Figure 2. Active m⁶A methylation, demethylation, and downstream consequences for protein-RNA interactions.

(A) m⁶A is installed co-transcriptionally by a complex consisting of METTL3, METTL14, WTAP, and KIAA1429. Each of these components binds mRNA and is required for complete methylation, but only METTL3 contributes to the catalytic activity of the complex.

(B) m⁶A methylation affects protein-RNA interactions through multiple mechanisms. Methylation can perturb the secondary structure of mRNA, exposing or masking potential RNA-binding motifs (top). Selective m⁶A-binding proteins exhibit increased affinity for methylated mRNAs, and in turn incorporate these transcripts into various steps of mRNA metabolism (middle). Methylation itself introduces hydrophobic moieties. In the case of m⁶A, association with hydrophobic amino acid side chains or low complexity regions of proteins may assist in solvation of the modified base (bottom).