Abstract
The 60-kDa HIV-Tat interactive protein (Tip60) is a key member of the MYST family of histone acetyltransferases (HATs) that plays critical roles in multiple cellular processes. We report here that Tip60 undergoes autoacetylation at several lysine residues, including a key lysine residue (i.e. Lys-327) in the active site of the MYST domain. The mutation of K327 to arginine led to loss of both the autoacetylation activity and the cognate HAT activity. Interestingly, deacetylated Tip60 still kept a substantial degree of HAT activity. We also investigated the effect of cysteine 369 and glutamate 403 in Tip60 autoacetylation in order to understand the molecular pathway of the autoacetylation at K327. Together, we conclude that the acetylation of K327 which is located in the active site of Tip60 regulates but is not obligatory for the catalytic activity of Tip60. Since acetylation at this key residue appears to be evolutionarily conserved amongst all MYST proteins, our findings provide an interesting insight into the regulatory mechanism of MYST activities.
Highlights
Histone acetylation is an evolutionarily conserved post-translational modification mark on the chromatin template in eukaryotic systems
We found that the Tip60 protein contained several acetylated lysine residues: K76, K80, K104, K150, K187, K327, and K383 (See Fig. 2 and Figures in Supporting Information S1)
We showed that mutation of this active site lysine to arginine almost completely abrogated the catalytic activity of Tip60 in protein autoacetylation and H4 acetylation (Fig. 4 and 5)
Summary
Histone acetylation is an evolutionarily conserved post-translational modification mark on the chromatin template in eukaryotic systems. Histone lysine acetylation can loosen nucleosome structures and regulate chromatin-associated nuclear processes such as gene transcription and DNA repair [6,7,8,9,10,11,12,13,14,15]. We report that Tip is autoacetylated at a conserved lysine residue in the active site and the autoacetylation mediates the catalytic activity of the enzyme. Since this lysine is strictly conserved amongst all the MYST proteins, our findings reveal a novel mechanism of MYST activity regulation
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