UCSF

During transcription in the nucleus, messenger RNA (mRNA) is endowed withmodifications that serve as important markers for its regulation in the cell. This includes the addition of a 7-methylguanosine cap (m7G) at the 5’ end, which is important for nuclear export, translation, and degradation of transcripts. Numerous mRNA quality control pathways end in the degradation of transcripts and pathogens can degrade RNA during infection to favor their survival. Removal of the cap structure, or decapping, commits mRNA to degradation and is a highly controlled step in post-transcriptional regulation. The conserved eukaryotic decapping complex Dcp1/Dcp2 is regulated through an intricate network of protein-protein interactions that can inhibit and accelerate decapping. While many of the interfaces required for these interactions have been studied, a mechanistic understanding of their consequences have not been well-characterized. This work describes a mechanism for autoinhibition of decapping and how the protein cofactors Edc3 and Edc1 relieve this autoinhibition to activate decapping through conformational changes in the Dcp2 active site. Furthermore, these regulatory mechanisms contribute to in vitro phase separation that causes localized sites of repressed and accelerated mRNA decapping. Together, these findings demonstrate how regulation at the ångstrom scale is coupled to microscopic behavior to enhance the catalytic power of decapping, which ensures mRNA degradation occurs only when specific conditions are met.