Insights into Structure and Function of GCN5⧸PCAF and yEsa 1 Histone Acetyltransferase Domains:

Abstract

This chapter discusses the recent X-ray crystallographic and biochemical studies that was carried out to understand the catalytic mechanism and substrate specificity of members of the (general control nonderepressible-5) GCN5/PCAF and MYST HAT families. GCN5/PCAF participates in an ordered sequential (ternary complex) catalytic mechanism whereas Esa1 uses a ping-pong mechanism. The fact that different MYST HAT complexes exhibit diverse substrate specificities, suggests that other proteins in MYST complexes contribute greatly to the substrate specificity of this class of enzymes. Conversely, the GCN5/PCAF HAT domain has a more pronounced histone-binding cleft defined partly by the α5-loop region. It is important to note that this region has no structural homology with Esa1, or with other GNAT crystal structures. The structurally conserved CoA-binding domain for both of these HAT families, suggests that other nuclear HAT families may interact with the cofactor comparably. Similar to Esa1, steady-state kinetic analysis suggests that p300 participates in a ping-pong mechanism, which raises the possibility that the Esa1 structure has some similarity with the p300/CBP HAT domain. Further mechanistic insights in the chemistry of this fascinating HAT superfamily requires additional structural and biochemical studies on members of other nuclear HAT families, along with biologically relevant multi-protein in vivo HAT complexes.