Acetylation is one of the major post-translational protein modifications in the cell, with manifold effects on the protein level as well as on the metabolome level. The acetyl group, donated by the metabolite acetyl-coenzyme A, can be co- or post-translationally attached to either the α-amino group of the N-terminus of proteins or to the ε-amino group of lysine residues. These reactions are catalyzed by various N-terminal and lysine acetyltransferases. In case of lysine acetylation, the reaction is enzymatically reversible via tightly regulated and metabolism-dependent mechanisms. The interplay between acetylation and deacetylation is crucial for many important cellular processes. In recent years, our understanding of protein acetylation has increased significantly by global proteomics analyses and in depth functional studies. This review gives a general overview of protein acetylation and the respective acetyltransferases, and focuses on the regulation of metabolic processes and physiological consequences that come along with protein acetylation.

N-terminal acetylation (Nt-acetylation) is a widespread protein modification among eukaryotes and prokaryotes alike. By appending an acetyl group to the N-terminal amino group, the charge, hydrophobicity, and size of the N-terminus is altered in an irreversible manner. This alteration has implications for the lifespan, folding characteristics and binding properties of the acetylated protein. The enzymatic machinery responsible for Nt-acetylation has been largely described, but significant knowledge gaps remain. In this review, we provide an overview of eukaryotic N-terminal acetyltransferases (NATs) and the impact of Nt-acetylation. We also discuss other functions of known NATs and outline methods for studying Nt-acetylation.

Significance: N-terminal acetylation performed by N-terminal acetyltransferases (NATs) is a common protein modification in human cells. A unique NAT, NAA80, was recently found to control actin N-terminal acetylation and cytoskeletal dynamics. In this study, we developed potent and specific bisubstrate inhibitors against NAA80 and determined the crystal structure of NAA80 in complex with an inhibitor mimicking the β-actin N terminus, thus revealing molecular determinants for the substrate specificity and selective inhibition of NAA80. A yeast model uncovered how a cellular determinant, the NatB enzyme, acts to restrict the number of in vivo NAA80 substrates relative to the broader intrinsic capacity of NAA80. Our data provide a starting point for further development of inhibitors for the regulation of actin and cytoskeletal functions.

NAA80 Nt-acetylates the six actin isoforms by specifically targeting the complex of actin-profilin among all cellular proteins.

N-terminal acetylation, catalyzed by N-terminal acetyltransferases (NATs), is among the most common protein modifications in eukaryotes and involves the transfer of an acetyl group from acetyl-CoA to the a-amino group of the first amino acid. Functions of N-terminal acetylation include protein degradation and subcellular targeting. Recent findings in humans indicate that a dysfunctional N-alpha acetyltransferase (Naa) 10, the catalytic subunit of NatA, the major NAT, is associated with lethality during infancy. Here, we identified the Danio rerio orthologue zNaa10. In vitro N-terminal acetylation assays revealed that zNaa10 has NAT-activity with substrate specificity highly similar to that of human Naa10. Spatiotemporal expression pattern was determined by in situ hybridization, showing ubiquitous expression with especially strong staining in brain and eye. By morpholino-mediated knockdown, we demonstrated that naa10 morphants displayed increased lethality, growth retardation and developmental abnormalities like bent axis, abnormal eyes and bent tails. In conclusion, we identified the zebrafish Naa10 orthologue, and revealed that it is essential for normal development and viability of zebrafish.