6gfn
METTL16 MTase domain
Structural highlights
FunctionMET16_HUMAN RNA N6-methyltransferase that methylates adenosine residues of a subset of RNAs and plays a key role in S-adenosyl-L-methionine homeostasis by regulating expression of MAT2A transcripts (PubMed:28525753). Able to N6-methylate a subset of mRNAs and U6 small nuclear RNAs (U6 snRNAs) (PubMed:28525753). In contrast to the METTL3-METTL14 heterodimer, only able to methylate a limited number of RNAs: requires both a 5'UACAGAGAA-3' nonamer sequence and a specific RNA structure (PubMed:28525753). In presence of S-adenosyl-L-methionine, binds the 3'-UTR region of MAT2A mRNA and specifically N6-methylates the first hairpin of MAT2A mRNA, impairing MAT2A expression (PubMed:28525753). In S-adenosyl-L-methionine-limiting conditions, binds the 3'-UTR region of MAT2A mRNA but stalls due to the lack of a methyl donor, preventing N6-methylation and promoting expression of MAT2A (PubMed:28525753). In addition to mRNAs, also able to mediate N6-methylation of U6 small nuclear RNA (U6 snRNA): specifically N6-methylates adenine in position 43 of U6 snRNAs (PubMed:28525753, PubMed:29051200). Also able to bind various lncRNAs (PubMed:29051200). Specifically binds the 3'-end of the MALAT1 long non-coding RNA (PubMed:27872311).[1] [2] [3] Publication Abstract from PubMedInternal modification of RNAs with N(6)-methyladenosine (m(6)A) is a highly conserved means of gene expression control. While the METTL3/METTL14 heterodimer adds this mark on thousands of transcripts in a single-stranded context, the substrate requirements and physiological roles of the second m(6)A writer METTL16 remain unknown. Here we describe the crystal structure of human METTL16 to reveal a methyltransferase domain furnished with an extra N-terminal module, which together form a deep-cut groove that is essential for RNA binding. When presented with a random pool of RNAs, METTL16 selects for methylation-structured RNAs where the critical adenosine is present in a bulge. Mouse 16-cell embryos lacking Mettl16 display reduced mRNA levels of its methylation target, the SAM synthetase Mat2a. The consequence is massive transcriptome dysregulation in approximately 64-cell blastocysts that are unfit for further development. This highlights the role of an m(6)A RNA methyltransferase in facilitating early development via regulation of SAM availability. Methylation of Structured RNA by the m(6)A Writer METTL16 Is Essential for Mouse Embryonic Development.,Mendel M, Chen KM, Homolka D, Gos P, Pandey RR, McCarthy AA, Pillai RS Mol Cell. 2018 Sep 5. pii: S1097-2765(18)30638-5. doi:, 10.1016/j.molcel.2018.08.004. PMID:30197299[4] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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