Structure of the YTH domain of human YTHDF2 in complex with an m⁶A mononucleotide reveals an aromatic cage for m⁶A recognition

Recent discoveries suggest that N⁶-methyladenosine (m⁶A) modification, a prevalent internal modification in eukaryotic RNA, is an essential RNA regulatory mechanism. This modification is post-transcriptionally installed by m⁶A methyltransferases (METTL3-METTL14-WTAP complex)^1,2,3,4 and oxidatively removed by m⁶A demethylases (FTO and ALKBH5)^5,6. These 'writer' and 'eraser' enzymes are required for embryo development, energy homeostasis and fertility, suggesting fundamental regulatory roles of m⁶A^1,2,5.

Very recently, the human YTH (YT521-B homology) domain family proteins 1-3 (YTHDF1-3) were shown to act as specific m⁶A 'readers' to regulate mRNA degradation⁷. YTHDF2 specifically binds to m⁶A-containing mRNA via its C-terminal YTH domain, and recruits the mRNA to cytoplasmic foci (P bodies) to control mRNA degradation via its P/Q/N-rich N terminus⁷. A further mechanistic understanding of the function of m⁶A modification requires the knowledge of the molecular basis of m⁶A-specific recognition by the YTH domain.

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