Structure and chemistry of the p300/CBP and Rtt109 histone acetyltransferases: implications for histone acetyltransferase evolution and function

Abstract

The recent structure and associated biochemical studies of the metazoan-specific p300/CBP and fungal-specific Rtt109 histone acetyltransferases (HATs) have provided new insights into the ancestral relationship between HATs and their functions. These studies point to a common HAT ancester that has evolved around a common structural framework to form HATs with divergent catalytic and substrate-binding properties. These studies also point to the importance of regulatory loops within HATs and autoacetylation in HAT function. Implications for future studies are discussed.

Figure 1. Overall structure of nuclear HATs

(a) Tetrahymena Gcn5 (as cartoon) in complex with CoA (stick model in CPK coloring) and histone H3 (backbone trace colored in green) illustrates a representative Gcn5/PCAF HAT. The structurally conserved HAT core region is highlighted in magenta and the more structurally variable flanking regions are highlighted in cyan. (PDB ID 1PUA) (b) Yeast Esa1 in complex with CoA illustrates a representative MYST HAT, with the coloring scheme as in (a). (PDB ID 1FY7) (c) Human p300 in complex with the Lys-CoA bisubstrate inhibitor is the founding member of the p300/CBP HAT. In addition to the coloring scheme as in (a), the substrate binding L1 loop is highlighted in red. (PDB ID 3BIY) (d) Yeast Rtt109 in complex with Ac-CoA. The coloring scheme is as in (c). (PDB ID 3D35)

Figure 2. p300 and Rtt109 active sites

(a) The active site of p300 showing residues that are in position to play potential catalytic roles, highlighting Trp1436 and Tyr1467 (boxed). (b) The active site of Rtt109 showing the corresponding residues shown in (a) and also highlighting mutationally sensitive residues Trp222 and Tyr199 (boxed) for HAT activity. In both (a) and (b), highlighted residues, together with Lys-CoA and acetyl-CoA, are shown as sticks with CPK coloring, with overall protein structures shown as cartoons colored as in Figure 1. (c) Electrostatic surface of the p300 HAT substrate-binding pockets (P1 and P2) with blue, red and white representing electropositive, electronegative and neutral areas, respectively. Lys-CoA is shown in stick representation. (d) The electrostatic surface of Rtt109 corresponding to that of p300 in (c).

Figure 3. p300 and Rtt109 autoacetylation regions

(a) A model for the regulation of p300/CBP by autoacetylation is shown where it is proposed that the lysine-rich basic activation loop blocks the substrate-binding site when unacetylated but is displaced upon autoacetylation. (b) Autoacetylated Lys290 in Rtt109 is shown hydrogen bonded to Asp288 and buried within a hydrophobic core.