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TitleStructures and mechanisms of U6 snRNA mA modification by METTL16.
Journal, issue, pagesNat Commun, Vol. 16, Issue 1, Page 7708, Year 2025
Publish dateAug 21, 2025
AuthorsJue Ju / Kozo Tomita /
PubMed AbstractThe N-methyladenosine (mA) modification in U6 snRNA, catalyzed by METTL16 using S-adenosylmethionine (SAM) as the methyl donor, is required for efficient and accurate pre-mRNA splicing. However, the ...The N-methyladenosine (mA) modification in U6 snRNA, catalyzed by METTL16 using S-adenosylmethionine (SAM) as the methyl donor, is required for efficient and accurate pre-mRNA splicing. However, the mechanism by which METTL16 modifies U6 snRNA with mA remains elusive. Here, we present cryo-EM structures of METTL16 in complex with U6 snRNA, providing insights into the METTL16-mediated modification of U6 snRNA with mA. The structures reveal that U6 snRNA is recruited to METTL16 through specific interactions between the C-terminal kinase-associated 1 (KA-1) domain of METTL16 and the internal stem-loop (ISL) of U6 snRNA. Upon SAM binding to the catalytic pocket within the N-terminal methyltransferase domain (MTD), U6 snRNA undergoes a structural rearrangement that positions the target adenine-containing motif at the catalytic site. This conformational change is followed by an additional structural adjustment of U6 snRNA into a productive conformation, bringing the target adenosine closer to SAM within the catalytic pocket and thereby ensuring efficient mA modification. The KA-1 domain functions as a scaffold for initial substrate recognition and facilitates the subsequent dynamic methylation process within the MTD, highlighting the cooperative roles of METTL16 domains for U6 snRNA modification.
External linksNat Commun / PubMed:40841561 / PubMed Central
MethodsEM (single particle) / X-ray diffraction
Resolution2.795 - 3.4 Å
Structure data

EMDB-63833, PDB-9u47:
Cryo-EM structure of spMETTL16 in complex with U6 snRNA_delta17
Method: EM (single particle) / Resolution: 3.4 Å

EMDB-63834, PDB-9u48:
Cryo-EM structure of spMETTL16 in complex with U6 snRNA and SAM
Method: EM (single particle) / Resolution: 2.99 Å

PDB-9m86:
Crystal structure of SpMETTL16 kinase associated 1 domain in complex with U6 snRNA internal stem loop
Method: X-RAY DIFFRACTION / Resolution: 2.795 Å

Chemicals

ChemComp-SAM:
S-ADENOSYLMETHIONINE

Source
  • schizosaccharomyces pombe (fission yeast)
KeywordsTRANSFERASE/RNA / m6A methyltransferase / U6 snRNA / protein-RNA complex / splicing / TRANSFERASE / TRANSFERASE-RNA complex

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