NAA40 and NAC cooperate in co-translational histone acetylation in humans

Guan, Dandan; Denk, Timo; Klavaris, Ariel; Thoms, Matthias; Berninghausen, Otto; Beatrix, Birgitta; Kirmizis, Antonis; Beckmann, Roland (2026): NAA40 and NAC cooperate in co-translational histone acetylation in humans. Nature Communications, 17: 2486. ISSN 2041-1723

Abstract

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.

• Doc-Type: Article (LMU)
• Organisational unit (Faculties): 18 Chemistry and Pharmacy > GeneCenter
• DFG subject classification of scientific disciplines: Life sciences
• DFG: Funded by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) - 512515806
• DFG: Funded by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) - 491502892