Abstract
In tRNA, the epigenetic m3C 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 Å 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 tRNASer 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.
Highlights
In transfer RNA (tRNA), the epigenetic m3C modification at position 32 in the anticodon loop is highly conserved in eukaryotes, which maintains the folding and basepairing functions of the anticodon
The homologs of Trm[140] and Trm[141] encoded by the METTL2A, METTL2B, METTL6, and METTL8 genes have been identified by sequence similarity analyses[15,16]
METTL6 is a tRNASer-specific m3C methyltransferase, whose knockdown would substantially reduce the susceptibility of lung cancer cells to cisplatin[23]
Summary
In tRNA, the epigenetic m3C modification at position 32 in the anticodon loop is highly conserved in eukaryotes, which maintains the folding and basepairing functions of the anticodon. A study showed that METTL6 catalyzes the methylation of C32 in several tRNASer isoacceptors[25] It enhances the proliferative activity of hepatocellular carcinoma (HCC) by affecting the relevant genes involved in multiple cellular processes including cell cycles, apoptosis, stemness, and maintains the self-renewal potential in mESCs cells[25]. These studies demonstrated that METTL6 plays critical role in tumorigenesis and the development, invasion as well as susceptibility to drugs. The anticodon loop and the long variable arm of tRNASer(GCU) are key determinants for its
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