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TitleNAA40 and NAC cooperate in co-translational histone acetylation in humans.
Journal, issue, pagesNat Commun, Vol. 17, Issue 1, Year 2026
Publish dateMar 12, 2026
AuthorsDandan Guan / Timo Denk / Ariel Klavaris / Matthias Thoms / Otto Berninghausen / Birgitta Beatrix / Antonis Kirmizis / Roland Beckmann /
PubMed AbstractN-terminal acetylation is an abundant and predominantly co-translational modification in eukaryotes that profoundly affects folding, compartmentalization fidelity and turnover of target proteins. ...N-terminal acetylation is an abundant and predominantly co-translational modification in eukaryotes that profoundly affects folding, compartmentalization fidelity and turnover of target proteins. Unlike other N-acetyltransferases, human NatD is composed solely of the catalytic subunit NAA40 and exclusively modifies histone proteins H2A and H4. However, the molecular details of co-translational NAA40 activity have remained elusive. Here, we show biochemically and by cryo-EM how NAA40 activity is coordinated at the ribosomal peptide tunnel exit involving the NAC complex. We demonstrate that the NAA40-NAC interaction is required for efficient ribosome binding and histone acetylation. Furthermore, we provide insights on the potential coordination of methionine removal and subsequent NAA40-mediated acetylation by formation of a multienzyme complex on the ribosome involving METAP1. Therefore, our results illustrate the details of N-terminal histone acetylation by NAA40 and highlight the role of NAC as a general coordinator of nascent protein modification.
External linksNat Commun / PubMed:41820326 / PubMed Central
MethodsEM (single particle)
Resolution2.67 - 3.54 Å
Structure data

EMDB-55610, PDB-9t69:
In vitro reconstituted METAP1-NAA40-NAC bound 80S - State 1
Method: EM (single particle) / Resolution: 3.54 Å

EMDB-55612, PDB-9t6c:
NAA40-NAC bound active human 80S
Method: EM (single particle) / Resolution: 2.91 Å

EMDB-55613, PDB-9t6d:
NAA40-NAC bound human 80S (combined translation states)
Method: EM (single particle) / Resolution: 2.67 Å

EMDB-55616, PDB-9t6i:
In vitro reconstituted METAP1-NAA40-NAC bound 80S - State 2
Method: EM (single particle) / Resolution: 3.44 Å

Chemicals

ChemComp-MG:
Unknown entry

ChemComp-ZN:
Unknown entry

ChemComp-HOH:
WATER

Source
  • homo sapiens (human)
KeywordsRIBOSOME / 80S / co-translational / NAA40 / NAC / histone acetylation / N-terminal acetylation / human

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