Stat Family Proteins

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 Stat Family Proteins Background

Signal transducers and activators of transcription (Stats)

In mammals, there are seven members of Stat transcription factor family including Stat 1, Stat 2, Stat 3, Stat 4, Stat 5A & 5B, and Stat 6. The Stat proteins contain 700 to 900 amino acids and their molecular size ranges from 80 to 120 KDa. Most of the genes encoding Stat proteins contain multiple exons (>15-20 exons), and, alternative splicing of the primary transcript results in the generation of αβ isoform for several Stat proteins, including Stat l, 3, 4 and 5A & 5B. Different combinations of STAT family proteins are activated depending on the type of cytokine or growth factor receptor activated and drive the expression of both overlapping and often distinct set of genes. Interestingly, the β isoforms of the Stat proteins often function as negative regulators of their full length Stat proteins, although sometimes they mediate the expression of totally different genes. Based on sequence homology, the structure of Stat proteins can be divided into several domains, including an N-terminal regulatory domain (NTD), a coiled-coil domain (CC), a DNA-binding domain (DBD), a SH2 domain (SH2), a linker domain (LD), and a C-terminal transactivation domain (TAD).

The N-terminal regulatory domain of Stats, comprising the first 120 to 150 amino acids, has been shown to be involved in 1) interaction of Stat protein with the cytosolic surface of their specific receptors, 2) oligomerization of Stat dimers, 3) interaction with CBP/p300 a transcriptional co-activator protein, 4) regulation of dephosphorylation of Tyr701 in Stat l, and 5) regulation of nuclear translocation. Interestingly, a conserved arginine residue at 31 amino acid position (Arg31) in the NTD in almost all the Stats is thought to be methylated in case of Stat 1 by protein arginine methyl transferase 1 (PRMT1). This event of arginine methylation in Stat l has been shown to increase the DNA binding efficiency and transcriptional activity of Stat l.

The coiled-coil domain of Stats contains four α-helices and is important for mediating protein-proteins interactions of Stats with other proteins of the transcription machinery. For example, the CC domain of all the Stats, except Stat 2, has been shown to interact with N-myc interacting protein (Nmi), the CC domain of Stat 3 interacts with c-Jun, and that of Stat l interacts with p48/IRF-9.

The DNA binding domain (DBD) of Stats is approximately 100 amino acids in length and shares a high degree of homology with Rel family proteins. Interferon stimulated gene factor 3 (ISGF3), a hetero trimeric protein complex composed of S tatl, Stat2, and p48, contact specific DNA elements in the nuclear promoters termed interferon-stimulated response elements (ISRE) with the consensus 5’ AGTTTCNNTTTCNC/T 3’. Other Stat homo- or heterodimers bind to structurally distinct DNA elements termed as gamma-interferon activation sequence (GAS) with the consensus 5’ TTNCNNNAA 3’.

Although the structure of linker domain (LD) in Stats is well conserved, its role in Stat’s function is not dear. Recent reports suggest that the linker domain of Stat 3 can serve as a site of interaction with GRIM-19, a component of the electron transport chain within the mitochondria.

The SH2 domain, located in between the 550 to 870 amino acid positions in all the Stats, mediates two important functions - 1) interaction of Stats with the receptors, and 2) dimerization of Stats, via phospho-tyrosine and SH2 domain interactions. A conserved tyrosine residue is present in all the Stats, next to the C-terminus of SH2 domain. Phosphorylation of this tyrosine residue by Jaks and/or other tyrosine kinases plays an important role in the transcriptional function of Stat proteins

Although, the C-terminal transactivation domain (TAD) is the least conserved domain in Stats, it plays an important role in enhancing the transcriptional efficiency of Stat proteins by promoting the association of Stats with other activators or co-activators of transcriptional machinery, including CBP/p300, MCM5, and BRCA1. A conserved serine residue is present in the TAD domain of Stat l, 3, 4 and 5 which is phosphorylated and plays an important role in full activation of transcription by Stats. For example, phosphorylation of Ser727 in Stat l is required for the ability of Stat l to interact with MCM5.