Stat protein transactivation domains recruit p300/CBP through widely divergent sequences

The signal transduction and activator of transcription (Stat) gene family h as been highly conserved throughout evolution. Gene duplication and diverge nce has produced 7 mammalian Stat genes, each of which mediates a distinct process. While some Stat proteins are activated by multiple cytokines, Stat 2 is highly specific for responses to type I interferon, We have cloned mou se Stat2 and found that while its sequence was more divergent from its huma n homologue than any other mouse-human Stat pairs, it was fully functional even in human cells. Overall sequence identity was only 69%, compared with 85-99% similarity for other Stab genes, and several individual domains that still served similar or identical functions in both species were even less well conserved. The coiled-coil domain responsible for interaction with IR F9 was only 65% identical and yet mouse Stat2 interacted with either human or mouse IRFS; the carboxyl terminus was only 30% identical and yet both re gions functioned as equal transactivation domains. Both mouse and human tra nsactivation domains recruited the p300/CBP coactivator and were equally se nsitive to inhibition by adenovirus E1A protein. Interestingly, the Stat3 c arboxyl terminus also functioned as a transactivator capable of recruiting p300/CBP, as does the Stat1 protein, although with widely differing potenci es. Yet these proteins share no sequence similarity with Stat2, These data demonstrate that highly diverged primary sequences can serve similar or ide ntical functions, and that the minimal regions of similarity between human and mouse Stat2 may define the critical determinants for function.