Cellular context restricts IDR plasticity to a single essential effector interface for m6A-dependent mRNA turnover [Chan_RNA-seq_experiment 1]

Using yeast meiosis as a model, we investigated how the YTH-domain protein Pho92 promotes decay of m6A-modified transcripts through its intrinsically disordered region (IDR). In vitro, the Pho92 IDR makes multiple contacts with the Ccr4-NOT deadenylase complex and drives tethered reporter decay in the absence of any single subunit.

Yet in meiosis, turnover of endogenous m6A-modified transcripts strictly depends on a single interface: direct binding of the Pho92 IDR to Caf40. A single hydrophobic residue substitution is sufficient to abolish Caf40 binding and halt transcript decay. Human YTHDF proteins can functionally substitute for Pho92, but require multiple hydrophobic patches within the IDR for decay activity.