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Peer-reviewedCC BYNature Communications

Structure of the NAT10 acetyltransferase and mechanism of tRNA acetylation

  • Mingyang Zhou1,2
  • Supuni Thalalla Gamage3
  • Khoa A. Tran4,5
  • David Bartee3
  • Xuepeng Wei1,6,7
  • Boyu Yin1,2
  • Shelley L. Berger8,4,9,5
  • Jordan L. Meier10
  • Ronen Marmorstein11,12,13,14
14 affiliations
  1. 1Abramson Family Cancer Research Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
  2. 2Department of Chemistry, University of Pennsylvania, Philadelphia, PA, USA
  3. 3Chemical Biology Laboratory, National Cancer Institute, Frederick, MD, USA
  4. 4Department of Cell and Developmental Biology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
  5. 5Epigenetics Institute, Perelman School of Medicine, University of Philadelphia, Philadelphia, PA, USA
  6. 6Department of Biochemistry and Biophysics Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
  7. 7Guangzhou National Laboratory, Guangzhou, China
  8. 8Department of Biology, School of Arts and Sciences, University of Pennsylvania, Philadelphia, PA, USA
  9. 9Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
  10. 10Chemical Biology Laboratory, National Cancer Institute, Frederick, MD, USA. [email protected]
  11. 11Abramson Family Cancer Research Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. [email protected]
  12. 12Department of Biochemistry and Biophysics Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. [email protected]
  13. 13Department of Chemistry, University of Pennsylvania, Philadelphia, PA, USA. [email protected]
  14. 14Epigenetics Institute, Perelman School of Medicine, University of Philadelphia, Philadelphia, PA, USA. [email protected]
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Abstract

Human NAT10 acetylates the N4 position of cytidine in RNA, predominantly on rRNA and tRNA, to facilitate ribosome biogenesis and protein translation. NAT10 has been proposed as a therapeutic target in cancers as well as aging-associated pathologies such as Hutchinson-Gilford Progeria Syndrome (HGPS). The ∼120 kDa NAT10 protein uses its acetyl-CoA-dependent acetyltransferase, ATP-dependent helicase, and RNA binding domains in concert to mediate RNA-specific N4-cytidine acetylation. While the biochemical activity of NAT10 is well known, the molecular basis for catalysis of eukaryotic RNA acetylation remains relatively undefined. To provide molecular insights into the RNA-specific acetylation by NAT10, we determined the single particle cryo-EM structures of Chaetomium thermophilum NAT10 ( Ct NAT10) bound to a bisubstrate cytidine-CoA probe with and without ADP. The structures reveal that NAT10 forms a symmetrical heart-shaped dimer with conserved functional domains surrounding the acetyltransferase active sites harboring the cytidine-CoA probe. Structure-based mutagenesis with analysis of mutants in vitro supports the catalytic role of two conserved active site residues (His548 and Tyr549 in Ct NAT10), and two basic patches, both proximal and distal to the active site for RNA-specific acetylation. Yeast complementation analyses and senescence assays in human cells also implicates NAT10 catalytic activity in yeast thermoadaptation and cellular senescence. Comparison of the NAT10 structure to protein lysine and N-terminal acetyltransferase enzymes reveals an unusually open active site suggesting that these enzymes have been evolutionarily tailored for RNA recognition and cytidine-specific acetylation.

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Cite

BibTeXRIS
BibTeX
@article{zhou2026structure,
  title = {{Structure of the NAT10 acetyltransferase and mechanism of tRNA acetylation}},
  author = {Mingyang Zhou and Supuni Thalalla Gamage and Khoa A. Tran and David Bartee and Xuepeng Wei and Boyu Yin and Shelley L. Berger and Jordan L. Meier and Ronen Marmorstein},
  journal = {Nature Communications},
  year = {2026},
  month = jun,
  doi = {10.1038/s41467-026-74222-6},
  url = {https://doi.org/10.1038/s41467-026-74222-6},
  note = {CC BY},
}
RIS
TY  - JOUR
TI  - Structure of the NAT10 acetyltransferase and mechanism of tRNA acetylation
AU  - Mingyang Zhou
AU  - Supuni Thalalla Gamage
AU  - Khoa A. Tran
AU  - David Bartee
AU  - Xuepeng Wei
AU  - Boyu Yin
AU  - Shelley L. Berger
AU  - Jordan L. Meier
AU  - Ronen Marmorstein
PY  - 2026
DA  - 2026/06/19
JO  - Nature Communications
DO  - 10.1038/s41467-026-74222-6
UR  - https://doi.org/10.1038/s41467-026-74222-6
AB  - Human NAT10 acetylates the N4 position of cytidine in RNA, predominantly on rRNA and tRNA, to facilitate ribosome biogenesis and protein translation. NAT10 has been proposed as a therapeutic target in cancers as well as aging-associated pathologies such as Hutchinson-Gilford Progeria Syndrome (HGPS). The ∼120 kDa NAT10 protein uses its acetyl-CoA-dependent acetyltransferase, ATP-dependent helicase, and RNA binding domains in concert to mediate RNA-specific N4-cytidine acetylation. While the biochemical activity of NAT10 is well known, the molecular basis for catalysis of eukaryotic RNA acetylation remains relatively undefined. To provide molecular insights into the RNA-specific acetylation by NAT10, we determined the single particle cryo-EM structures of Chaetomium thermophilum NAT10 ( Ct NAT10) bound to a bisubstrate cytidine-CoA probe with and without ADP. The structures reveal that NAT10 forms a symmetrical heart-shaped dimer with conserved functional domains surrounding the acetyltransferase active sites harboring the cytidine-CoA probe. Structure-based mutagenesis with analysis of mutants in vitro supports the catalytic role of two conserved active site residues (His548 and Tyr549 in Ct NAT10), and two basic patches, both proximal and distal to the active site for RNA-specific acetylation. Yeast complementation analyses and senescence assays in human cells also implicates NAT10 catalytic activity in yeast thermoadaptation and cellular senescence. Comparison of the NAT10 structure to protein lysine and N-terminal acetyltransferase enzymes reveals an unusually open active site suggesting that these enzymes have been evolutionarily tailored for RNA recognition and cytidine-specific acetylation.
SN  - 2041-1723
ER  -