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

## TL;DR

This study reveals how NAA40 and NAC work together during protein synthesis to acetylate histones, influencing gene regulation in humans.

## Contribution

The study provides biochemical and cryo-EM evidence of NAA40-NAC coordination at the ribosome for co-translational histone acetylation.

## Key findings

- NAA40 activity is coordinated at the ribosomal peptide tunnel exit with the NAC complex.
- NAA40-NAC interaction is essential for efficient ribosome binding and histone acetylation.
- A multienzyme complex involving METAP1 coordinates methionine removal and NAA40-mediated acetylation on the ribosome.

## 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.

N-terminal histone acetylation by human NAA40 alters epigenetic signaling and affects gene regulation. Here, the authors combine biochemistry and cryo-EM to unravel the foundation for the co-translational modification activity of NAA40.