The linker domain of Stat1 is required for gamma interferon-driven transcription

Upon binding of gamma interferon (IFN-gamma) to its receptor, the latent tr anscription factor Stat1 becomes phosphorylated, dimerizes, and enters the nucleus to activate transcription. In response to IFN-alpha, Stat1 binds to Stat2 in a heterodimer that recruits p48, an IRF family member, to activat e transcription. A number of functional domains of the STATs, including a C -terminal transactivation domain, a dimerization domain, and an SH2 domain, are known. However, the highly conserved residues between the DNA binding and SH2 domains (463 to 566), recently christened the linker domain on the basis of crystallographic studies, have remained without a known function. In the present study, we report that KE544-545AA point mutants in Stat1 abo lish transcriptional responses to IFN-gamma but not to IFN-alpha. We furthe r show that this mutant Stat1 undergoes normal phosphorylation, nuclear tra nslocation, and DNA binding. Taken together with recent structural evidence , these results suggest that the linker domain acts as a critical contact p oint during the construction of a Stat1-driven transcriptional complex.