Structural Basis Of STAT2 Recognition By IRF9 Reveals Molecular Insights Into ISGF3 Function

Abstract

Cytokine signalling is mediated by the activation of distinct sets of structurally homologous JAK and STAT signalling molecules, which control nuclear gene expression and cell fate. A significant expansion in the gene regulatory repertoire controlled by JAK/STAT signalling has arisen by the selective interaction of STATs with IRF transcription factors. Type I interferons (IFN), the major antiviral cytokines, trigger the formation of the ISGF3 complex containing STAT1, STAT2 and IRF9. ISGF3 regulates the expression of IFN-stimulated genes (ISGs). ISGF3 assembly depends on selective interaction between IRF9, through its IRF-association domain (IAD), with the coiled-coil domain (CCD) of STAT2. Here, we report the crystal structures of the IRF9-IAD alone and in a complex with STAT2-CCD. Despite similarity in the overall structure among respective paralogs, the surface features of the IRF9-IAD and STAT2- CCD have diverged to enable specific interaction between these family members, thus enabling ISGF3 formation and expression of ISGs.