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The key enzyme discovered first is TRM140 from Saccharomyces cerevisiae, specific to tRNA Thr and tRNA Ser methylation. In tRNA, the m 3C modification at position 32 in the anticodon loop is highly conserved in eukaryotes, which maintains the folding and basepairing functions of the anticodon 20. The 3-methylcytosine (m 3C) modification is present in both tRNA and mRNA and displays diverse roles in developing diseases through the regulation of tRNA fate 19. Multiple METTL proteins, including METT元 and METTL14, have been well characterized, which produce the 6-methyladenosine (m 6A) modification in mRNA, long intergenic ncRNA (lincRNA), and microRNA (miRNA), etc. Methylation is most common, and it can be catalyzed by a large family of methyltransferase-like proteins (METTLs) that transfer the methyl group from S-adenosylmethionine (SAM) to a variety of positions in RNA nucleosides 13, 14, 15, 16. To date, more than 170 different types of RNA modification have been identified 12, as a result of the recent development of more sensitive and quantitative technologies. Additionally, these modifications may mediate other critical biological and physiological processes as several lines of evidence indicate that defects in many modifications in humans are associated with the pathogenesis of various cancers, underscoring the pivotal roles of tRNA modifications in organismal physiology and fitness 4. For instance, the prevalent modifications in the anticodon loop of tRNA promote translation efficiencies by maintaining the conformation of the anticodon loop, enhancing codon-anticodon interactions, and preventing frameshifting, etc 5, 6, 7, 8, 9, 10, 11. The modifications affect the folding, stabilities, and biological functions of tRNA 3, 4. All known RNA species are subjected to chemical modifications, among which transfer RNA (tRNA) is the most extensively modified type 2. 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.Įpigenetic modifications on nucleic acids play crucial roles in gene regulation 1. We further generated a model for the quaternary complex with tRNA Ser as a component, which reasonably explained the biochemical behaviors of hMETTL6.
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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 generated a docking model for the hMETTL6-SAH-CMP ternary complex.
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The key residues interacting with the ligand were identified and their roles were confirmed by ITC. Here we present the 1.9 Å high-resolution crystal structure of hMETTL6 bound by SAH. Despite its important functions, the catalytic mechanism of the C32 methylation by this enzyme is poorly understood.
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The loss of human METTL6 (hMETTL6) affects the translational process and proteostasis in cells, while in mESCs cells, it leads to defective pluripotency potential. However, the responsible enzymes METTL2 and METTL6 were identified only in recent years. In tRNA, the epigenetic m 3C modification at position 32 in the anticodon loop is highly conserved in eukaryotes, which maintains the folding and basepairing functions of the anticodon.