Towards a functional understanding of protein N-terminal acetylation

Abstract

Protein N-terminal acetylation is a major modification of eukaryotic proteins. Its functional implications include regulation of protein-protein interactions and targeting to membranes, as demonstrated by studies of a handful of proteins. Fifty years after its discovery, a potential general function of the N-terminal acetyl group carried by thousands of unique proteins remains enigmatic. However, recent functional data suggest roles for N-terminal acetylation as a degradation signal and as a determining factor for preventing protein targeting to the secretory pathway, thus highlighting N-terminal acetylation as a major determinant for the life and death of proteins. These contributions represent new and intriguing hypotheses that will guide the research in the years to come.

Figure 1. Schematic overview of N-terminal processing in eukaryotes.

N-termini with small amino acid residues in the second position (Met-Xxx-) are mostly processed by methionine aminopeptidase (MAP), whereafter the newly generated N-termini may be acetylated by NatA (*or by NatD in the case of histones H2A and H4). This class of N-termini may also be acetylated on the initiator methionine (iMet) by unknown NATs or by NatF, which is specific for higher eukaryotes. N-termini with larger amino acid residues in the second position (Met-Yyy-) are not normally cleaved by MAPs, but potentially acetylated directly on the iMet by a variety of NATs depending on the N-terminal sequence. NatB potentially acetylates N-termini with acidic or hydrophilic residues in the second position. Hydrophobic N-termini are acetylated by NatC and potentially NatE, and in higher eukaryotes also NatF. NatF and perhaps other NATs acetylate Met-Met- and Met-Lys- N-termini. Information derived from and references herein and NatF identification (P. Van Damme, K. Hole, A. Pimenta-Marques, J. Vandekerckhove, R. G. Martinho, et al., unpublished data).

Figure 2. Functional effects of N-terminal acetylation. 1.

Nat complexes associate with ribosomes to perform co-translational Nt-acetylation of a majority of eukaryotic proteins . 2. N-terminal ubiquitination promotes degradation of N-terminally unacetylated proteins, thus Nt-acetylation may protect proteins from this degradation pathway . 3. The newly discovered N-end rule branch involves the degradation of Ac-N-degrons via the Doa10 E3 ubiquitin ligase . 4. Nt-acetylation is essential for the functioning of actin filaments by modulating protein–protein interactions –. 5. Tfs1 requires its acetylated N-terminus to directly inhibit the cytosolic carboxypeptidase CPY . 6. Nt-acetylation targets the GTPases Arl3p and Grh1p to the Golgi membrane –. 7. Trm1p-II requires Nt-acetylation for proper association to the inner nuclear membrane . 8. Nt-acetylated Sir3p specifically interacts with unmethylated lysine 79 of histone H3 in silenced chromatin and is essential for proper gene silencing . 9. Nt-acetylation prevents post-translational translocation through the ER membrane .