FAM220A, also known as SIPAR, inhibits STAT3 activity by accelerating its dephosphorylation []. STAT3 is a member of the STAT family (signal transducers and activators of transcription) that plays an esential role in cell growth and differentiation.
This domain is found in SIPAR (STAT3-Interacting Protein As a Repressor). SIPAR inhibits STAT3 activity by accelerating its dephosphorylation []. STAT3 is a member of the STAT family (signal transducers and activators of transcription) that plays an esential role in cell growth and differentiation.
CUEDC2 is a novel negative regulator of progesterone receptor (PR) and functions to promote the progesterone-induced PR degradation by the ubiquitin-proteasome pathway []. It also acts as the regulator of JAK1/STAT3 signaling through inhibiting cytokine-induced phosphorylation of JAK1 and STAT3 and the subsequent STAT3 transcriptional activity []. This entry represents the CUE domain found in CUEDC2.
STAT3 is a member of the STAT protein family. STAT3 mediates the expression of a variety of genes in response to cell stimuli, and plays a key role in many cellular processes such as cell growth and apoptosis. STAT3 has been shown to interact with Rho GTPases []Three alternatively spliced transcript variants encoding distinct isoforms have been described. STAT3 activation is required for self-renewal of embryonic stem cells (ESCs) []and is essential for the differentiation of the TH17 helper T cells []. Mutations in the STAT3 gene result in hyperimmunoglobulin E syndrome and human cancers []. This entry represents the SH2 domain of STAT3.STAT proteins have a dual function: signal transduction and activation of transcription. When cytokines are bound to cell surface receptors, the associated Janus kinases (JAKs) are activated, leading to tyrosine phosphorylation of the given STAT proteins []. Phosphorylated STATs form dimers, translocate to the nucleus, and bind specific response elements to activate transcription of target genes []. STAT proteins contain an N-terminal domain (NTD), a coiled-coil domain (CCD), a DNA-binding domain (DBD), an α-helical linker domain (LD), an SH2 domain, and a transactivation domain (TAD). The SH2 domain is necessary for receptor association and tyrosine phosphodimer formation. There are seven mammalian STAT family members which have been identified: STAT1, STAT2, STAT3, STAT4, STAT5 (STAT5A and STAT5B), and STAT6 [].
SOCS7 is a member of the suppressor of cytokine signaling family of proteins. SOCS7 functions in insulin signaling and glucose homeostasis through IRS1 ubiquitination and subsequent proteasomal degradation []. SOCS7 inhibits also prolactin, growth hormone and leptin signaling by preventing STAT3 and STAT5 activation, sequestering them in the cytoplasm and reducing their binding to DNA [].
SOCS7 is a member of the suppressor of cytokine signaling family of proteins. SOCS7 functions in insulin signaling and glucose homeostasis through IRS1 ubiquitination and subsequent proteasomal degradation []. SOCS7 inhibits also prolactin, growth hormone and leptin signaling by preventing STAT3 and STAT5 activation, sequestering them in the cytoplasm and reducing their binding to DNA [].This entry represents the SH2 domain of SOCS7.
Signal transducers and activators of transcription (STATs) mediate cell proliferation, differentiation and survival in immune responses. ADP-ribosylation factor-like protein 2-binding protein, also known as BART, plays an essential role in the nuclear retention of STAT3 through interaction with GTPase ARL2 (ARF-like 2) []. BART is predominantly cytosolic but can also be found to be associated with mitochondria. BART is also involved in binding to the adenine nucleotide transporter ANT1 and may have a role in mitochondria transport and/or apoptosis [].
This family consists of several eukaryotic gene associated with retinoic-interferon-induced mortality 19 (GRIM-19) proteins. GRIM-19, was reported to encode a small protein primarily distributed in the nucleus and was able to promote cell death induced by IFN-beta and RA. A bovine homologue of GRIM-19 was co-purified with mitochondrial NADH:ubiquinone oxidoreductase (complex I) in bovine heart. Therefore, its exact cellular localisation and function are unclear. It has now been discovered that GRIM-19 is a specific interacting protein which negatively regulates Stat3 activity [].
UBL4A (also known as GdX) is a ubiquitously expressed ubiquitin-like (Ubl) protein that forms a complex with partner proteins and participates in the protein processing through endoplasmic reticulum (ER), acting as a chaperone. As a key component of the BCL2-associated athanogene 6 (BAG6) chaperone complex, UBL4A plays a role in mediating DNA damage signaling and cell death [, ]. UBL4A also regulates insulin-induced Akt plasma membrane translocation through promotion of Arp2/3-dependent actin branching []. Moreover, UBL4A specifically stabilises the TC45/STAT3 association and promotes dephosphorylation of STAT3 to repress tumorigenesis [].This is the ubiquitin-like domain of UBL4A and related proteins.
This entry represents the C-terminal domain found in members of the transmembrane protein 132 family. The family consists of TMEM132A, TMEM132B, TMEM132C, TMEM132D, TMEM132E.TMEM132A may play a role in embryonic and postnatal development of the brain. It increased resistance to cell death induced by serum starvation in cultured cells. It regulates cAMP-induced GFAP gene expression via STAT3 phosphorylation [, ]. TMEM132D is a single-pass transmembrane protein that is highly expressed in the cortical regions of the human and mouse brain. The function is still unknown. It may act as a cell-surface marker for oligodendrocyte differentiation [, ]. Additionally, as it may be most strongly expressed in neurons and it colocalises with actin filaments, TMEM132D may be implicated in neuronal sprouting and connectivity in brain regions important for anxiety-related behaviour [].
This entry represents the N-terminal domain found in members of the transmembrane protein 132 family. The family consists of TMEM132A, TMEM132B, TMEM132C, TMEM132D, TMEM132E.TMEM132A may play a role in embryonic and postnatal development of the brain. It increased resistance to cell death induced by serum starvation in cultured cells. It regulates cAMP-induced GFAP gene expression via STAT3 phosphorylation [, ]. TMEM132D is a single-pass transmembrane protein that is highly expressed in the cortical regions of the human and mouse brain. The function is still unknown. It may act as a cell-surface marker for oligodendrocyte differentiation [, ]. Additionally, as it may be most strongly expressed in neurons and it colocalises with actin filaments, TMEM132D may be implicated in neuronal sprouting and connectivity in brain regions important for anxiety-related behaviour [].
This family consists of TMEM132A, TMEM132B, TMEM132C, TMEM132D, TMEM132E. They all have transmembrane domains. TMEM132A may play a role in embryonic and postnatal development of the brain. It increased resistance to cell death induced by serum starvation in cultured cells. It regulates cAMP-induced GFAP gene expression via STAT3 phosphorylation [, ]. TMEM132D is a single-pass transmembrane protein that is highly expressed in the cortical regions of the human and mouse brain. The function is still unknown. It may act as a cell-surface marker for oligodendrocyte differentiation [, ]. Additionally, as it may be most strongly expressed in neurons and it colocalises with actin filaments, TMEM132D may be implicated in neuronal sprouting and connectivity in brain regions important for anxiety-related behaviour [].
Interleukins are the cytokines that act specifically as mediators between leukocytes by binding to specific interleukin receptors. Despite this common role this group of receptors is somewhat structurally and functionally diverse. There are at least 29 distinct interleukins with corresponding receptors []. Because a variety of human solid tumours have been shown to specifically express certain interleukin receptors such as the interleukin-4 and interleukin-13 receptors, these proteins are being investigated as therapeutic targets [, ]. Interleukin signalling plays a role in autoimmune disease and therapeutic targeting of the interleukins and their receptors is being investigated here as well [, ].The IL-20 receptor alpha subunit forms a functional heterodimer with the IL-20 beta subunit, and transduces ligand-binding at least in part through STAT3 activation [].This entry represents interleukin-20 receptor, alpha.
The Leptin receptor is a single membrane-spanning receptor of the class I cytokine receptor family []. It is bound by leptin, an approximately 16kDa double protein produced primarily in adipose tissue. Leptin and its receptor are intimately involved in the regulation of body fat levels. Mice and rats mutant for Leptin (ob/ob) and the Leptin receptor (db/db mice and fa/fa rats) are obese, and show multiple symptoms of mis-regulation of body weight and energy storage. The leptin receptor has multiple splice forms, and only the longest splice form has a significant cytosolic domain and appears sufficient for cytosolic signalling. The splice form has been shown to be expressed overwhelmingly in the hypothalamus, and to activate STAT3 and STAT5 [].
This entry represents the SOCS box domain of SOCS7.SOCS7 is a member of the suppressor of cytokine signaling family of proteins. SOCS7 functions in insulin signaling and glucose homeostasis through IRS1 ubiquitination and subsequent proteasomal degradation []. SOCS7 inhibits also prolactin, growth hormone and leptin signaling by preventing STAT3 and STAT5 activation, sequestering them in the cytoplasm and reducing their binding to DNA [].The general function of the SOCS box is the recruitment of the ubiquitin-transferase system. The SOCS box interacts with Elongins B and C, Cullin-5 or Cullin-2, Rbx-1, and E2. Therefore, SOCS-box-containing proteins probably function as E3 ubiquitin ligases and mediate the degradation of proteins associated through their N-terminal regions [, ].
The STAT protein (Signal Transducers and Activators of Transcription) family contains transcription factors that are specifically activated to regulate gene transcription when cells encounter cytokines and growth factors, hence they act as signal transducers in the cytoplasm and transcription activators in the nucleus []. Binding of these factors to cell-surface receptors leads to receptor autophosphorylation at a tyrosine, the phosphotyrosine being recognised by the STAT SH2 domain, which mediates the recruitment of STAT proteins from the cytosol and their association with the activated receptor. The STAT proteins are then activated by phosphorylation via members of the JAK family of protein kinases, causing them to dimerise and translocated to the nucleus, where they bind to specific promoter sequences in target genes. In mammals, STATs comprise a family of seven structurally and functionally related proteins: Stat1, Stat2, Stat3, Stat4, Stat5a and Stat5b, Stat6. STAT proteins play a critical role in regulating innate and acquired host immune responses. Dysregulation of at least two STAT signalling cascades (i.e. Stat3 and Stat5) is associated with cellular transformation.Signalling through the JAK/STAT pathway is initiated when a cytokine binds to its corresponding receptor. This leads to conformational changes in the cytoplasmic portion of the receptor, initiating activation of receptor associated members of the JAK family of kinases. The JAKs, in turn, mediate phosphorylation at the specific receptor tyrosine residues, which then serve as docking sites for STATs and other signalling molecules. Once recruited to the receptor, STATs also become phosphorylated by JAKs, on a single tyrosine residue. Activated STATs dissociate from the receptor, dimerise, translocate to the nucleus and bind to members of the GAS (gamma activated site) family of enhancers.The seven STAT proteins identified in mammals range in size from 750 and 850 amino acids. The chromosomal distribution of these STATs, as well as the identification of STATs in more primitive eukaryotes, suggest that this family arose from a single primordial gene. STATs share 6 structurally and functionally conserved domains including: an N-terminal domain (ND) that strengthens interactions between STAT dimers on adjacent DNA-binding sites; a coiled-coil STAT domain (CCD) that is implicated in protein-protein interactions; a DNA-binding domain (DBD) with an immunoglobulin-like fold similar to p53 tumour suppressor protein; an EF-hand-like linker domain connecting the DNA-binding and SH2 domains; an SH2 domain () that acts as a phosphorylation-dependent switch to control receptor recognition and DNA-binding; and a C-terminal transactivation domain [, , ]. The crystal structure of the N terminus of Stat4 reveals a dimer. The interface of this dimer is formed by a ring-shaped element consisting of five short helices. Several studies suggest that this N-terminal dimerisation promotes cooperativity of binding to tandem GAS elements and with the transcriptional coactivator CBP/p300.
The STAT protein (Signal Transducers and Activators of Transcription) family contains transcription factors that are specifically activated to regulate gene transcription when cells encounter cytokines and growth factors, hence they act as signal transducers in the cytoplasm and transcription activators in the nucleus []. Binding of these factors to cell-surface receptors leads to receptor autophosphorylation at a tyrosine, the phosphotyrosine being recognised by the STAT SH2 domain, which mediates the recruitment of STAT proteins from the cytosol and their association with the activated receptor. The STAT proteins are then activated by phosphorylation via members of the JAK family of protein kinases, causing them to dimerise and translocated to the nucleus, where they bind to specific promoter sequences in target genes. In mammals, STATs comprise a family of seven structurally and functionally related proteins: Stat1, Stat2, Stat3, Stat4, Stat5a and Stat5b, Stat6. STAT proteins play a critical role in regulating innate and acquired host immune responses. Dysregulation of at least two STAT signalling cascades (i.e. Stat3 and Stat5) is associated with cellular transformation.Signalling through the JAK/STAT pathway is initiated when a cytokine binds to its corresponding receptor. This leads to conformational changes in the cytoplasmic portion of the receptor, initiating activation of receptor associated members of the JAK family of kinases. The JAKs, in turn, mediate phosphorylation at the specific receptor tyrosine residues, which then serve as docking sites for STATs and other signalling molecules. Once recruited to the receptor, STATs also become phosphorylated by JAKs, on a single tyrosine residue. Activated STATs dissociate from the receptor, dimerise, translocate to the nucleus and bind to members of the GAS (gamma activated site) family of enhancers.The seven STAT proteins identified in mammals range in size from 750 and 850 amino acids. The chromosomal distribution of these STATs, as well as the identification of STATs in more primitive eukaryotes, suggest that this family arose from a single primordial gene. STATs share 6 structurally and functionally conserved domains including: an N-terminal domain (ND) that strengthens interactions between STAT dimers on adjacent DNA-binding sites; a coiled-coil STAT domain (CCD) that is implicated in protein-protein interactions; a DNA-binding domain (DBD) with an immunoglobulin-like fold similar to p53 tumour suppressor protein; an EF-hand-like linker domain connecting the DNA-binding and SH2 domains; an SH2 domain () that acts as a phosphorylation-dependent switch to control receptor recognition and DNA-binding; and a C-terminal transactivation domain [, , ]. The crystal structure of the N terminus of Stat4 reveals a dimer. The interface of this dimer is formed by a ring-shaped element consisting of five short helices. Several studies suggest that this N-terminal dimerisation promotes cooperativity of binding to tandem GAS elements and with the transcriptional coactivator CBP/p300.This superfamily represents the N terminus part of the p53-like DNA-binding domain of STAT proteins. Both the DNA-binding domain and the linker domain help determine DNA-specificity.
The STAT protein (Signal Transducers and Activators of Transcription) family contains transcription factors that are specifically activated to regulate gene transcription when cells encounter cytokines and growth factors, hence they act as signal transducers in the cytoplasm and transcription activators in the nucleus []. Binding of these factors to cell-surface receptors leads to receptor autophosphorylation at a tyrosine, the phosphotyrosine being recognised by the STAT SH2 domain, which mediates the recruitment of STAT proteins from the cytosol and their association with the activated receptor. The STAT proteins are then activated by phosphorylation via members of the JAK family of protein kinases, causing them to dimerise and translocated to the nucleus, where they bind to specific promoter sequences in target genes. In mammals, STATs comprise a family of seven structurally and functionally related proteins: Stat1, Stat2, Stat3, Stat4, Stat5a and Stat5b, Stat6. STAT proteins play a critical role in regulating innate and acquired host immune responses. Dysregulation of at least two STAT signalling cascades (i.e. Stat3 and Stat5) is associated with cellular transformation.Signalling through the JAK/STAT pathway is initiated when a cytokine binds to its corresponding receptor. This leads to conformational changes in the cytoplasmic portion of the receptor, initiating activation of receptor associated members of the JAK family of kinases. The JAKs, in turn, mediate phosphorylation at the specific receptor tyrosine residues, which then serve as docking sites for STATs and other signalling molecules. Once recruited to the receptor, STATs also become phosphorylated by JAKs, on a single tyrosine residue. Activated STATs dissociate from the receptor, dimerise, translocate to the nucleus and bind to members of the GAS (gamma activated site) family of enhancers.The seven STAT proteins identified in mammals range in size from 750 and 850 amino acids. The chromosomal distribution of these STATs, as well as the identification of STATs in more primitive eukaryotes, suggest that this family arose from a single primordial gene. STATs share 6 structurally and functionally conserved domains including: an N-terminal domain (ND) that strengthens interactions between STAT dimers on adjacent DNA-binding sites; a coiled-coil STAT domain (CCD) that is implicated in protein-protein interactions; a DNA-binding domain (DBD) with an immunoglobulin-like fold similar to p53 tumour suppressor protein; an EF-hand-like linker domain connecting the DNA-binding and SH2 domains; an SH2 domain () that acts as a phosphorylation-dependent switch to control receptor recognition and DNA-binding; and a C-terminal transactivation domain [, , ]. The crystal structure of the N terminus of Stat4 reveals a dimer. The interface of this dimer is formed by a ring-shaped element consisting of five short helices. Several studies suggest that this N-terminal dimerisation promotes cooperativity of binding to tandem GAS elements and with the transcriptional coactivator CBP/p300.This entry represents a domain found in Dictyostelium STAT proteins. This domain adopts a structure consisting of four long α-helices, folded into a coiled coil. It is responsible for nuclear export of the protein [].
The STAT protein (Signal Transducers and Activators of Transcription) family contains transcription factors that are specifically activated to regulate gene transcription when cells encounter cytokines and growth factors, hence they act as signal transducers in the cytoplasm and transcription activators in the nucleus []. Binding of these factors to cell-surface receptors leads to receptor autophosphorylation at a tyrosine, the phosphotyrosine being recognised by the STAT SH2 domain, which mediates the recruitment of STAT proteins from the cytosol and their association with the activated receptor. The STAT proteins are then activated by phosphorylation via members of the JAK family of protein kinases, causing them to dimerise and translocated to the nucleus, where they bind to specific promoter sequences in target genes. In mammals, STATs comprise a family of seven structurally and functionally related proteins: Stat1, Stat2, Stat3, Stat4, Stat5a and Stat5b, Stat6. STAT proteins play a critical role in regulating innate and acquired host immune responses. Dysregulation of at least two STAT signalling cascades (i.e. Stat3 and Stat5) is associated with cellular transformation.Signalling through the JAK/STAT pathway is initiated when a cytokine binds to its corresponding receptor. This leads to conformational changes in the cytoplasmic portion of the receptor, initiating activation of receptor associated members of the JAK family of kinases. The JAKs, in turn, mediate phosphorylation at the specific receptor tyrosine residues, which then serve as docking sites for STATs and other signalling molecules. Once recruited to the receptor, STATs also become phosphorylated by JAKs, on a single tyrosine residue. Activated STATs dissociate from the receptor, dimerise, translocate to the nucleus and bind to members of the GAS (gamma activated site) family of enhancers.The seven STAT proteins identified in mammals range in size from 750 and 850 amino acids. The chromosomal distribution of these STATs, as well as the identification of STATs in more primitive eukaryotes, suggest that this family arose from a single primordial gene. STATs share 6 structurally and functionally conserved domains including: an N-terminal domain (ND) that strengthens interactions between STAT dimers on adjacent DNA-binding sites; a coiled-coil STAT domain (CCD) that is implicated in protein-protein interactions; a DNA-binding domain (DBD) with an immunoglobulin-like fold similar to p53 tumour suppressor protein; an EF-hand-like linker domain connecting the DNA-binding and SH2 domains; an SH2 domain () that acts as a phosphorylation-dependent switch to control receptor recognition and DNA-binding; and a C-terminal transactivation domain [, , ]. The crystal structure of the N terminus of Stat4 reveals a dimer. The interface of this dimer is formed by a ring-shaped element consisting of five short helices. Several studies suggest that this N-terminal dimerisation promotes cooperativity of binding to tandem GAS elements and with the transcriptional coactivator CBP/p300.This entry represents a domain consisting of four long helices that forms a bundle with a left-handed twist (coiled coil), in a right-handed superhelix.
The STAT protein (Signal Transducers and Activators of Transcription) family contains transcription factors that are specifically activated to regulate gene transcription when cells encounter cytokines and growth factors, hence they act as signal transducers in the cytoplasm and transcription activators in the nucleus []. Binding of these factors to cell-surface receptors leads to receptor autophosphorylation at a tyrosine, the phosphotyrosine being recognised by the STAT SH2 domain, which mediates the recruitment of STAT proteins from the cytosol and their association with the activated receptor. The STAT proteins arethen activated by phosphorylation via members of the JAK family of protein kinases, causing them to dimerise and translocated to the nucleus, where they bind to specific promoter sequences in target genes. In mammals, STATs comprise a family of seven structurally and functionally related proteins: Stat1, Stat2, Stat3, Stat4, Stat5a and Stat5b, Stat6. STAT proteins play a critical role in regulating innate and acquired host immune responses. Dysregulation of at least two STAT signalling cascades (i.e. Stat3 and Stat5) is associated with cellular transformation.Signalling through the JAK/STAT pathway is initiated when a cytokine binds to its corresponding receptor. This leads to conformational changes in the cytoplasmic portion of the receptor, initiating activation of receptor associated members of the JAK family of kinases. The JAKs, in turn, mediate phosphorylation at the specific receptor tyrosine residues, which then serve as docking sites for STATs and other signalling molecules. Once recruited to the receptor, STATs also become phosphorylated by JAKs, on a single tyrosine residue. Activated STATs dissociate from the receptor, dimerise, translocate to the nucleus and bind to members of the GAS (gamma activated site) family of enhancers.The seven STAT proteins identified in mammals range in size from 750 and 850 amino acids. The chromosomal distribution of these STATs, as well as the identification of STATs in more primitive eukaryotes, suggest that this family arose from a single primordial gene. STATs share 6 structurally and functionally conserved domains including: an N-terminal domain (ND) that strengthens interactions between STAT dimers on adjacent DNA-binding sites; a coiled-coil STAT domain (CCD) that is implicated in protein-protein interactions; a DNA-binding domain (DBD) with an immunoglobulin-like fold similar to p53 tumour suppressor protein; an EF-hand-like linker domain connecting the DNA-binding and SH2 domains; an SH2 domain () that acts as a phosphorylation-dependent switch to control receptor recognition and DNA-binding; and a C-terminal transactivation domain [, , ]. The crystal structure of the N terminus of Stat4 reveals a dimer. The interface of this dimer is formed by a ring-shaped element consisting of five short helices. Several studies suggest that this N-terminal dimerisation promotes cooperativity of binding to tandem GAS elements and with the transcriptional coactivator CBP/p300.This entry represents the DNA-binding domain, which has an immunoglobulin-like structural fold.
The STAT protein (Signal Transducers and Activators of Transcription) family contains transcription factors that are specifically activated to regulate gene transcription when cells encounter cytokines and growth factors, hence they act as signal transducers in the cytoplasm and transcription activators in the nucleus []. Binding of these factors to cell-surface receptors leads to receptor autophosphorylation at a tyrosine, the phosphotyrosine being recognised by the STAT SH2 domain, which mediates the recruitment of STAT proteins from the cytosol and their association with the activated receptor. The STAT proteins are then activated by phosphorylation via members of the JAK family of protein kinases, causing them to dimerise and translocated to the nucleus, where they bind to specific promoter sequences in target genes. In mammals, STATs comprise a family of seven structurally and functionally related proteins: Stat1, Stat2, Stat3, Stat4, Stat5a and Stat5b, Stat6. STAT proteins play a critical role in regulating innate and acquired host immune responses. Dysregulation of at least two STAT signalling cascades (i.e. Stat3 and Stat5) is associated with cellular transformation.Signalling through the JAK/STAT pathway is initiated when a cytokine binds to its corresponding receptor. This leads to conformational changes in the cytoplasmic portion of the receptor, initiating activation of receptor associated members of the JAK family of kinases. The JAKs, in turn, mediate phosphorylation at the specific receptor tyrosine residues, which then serve as docking sites for STATs and other signalling molecules. Once recruited to the receptor, STATs also become phosphorylated by JAKs, on a single tyrosine residue. Activated STATs dissociate from the receptor, dimerise, translocate to the nucleus and bind to members of the GAS (gamma activated site) family of enhancers.The seven STAT proteins identified in mammals range in size from 750 and 850 amino acids. The chromosomal distribution of these STATs, as well as the identification of STATs in more primitive eukaryotes, suggest that this family arose from a single primordial gene. STATs share 6 structurally and functionally conserved domains including: an N-terminal domain (ND) that strengthens interactions between STAT dimers on adjacent DNA-binding sites; a coiled-coil STAT domain (CCD) that is implicated in protein-protein interactions; a DNA-binding domain (DBD) with an immunoglobulin-like fold similar to p53 tumour suppressor protein; an EF-hand-like linker domain connecting the DNA-binding and SH2 domains; an SH2 domain () that acts as a phosphorylation-dependent switch to control receptor recognition and DNA-binding; and a C-terminal transactivation domain [, , ]. The crystal structure of the N terminus of Stat4 reveals a dimer. The interface of this dimer is formed by a ring-shaped element consisting of five short helices. Several studies suggest that this N-terminal dimerisation promotes cooperativity of binding to tandem GAS elements and with the transcriptional coactivator CBP/p300.This entry represents the all-alpha helical domain, which consists of four long helices arranged in a bundle with a left-handed twist (coiled-coil), which in turn forms a right-handed superhelix.
The STAT protein (Signal Transducers and Activators of Transcription) family contains transcription factors that are specifically activated to regulate gene transcription when cells encounter cytokines and growth factors, hence they act as signal transducers in the cytoplasm and transcription activators in the nucleus []. Binding of these factors to cell-surface receptors leads to receptor autophosphorylation at a tyrosine, the phosphotyrosine being recognised by the STAT SH2 domain, which mediates the recruitment of STAT proteins from the cytosol and their association with the activated receptor. The STAT proteins are then activated by phosphorylation via members of the JAK family of protein kinases, causing them to dimerise and translocated to the nucleus, where they bind to specific promoter sequences in target genes. In mammals, STATs comprise a family of seven structurally and functionally related proteins: Stat1, Stat2, Stat3, Stat4, Stat5a and Stat5b, Stat6. STAT proteins play a critical role in regulating innate and acquired host immune responses. Dysregulation of at least two STAT signalling cascades (i.e. Stat3 and Stat5) is associated with cellular transformation.Signalling through the JAK/STAT pathway is initiated when a cytokine binds to its corresponding receptor. This leads to conformational changes in the cytoplasmic portion of the receptor, initiating activation of receptor associated members of the JAK family of kinases. The JAKs, in turn, mediate phosphorylation at the specific receptor tyrosine residues, which then serve as docking sites for STATs and other signalling molecules. Once recruited to the receptor, STATs also become phosphorylated by JAKs, on a singletyrosine residue. Activated STATs dissociate from the receptor, dimerise, translocate to the nucleus and bind to members of the GAS (gamma activated site) family of enhancers.The seven STAT proteins identified in mammals range in size from 750 and 850 amino acids. The chromosomal distribution of these STATs, as well as the identification of STATs in more primitive eukaryotes, suggest that this family arose from a single primordial gene. STATs share 6 structurally and functionally conserved domains including: an N-terminal domain (ND) that strengthens interactions between STAT dimers on adjacent DNA-binding sites; a coiled-coil STAT domain (CCD) that is implicated in protein-protein interactions; a DNA-binding domain (DBD) with an immunoglobulin-like fold similar to p53 tumour suppressor protein; an EF-hand-like linker domain connecting the DNA-binding and SH2 domains; an SH2 domain () that acts as a phosphorylation-dependent switch to control receptor recognition and DNA-binding; and a C-terminal transactivation domain [, , ]. The crystal structure of the N terminus of Stat4 reveals a dimer. The interface of this dimer is formed by a ring-shaped element consisting of five short helices. Several studies suggest that this N-terminal dimerisation promotes cooperativity of binding to tandem GAS elements and with the transcriptional coactivator CBP/p300.This entry represents the N-terminal domain, which is responsible for protein interactions. This domain has a multi-helical structure that can be subdivided into two structural sub-domains.
