A family-wide assessment of latent STAT transcription factor interactions reveals divergent dimer repertoires

The conversion of STAT proteins from latent to active transcription factors is central to cytokine signalling. Triggered by their signal-induced tyrosine phosphorylation, it is the assembly of a range of cytokine-specific STAT homo- and heterodimers that marks a key step in the transition of hitherto latent proteins to transcription activators. In contrast, the constitutive self-assembly of latent STATs and how it relates to the functioning of activated STATs, is understood less well. To provide a more complete picture, we developed a co-localisation-based assay and tested all 28 possible combinations of the seven unphosphorylated STAT proteins in living cells. It led to the identification of five U-STAT homodimers ―STAT1, STAT3, STAT4, STAT5A and STAT5B― and two heterodimers ―STAT1:STAT2 and STAT5A:STAT5B― as well as semi-quantitative assessments of the forces and characterisations of binding interfaces that support them. One STAT protein ―STAT6― was found to be monomeric. This comprehensive analysis of latent STAT self-assembly lays bare considerable structural and functional diversity in the ways that link STAT dimerization before and after activation.