| Structural highlights
Function
METL6_HUMAN S-adenosyl-L-methionine-dependent methyltransferase that mediates N(3)-methylcytidine modification of residue 32 of the tRNA anticodon loop of tRNA(Ser), including tRNA(Ser)(UGA) and tRNA(Ser)(GCU) (PubMed:32923617, PubMed:34922197, PubMed:34268557, PubMed:34862464). Interaction with SARS1/SerRS is required for N(3)-methylcytidine methylation (PubMed:34268557).[1] [2] [3] [4]
Publication Abstract from PubMed
In tRNA, the epigenetic m(3)C modification at position 32 in the anticodon loop is highly conserved in eukaryotes, which maintains the folding and basepairing functions of the anticodon. However, the responsible enzymes METTL2 and METTL6 were identified only in recent years. The loss of human METTL6 (hMETTL6) affects the translational process and proteostasis in cells, while in mESCs cells, it leads to defective pluripotency potential. Despite its important functions, the catalytic mechanism of the C32 methylation by this enzyme is poorly understood. Here we present the 1.9 A high-resolution crystal structure of hMETTL6 bound by SAH. The key residues interacting with the ligand were identified and their roles were confirmed by ITC. We generated a docking model for the hMETTL6-SAH-CMP ternary complex. Interestingly, the CMP molecule binds into a cavity in a positive patch with the base ring pointing to the inside, suggesting a flipped-base mechanism for methylation. We further generated a model for the quaternary complex with tRNA(Ser) as a component, which reasonably explained the biochemical behaviors of hMETTL6. Taken together, our crystallographic and biochemical studies provide important insight into the molecular recognition mechanism by METTL6 and may aid in the METTL-based rational drug design in the future.
Crystal structure of human METTL6, the m(3)C methyltransferase.,Chen R, Zhou J, Liu L, Mao XL, Zhou X, Xie W Commun Biol. 2021 Dec 3;4(1):1361. doi: 10.1038/s42003-021-02890-9. PMID:34862464[5]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Ignatova VV, Kaiser S, Ho JSY, Bing X, Stolz P, Tan YX, Lee CL, Gay FPH, Lastres PR, Gerlini R, Rathkolb B, Aguilar-Pimentel A, Sanz-Moreno A, Klein-Rodewald T, Calzada-Wack J, Ibragimov E, Valenta M, Lukauskas S, Pavesi A, Marschall S, Leuchtenberger S, Fuchs H, Gailus-Durner V, de Angelis MH, Bultmann S, Rando OJ, Guccione E, Kellner SM, Schneider R. METTL6 is a tRNA m(3)C methyltransferase that regulates pluripotency and tumor cell growth. Sci Adv. 2020 Aug 26;6(35):eaaz4551. PMID:32923617 doi:10.1126/sciadv.aaz4551
- ↑ Mao XL, Li ZH, Huang MH, Wang JT, Zhou JB, Li QR, Xu H, Wang XJ, Zhou XL. Mutually exclusive substrate selection strategy by human m3C RNA transferases METTL2A and METTL6. Nucleic Acids Res. 2021 Aug 20;49(14):8309-8323. PMID:34268557 doi:10.1093/nar/gkab603
- ↑ Chen R, Zhou J, Liu L, Mao XL, Zhou X, Xie W. Crystal structure of human METTL6, the m(3)C methyltransferase. Commun Biol. 2021 Dec 3;4(1):1361. PMID:34862464 doi:10.1038/s42003-021-02890-9
- ↑ Li S, Zhou H, Liao S, Wang X, Zhu Z, Zhang J, Xu C. Structural basis for METTL6-mediated m3C RNA methylation. Biochem Biophys Res Commun. 2022 Jan 22;589:159-164. PMID:34922197 doi:10.1016/j.bbrc.2021.12.013
- ↑ Chen R, Zhou J, Liu L, Mao XL, Zhou X, Xie W. Crystal structure of human METTL6, the m(3)C methyltransferase. Commun Biol. 2021 Dec 3;4(1):1361. PMID:34862464 doi:10.1038/s42003-021-02890-9
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