dependence of NFAT proteins makes them targets of the 
immunosuppressive drugs cyclosporin A (CsA) and FK506. These powerful agents
have not only contributed in a major way to the success of transplant 
surgery, but may also prove important in the treatment of cardiac 
hypertrophy (where NFAT3 is specifically implicated) [4].
 
NUCFACTORATC is a 4-element fingerprint that provides a signature for the 
NFAT proteins. The fingerprint was derived from an initial alignment of 5 
sequences: the motifs were drawn from conserved regions largely spanning 
the central portion of the alignment, focusing on those sections that
characterise the NFAT1-4 proteins but distinguish them from the rest of the 
Rel-domain containing proteins (rel/Dorsal/NFkB) - motifs 1 and 2 span the 
DNA-binding domain. Two iterations on SPTR39_17f were required to reach 
convergence, at which point a true set comprising 11 sequences was 
identified.
Summary Information
11 codes involving  4 elements
0 codes involving 3 elements
0 codes involving 2 elements
Composite Feature Index
411111111
30000
20000
1234
True Positives
NFC1_HUMAN    NFC1_MOUSE    NFC1_PIG      NFC2_HUMAN    
NFC2_MOUSE NFC3_HUMAN NFC3_MOUSE NFC4_HUMAN
Q9DBQ6 Q9EP91 Q9JHD3
Sequence Titles
NFC1_HUMAN  NUCLEAR FACTOR OF ACTIVATED T-CELLS, CYTOPLASMIC 1 (NFAT TRANSCRIPTION COMPLEX CYTOSOLIC COMPONENT) (NF-ATC1) (NF-ATC) - Homo sapiens (Human). 
NFC1_MOUSE NUCLEAR FACTOR OF ACTIVATED T-CELLS, CYTOPLASMIC 1 (NFAT TRANSCRIPTION COMPLEX CYTOSOLIC COMPONENT) (NF-ATC1) (NF-ATC) - Mus musculus (Mouse).
NFC1_PIG NUCLEAR FACTOR OF ACTIVATED T-CELLS, CYTOPLASMIC 1 (NFAT TRANSCRIPTION COMPLEX CYTOSOLIC COMPONENT) (NF-ATC1) (NF-ATC) (NFATMAC) - Sus scrofa (Pig).
NFC2_HUMAN NUCLEAR FACTOR OF ACTIVATED T-CELLS, CYTOPLASMIC 2 (T CELL TRANSCRIPTION FACTOR NFAT1) (NFAT PRE-EXISTING SUBUNIT) (NF-ATP) - Homo sapiens (Human).
NFC2_MOUSE NUCLEAR FACTOR OF ACTIVATED T-CELLS, CYTOPLASMIC 2 (T CELL TRANSCRIPTION FACTOR NFAT1) (NFAT PRE-EXISTING SUBUNIT) (NF-ATP) - Mus musculus (Mouse).
NFC3_HUMAN NUCLEAR FACTOR OF ACTIVATED T-CELLS, CYTOPLASMIC 3 (T CELL TRANSCRIPTION FACTOR NFAT4) (NF-ATC3) (NF-AT4) (NFATX) - Homo sapiens (Human).
NFC3_MOUSE NUCLEAR FACTOR OF ACTIVATED T-CELLS, CYTOPLASMIC 3 (T CELL TRANSCRIPTION FACTOR NFAT4) (NF-ATC3) (NF-AT4) (NFATX) - Mus musculus (Mouse).
NFC4_HUMAN NUCLEAR FACTOR OF ACTIVATED T-CELLS, CYTOPLASMIC 4 (T CELL TRANSCRIPTION FACTOR NFAT3) (NF-ATC4) (NF-AT3) - Homo sapiens (Human).
Q9DBQ6 NUCLEAR FACTOR OF ACTIVATED T-CELLS, CYTOPLASMIC 1 - Mus musculus (Mouse).
Q9EP91 TRANSCRIPTION COMPLEX SUBUNIT NF-ATC4 - Mus musculus (Mouse).
Q9JHD3 NUCLEAR FACTOR OF ACTIVATED T CELLS C - Mus musculus (Mouse).
Scan History
SPTR39_17f 2  250  NSINGLE    
Initial Motifs
Motif 1  width=17
Element Seqn Id St Int Rpt
KASAGGHPIVQLHGYLE NFC1_HUMAN 452 452 -
KASAGGHPIVQLHGYLE Q9JHD3 453 453 -
KASAGGHPIVQLHGYLE Q9DBQ6 439 439 -
KASAGGHPIVQLHGYLE NFC1_MOUSE 453 453 -
KASAGGHPSVQLHGYVE NFC1_PIG 442 442 -

Motif 2 width=23
Element Seqn Id St Int Rpt
RTLSLQVASNPIECSQRSAQELP NFC1_HUMAN 574 105 -
RTLSLQVASNPIECSQRSAQELP Q9JHD3 575 105 -
RTLSLQVASNPIECSQRSAQELP Q9DBQ6 561 105 -
RTLSLQVASNPIECSQRSAQELP NFC1_MOUSE 575 105 -
RTLSLQVASNPIECSQRSAQELP NFC1_PIG 564 105 -

Motif 3 width=20
Element Seqn Id St Int Rpt
SGHNFLQDSKVIFVEKAPDG NFC1_HUMAN 617 20 -
SGHNFLQDSKVIFVEKAPDG Q9JHD3 618 20 -
SGHNFLQDSKVIFVEKAPDG Q9DBQ6 604 20 -
SGHNFLQDSKVIFVEKAPDG NFC1_MOUSE 618 20 -
TGHNFLQDSKVVFVEKAPDG NFC1_PIG 607 20 -

Motif 4 width=20
Element Seqn Id St Int Rpt
FYVCNGKRKRSQYQRFTYLP NFC1_HUMAN 676 39 -
FYVCNGKRKRSQYQRFTYLP Q9JHD3 677 39 -
FYVCNGKRKRSQYQRFTYLP Q9DBQ6 663 39 -
FYVCNGKRKRSQYQRFTYLP NFC1_MOUSE 677 39 -
FYVCNGKRKRSQYQHFTYLP NFC1_PIG 666 39 -
Final Motifs
Motif 1  width=17
Element Seqn Id St Int Rpt
KASAGGHPIVQLHGYLE NFC1_HUMAN 452 452 -
KASAGGHPIVQLHGYLE Q9JHD3 453 453 -
KASAGGHPIVQLHGYLE Q9DBQ6 439 439 -
KASAGGHPIVQLHGYLE NFC1_MOUSE 453 453 -
KASAGGHPSVQLHGYVE NFC1_PIG 442 442 -
KASTGGHPVVKLLGYSE NFC3_MOUSE 457 457 -
KAPTGGHPVVQLHGYME NFC2_MOUSE 436 436 -
KAPTGGHPVVQLHGYME NFC2_HUMAN 434 434 -
KASTGGHPVVKLLGYNE NFC3_HUMAN 457 457 -
KAAPGGHPVVKLLGYSE NFC4_HUMAN 443 443 -
KAAPGGHPVVKLLGYSE Q9EP91 443 443 -

Motif 2 width=23
Element Seqn Id St Int Rpt
RTLSLQVASNPIECSQRSAQELP NFC1_HUMAN 574 105 -
RTLSLQVASNPIECSQRSAQELP Q9JHD3 575 105 -
RTLSLQVASNPIECSQRSAQELP Q9DBQ6 561 105 -
RTLSLQVASNPIECSQRSAQELP NFC1_MOUSE 575 105 -
RTLSLQVASNPIECSQRSAQELP NFC1_PIG 564 105 -
KVLSLQIASIPVECSQRSAQELP NFC3_MOUSE 578 104 -
RIVSLQAASNPIECSQRSAHELP NFC2_MOUSE 558 105 -
RIVSLQTASNPIECSQRSAHELP NFC2_HUMAN 556 105 -
KVLSLQIASIPVECSQRSAQELP NFC3_HUMAN 578 104 -
KVVSVQAASVPIECSQRSAQELP NFC4_HUMAN 564 104 -
KVVSVQAASVPIECSQRSAQELP Q9EP91 564 104 -

Motif 3 width=20
Element Seqn Id St Int Rpt
SGHNFLQDSKVIFVEKAPDG NFC1_HUMAN 617 20 -
SGHNFLQDSKVIFVEKAPDG Q9JHD3 618 20 -
SGHNFLQDSKVIFVEKAPDG Q9DBQ6 604 20 -
SGHNFLQDSKVIFVEKAPDG NFC1_MOUSE 618 20 -
TGHNFLQDSKVVFVEKAPDG NFC1_PIG 607 20 -
TGSNFLPESKIIFLEKGQDG NFC3_MOUSE 621 20 -
TGQNFTAESKVVFMEKTTDG NFC2_MOUSE 601 20 -
TGQNFTSESKVVFTEKTTDG NFC2_HUMAN 599 20 -
TGSNFLPESKIIFLEKGQDG NFC3_HUMAN 621 20 -
TGSNFLPDSKVVFIERGPDG NFC4_HUMAN 607 20 -
TGSNFLPDSKVVFIERGPDG Q9EP91 607 20 -

Motif 4 width=20
Element Seqn Id St Int Rpt
FYVCNGKRKRSQYQRFTYLP NFC1_HUMAN 676 39 -
FYVCNGKRKRSQYQRFTYLP Q9JHD3 677 39 -
FYVCNGKRKRSQYQRFTYLP Q9DBQ6 663 39 -
FYVCNGKRKRSQYQRFTYLP NFC1_MOUSE 677 39 -
FYVCNGKRKRSQYQHFTYLP NFC1_PIG 666 39 -
FYLCNGKRKKSQSQRFTYTP NFC3_MOUSE 680 39 -
FYVINGKRKRSQPQHFTYHP NFC2_MOUSE 660 39 -
FYVINGKRKRSQPQHFTYHP NFC2_HUMAN 658 39 -
FYLCNGKRKKSQSQRFTYTP NFC3_HUMAN 680 39 -
FYVSNGRRKRSPTQSFRFLP NFC4_HUMAN 666 39 -
FYVSNGRRKRSPTQSFKFLP Q9EP91 666 39 -