Abstract The cytoplasm is compartmentalized into different translation environments. mRNAs use their 3′UTRs to localize to distinct cytoplasmic compartments, including TIS granules (TGs). Many transcription factors, including MYC, are translated in TGs. It was shown that translation of proteins in TGs enables the formation of protein complexes that cannot be established when these proteins are translated in the cytosol, but the mechanism is poorly understood. Here we show that MYC protein complexes that involve binding to the intrinsically disordered region (IDR) of MYC are only formed when MYC is translated in TGs. TG-dependent protein complexes require TG-enriched mRNAs for assembly. These mRNAs bind to a new and widespread RNA-binding domain in neutral or negatively charged IDRs in several transcription factors, including MYC. RNA-IDR interaction changes the conformational ensemble of the IDR, enabling the formation of MYC protein complexes that act in the nucleus and control functions that cannot be accomplished by cytosolically-translated MYC. We propose that certain mRNAs have IDR chaperone activity as they control IDR conformations. In addition to post-translational modifications, we found a novel mode of protein activity regulation. Since RNA-IDR interactions are prevalent, we suggest that mRNA-dependent control of protein functional states is widespread.

mRNA interactions with disordered regions control protein activity