ReviewAcetylation and deacetylation of non-histone proteins
Introduction
Protein acetylation is a widespread phenomenon among eukaryotes. Co-translational Nα-terminal acetylation is one of the most frequent protein modifications, occurring on approximately 85% of eukaryotic proteins (Polevoda and Sherman, 2000). A less common, but perhaps more important, form of protein acetylation takes place post-translationally on the ɛ-amino group of lysines. The addition of an acetyl group on lysines prevents positive charges from forming on the amino group, and as a result, has a significant impact on the electrostatic properties of the protein. Early studies suggested that many lysine residues in histones are acetylated abundantly and that acetylation of histones regulates gene transcription (Allfrey et al., 1964, Allfrey, 1996, Vidali et al., 1968). An enzyme responsible for histone acetylation, HAT A, was identified initially in Tetrahymena (Brownell et al., 1996). HAT A possesses a high degree of amino acid sequence similarity to the yeast protein GCN5, which also catalyzes histone acetylation. Subsequently, about 30 proteins have been found to contain histone acetyltransferase activity. Each of these HATs may have a particular histone substrate specificity, and different HATs are specific with regard to which histone amino acids they will acetylate. Interestingly, many “histone” acetyltransferases have a wide range of protein substrates in addition to histones.
Unlike Nα-terminal acetylation, post-translational ε-amino lysine acetylation of proteins is highly reversible. In humans, there are 18 potential deacetylase enzymes, HDAC1 to HDAC11 and SIRT1 to SIRT7, which are responsible for the removal of acetyl groups and maintenance of the equilibrium of lysine acetylation in histones. Like HATs, histone deacetylases (HDACs) also possess substrate specificity and accumulating evidence suggests that many, if not all, HDACs can deacetylate non-histone proteins at least in vitro. While many recent reviews discuss non-histone acetylation, we will focus primarily on the functional consequences of acetylation and importantly, deacetylation, of non-histone proteins.
Section snippets
p53
The founding member of non-histone targets of HAT acetylation is the tumor suppressor and sequence-specific DNA-binding transcription factor p53 (Gu and Roeder, 1997). p53 is acetylated by p300/CBP at multiple lysine residues at the C-terminal DNA binding regulatory domain. Acetylation of p53 by p300/CBP activates its sequence-specific DNA binding activity and, consequently, increases activation of its target genes. Although a report suggested that acetylation of the C terminus of p53 by p300
α-Tubulin
In addition to transcription factors, other classes of non-histone proteins are regulated by dynamic acetylation and deacetylation. The best characterized is the cytoskeletal protein α-tubulin. Although acetylation of α-tubulin was found in mammalian cells almost two decades ago, the acetyltransferase responsible remains unidentified (L'Hernault and Rosenbaum, 1985, Maruta et al., 1986, Schulze et al., 1987). Stable microtubules contain high levels of acetylated α-tubulin. In contrast, dynamic
E1A
Besides the many cellular proteins described above, some virally encoded proteins also are substrates of acetylation and deacetylation. Because the adenovirus E1A protein binds p300/CBP, it was not surprising to find that the E1A protein can be acetylated by p300 and PCAF. A study by Zhang et al. (2000) showed that one of the acetylation sites on 12S E1A is located at lysine 239, a residue that is adjacent to the C-terminal binding protein (CtBP) binding motif. Mutation of lysine 239 inhibited
Conclusions and future directions
It has been proposed that acetylation is a regulatory modification that rivals phosphorylation (Kouzarides, 2000). Although the exact number and variety of proteins that are post-translationally lysine-acetylated in the cell is still unknown, it is clear that far more proteins are modified by this mechanism than initially appreciated. Dynamic acetylation of non-histone proteins has pleiotropic effects on cellular function (Table 1). Given this wide array of possible outcomes, it is not possible
Acknowledgments
We apologize to all investigators whose works were not cited in this article due to space limitation. Work in our laboratory is supported by grants from the National Institutes of Health and an endowment from the Kaul Foundation.
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