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TitleStructural basis of tRNA recognition by the mC RNA methyltransferase METTL6 in complex with SerRS seryl-tRNA synthetase.
Journal, issue, pagesNat Struct Mol Biol, Vol. 31, Issue 10, Page 1614-1624, Year 2024
Publish dateJun 25, 2024
AuthorsPhilipp Throll / Luciano G Dolce / Palma Rico-Lastres / Katharina Arnold / Laura Tengo / Shibom Basu / Stefanie Kaiser / Robert Schneider / Eva Kowalinski /
PubMed AbstractMethylation of cytosine 32 in the anticodon loop of tRNAs to 3-methylcytosine (mC) is crucial for cellular translation fidelity. Misregulation of the RNA methyltransferases setting this modification ...Methylation of cytosine 32 in the anticodon loop of tRNAs to 3-methylcytosine (mC) is crucial for cellular translation fidelity. Misregulation of the RNA methyltransferases setting this modification can cause aggressive cancers and metabolic disturbances. Here, we report the cryo-electron microscopy structure of the human mC tRNA methyltransferase METTL6 in complex with seryl-tRNA synthetase (SerRS) and their common substrate tRNA. Through the complex structure, we identify the tRNA-binding domain of METTL6. We show that SerRS acts as the tRNA substrate selection factor for METTL6. We demonstrate that SerRS augments the methylation activity of METTL6 and that direct contacts between METTL6 and SerRS are necessary for efficient tRNA methylation. Finally, on the basis of the structure of METTL6 in complex with SerRS and tRNA, we postulate a universal tRNA-binding mode for mC RNA methyltransferases, including METTL2 and METTL8, suggesting that these mammalian paralogs use similar ways to engage their respective tRNA substrates and cofactors.
External linksNat Struct Mol Biol / PubMed:38918637 / PubMed Central
MethodsEM (single particle) / X-ray diffraction
Resolution2.42 - 5.6 Å
Structure data

EMDB-17528, PDB-8p7b:
CryoEM structure of METTL6 tRNA SerRS complex in a 1:2:2 stoichiometry
Method: EM (single particle) / Resolution: 2.42 Å

EMDB-17529, PDB-8p7c:
CryoEM structure of METTL6 tRNA SerRS complex in a 2:2:2 stoichiometry
Method: EM (single particle) / Resolution: 3.7 Å

EMDB-17530, PDB-8p7d:
CryoEM structure of METTL6 tRNA SerRS complex in a 1:1:2 stoichiometry
Method: EM (single particle) / Resolution: 4.2 Å

EMDB-17531: SerRS bound to serine tRNA
Method: EM (single particle) / Resolution: 3.8 Å

EMDB-17532: Serine tRNA from Trichoplusia ni
Method: EM (single particle) / Resolution: 5.6 Å

PDB-8owx:
Crystal Structure of METTL6 bound to SAH
Method: X-RAY DIFFRACTION / Resolution: 2.601 Å

PDB-8owy:
Crystal structure of METTL6 mutant 40-269 bound to SAH
Method: X-RAY DIFFRACTION / Resolution: 3.2 Å

Chemicals

ChemComp-SAH:
S-ADENOSYL-L-HOMOCYSTEINE

ChemComp-B3P:
2-[3-(2-HYDROXY-1,1-DIHYDROXYMETHYL-ETHYLAMINO)-PROPYLAMINO]-2-HYDROXYMETHYL-PROPANE-1,3-DIOL / pH buffer*YM

ChemComp-MG:
Unknown entry

ChemComp-HOH:
WATER

Source
  • homo sapiens (human)
  • trichoplusia ni (cabbage looper)
KeywordsRNA BINDING PROTEIN / tRNA modification / m3C / methyltransferase / METTL6 / tRNA / SerRS / Serine tRNA / 3-Methylcytosine

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