Structures and Regulation of the N6-Methyladenosine Methyltransferase METTL16

Chemical modifications of RNA control the abundance and function of both coding and non-coding RNA molecules. The most abundant mRNA modification is N6 methyladenosine (m6A), which has been shown to regulate RNA splicing, translation and decay. The m6A modification is deposited by methyltransferases using S-adenosylmethionine (SAM) as the methyl donor. Determining the specificity and mechanism of action of m6A methyltransfersaes is an essential step in dissecting the role of the m6A modification in RNA metabolism. Two enzymes that are responsible for creating the m6A mark on mRNA are the METTL3/METTL14 heterodimer and METTL16. METTL3/METTL14 are responsible for most of the m6A modifications found on RNAs, whereas the specific activity of METTL16 on the SAM synthetase gene, MAT2A, modulates SAM homeostasis, implicating METTL16 as a global regulator of methylation in the cell. Here, I present structural and biochemical data towards determining the specificity, function and regulation of both the METTL16 and METTL3/METTL14 methyltransferases. METTL16 uses a consensus RNA sequence and structure to specifically recognize and methylate its targets. METTL16 is also auto-inhibited, and its activity can be increased through perturbations in the protein and RNA structures. These perturbations potentially increase METTL16 activity through enhanced release of both the methylated RNA and cofactor reaction products, which allows for complex regulation of SAM homeostasis. In contrast, METTL3 mediated m6A modification requires METTL14 for structural support and RNA specificity. These data provide the foundation for understanding the function and regulation of two important m6A methyltransferases, which have implications for both SAM homeostasis and RNA metabolism.