InterPro domain: IPR007757

N6-methyladenosine (m6A) is present at internal sites in some mRNAs. m6A affects different aspects of mRNA metabolism, such as half-life, splicing, and translation [ 1 , 2 , 3 , 4 , 5 ].

MT-A70 (also known as METTL3) is the S-adenosylmethionine-binding subunit of human mRNA N6-adenosine-methyltransferase (MTase), an enzyme that sequence-specifically methylates adenines in pre-mRNAs. Proteins with sequence similarity to MT-A70 have been identified in eukaryotes and prokaryotes. The resulting family is defined by sequence similarity in the carboxyl-proximal regions of the respective proteins. The amino-proximal regions of the eukaryotic proteins are highly diverse, often Pro-rich, and are conserved only within individual subfamilies [ 6 ]. Corresponding regions are not present in prokaryotic members of the family. MT-A70-like proteins contain examples of some of the consensus methyltransferase motifs that have been derived from mutational and structural studies of bacterial DNA methyltransferases, including the universally conserved motif IV catalytic residues and a proposed motif I (AdoMet binding) element [ 7 ]. The MT-A70-like family comprises four subfamilies with varying degrees of interrelatedness. One subfamily is a small group of bacterial DNA: m6A MTases. The other three are paralogous eukaryotic lineages, two of which have not been associated with MTase activity but include proteins that regulate mRNA levels via unknown mechanisms apparently not involving methylation [ 8 ].

Some proteins known to belong to the MT-A70-like family are listed below:

• Human N6-adenosine-methyltransferase 70kDa subunit (MT-A70 or METTL3) ( 2.1.1.62 ), the catalytic component of the METTL3-METTL14 heterodimer that forms the N6-methyltransferase complex that methylates adenosine residues at the N6 position of some RNAs [ 8 ].
• Human N6-adenosine-methyltransferase non-catalytic subunit (METTL14), the non-catalytic component of the METTL3-METTL14 heterodimer.
• Yeast N6-adenosine-methyltransferase IME4 ( 2.1.1.62 ), which is important for induction of sporulation.
• Yeast karyogamy protein KAR4, a phosphoprotein required for expression of karyogamy-specific genes during mating and that it also acts during mitosis and meiosis [ 9 ]. It has been suggested that KAR4 is inactive for methyltransfer and may not even bind AdoMet.

1. N6-methyladenosine-dependent regulation of messenger RNA stability. Nature 505, 117-20
2. N(6)-methyladenosine in mRNA disrupts tRNA selection and translation-elongation dynamics. Nat. Struct. Mol. Biol. 23, 110-5
3. 5' UTR m(6)A Promotes Cap-Independent Translation. Cell 163, 999-1010
4. N(6)-methyladenosine Modulates Messenger RNA Translation Efficiency. Cell 161, 1388-99
5. N6-methyladenosine marks primary microRNAs for processing. Nature 519, 482-5
6. Induction of sporulation in Saccharomyces cerevisiae leads to the formation of N6-methyladenosine in mRNA: a potential mechanism for the activity of the IME4 gene. Nucleic Acids Res. 30, 4509-18
7. Structure prediction and phylogenetic analysis of a functionally diverse family of proteins homologous to the MT-A70 subunit of the human mRNA:m(6)A methyltransferase. J. Mol. Evol. 55, 431-44
8. A METTL3-METTL14 complex mediates mammalian nuclear RNA N6-adenosine methylation. Nat. Chem. Biol. 10, 93-5
9. Role of transcription factor Kar4 in regulating downstream events in the Saccharomyces cerevisiae pheromone response pathway. Mol. Cell. Biol. 27, 818-29