Actin's N‐terminal acetyltransferase uncovered

Humans express six highly conserved actin isoforms, which differ the most at their N‐termini. Actin's N‐terminus undergoes co‐ and post‐translational processing unique among eukaryotic proteins. During translation, the initiator methionine of the two cytoplasmic isoforms is N‐terminally acetylated (Nt‐acetylated) and that of the four muscle isoforms is removed and the exposed cysteine is Nt‐acetylated. Then, an unidentified acetylaminopeptidase post‐translationally removes the Ac‐Met (or Ac‐Cys), and all six isoforms are re‐acetylated at the N‐terminus. Despite the vital importance of actin for cellular processes ranging from cell motility to organelle trafficking and cell division, the mechanism and functional consequences of Nt‐acetylation remained unresolved. Two recent studies significantly advance our understanding of actin Nt‐acetylation. Drazic et al. (2018, Proc Natl Acad Sci U S A, 115, 4399–4404) identify actin's dedicated N‐terminal acetyltransferase (NAA80/NatH), and demonstrate that Nt‐acetylation critically impacts actin assembly in vitro and in cells. NAA80 knockout cells display increased filopodia and lamellipodia formation and accelerated cell motility. In vitro , the absence of Nt‐acetylation leads to a decrease in the rates of filament depolymerization and elongation, including formin‐induced elongation. Goris et al. (2018, Proc Natl Acad Sci U S A, 115, 4405–4410] describe the structure of Drosophila NAA80 in complex with a peptide‐CoA bi‐substrate analog mimicking the N‐terminus of β‐actin. The structure reveals the source of NAA80's specificity for actin's negatively‐charged N‐terminus. Nt‐acetylation neutralizes a positive charge, thus enhancing the overall negative charge of actin's unique N‐terminus. Actin's N‐terminus is exposed in the filament and influences the interactions of many actin‐binding proteins. These advances open the way to understanding the many likely consequences and functional roles of actin Nt‐acetylation.