Tyrosine phosphorylated STAT dimer

Chen X, Vinkemeier U, Zhao Y, Jeruzalmi D, Darnell JE Jr, Kuriyan J (1998) Crystal structure of a tyrosine phosphorylated Stat-1 dimer bound to DNA. Cell 93 827-839 Darnell JE Jr (1997) STATs and gene regulation. Science 277 1630-1635... 

Cytokine receptors, like receptor tyrosine kinases, have extracellular and intracellular domains and form dimers. However, after activation by an appropriate ligand, separate mobile protein tyrosine kinase molecules (JAK) are activated, resulting in phosphorylation of signal transducers and activation of transcription (STAT) molecules. STAT dimers then travel to the nucleus, where they regulate transcription. 

Figure 15.30. Phosphorylation-Induced Dimerization of STAT Proteins. The phosphorylation of a key tyrosine residue on each STAT protein leads to an interaction between the phosphotyrosine and an SH2 domain on another STAT monomer. The STAT dimer produced by these reciprocal interactions has a high affinity for specific DNA sequences and is able to alter gene expression after binding to DNA.

Fig. 11.8 A) Domain structure of STATs. STATs bind to receptors and dimerize via bivalent SH2-phosphotyrosine interactions. Phosphorylation ofthe conserved tyrosine is required for STATs dimerization. The N-terminal region mediates oligomerization of STAT dimers. B) Dimer of Stat2 bound to DNA. Dimerization is mediated by reciprocal SH2-Tyr-phosphate interactions ofthe monomers. The view is along the DNA helix. The DNA binding domain is in red, the linker domain in orange and the SH2 domain in light green. The C-termini ofthe two Stat2 molecules are shown in yellow and magenta.

Fig. 44.16. C54okine signaling through the JAK/STAT pathway. 1. Cytokine binding to receptors initiates dimerization and activation of the JAK kinase, which phosphorylates the receptor on tyrosine residues. 2. STAT proteins bind to the activated receptors and are themselves phosphorylated. 3. Phosphorylated STAT proteins dimerize, travel to the nucleus, and initiate gene transcription. 4. One of the proteins whose s5mthesis is stimulated by STATs is SOCS (suppressor of cytokine signaling), which inhibits further activation of STAT proteins (circle 5) by a variety of mechanisms.

FIGURE 8.12 Direct phosphorylation of the STAT class of transcription factors. Through their SH2 domains, the p84Slalla and p91StaIlb associate with the receptor and become phosphorylated on tyrosine residues. They form a dimer (called the Sis-inducible factor, or SIF) that translocates to the nucleus, where it binds to a Sis-inducible element (SIE) and activates transcription of, for example, the c-fos gene. 

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