Phosphorylation-dependent tuning of mRNA deadenylation rates

Shortening of messenger RNA poly(A) tails by the Ccr4-Not complex initiates mRNA decay and is a major determinant of gene regulation. RNA adaptors modulate the specificity of deadenylation by binding to Ccr4-Not through their intrinsically disordered regions (IDRs). However, the determinants of specificity and their regulation are largely unclear. Here we use nuclear magnetic resonance spectroscopy, biochemical reconstitution and structural modeling to show that dispersed segments within the IDR of the fission yeast Puf3 RNA adaptor interact with Ccr4-Not, consistent with multivalency. Binding can be modulated by phosphorylation, altering the deadenylation rate in a continuously tunable manner. Regulation of deadenylation through multivalency and phosphorylation likely occurs in evolutionarily divergent IDRs from additional RNA adaptors, including human Pumilio and Tristetraprolin. Overall, our in vitro data suggest that mRNA decay can be regulated not only as a bistable on-off switch but also by a graded mechanism, rationalizing how post-transcriptional gene expression can be fine-tuned.