Structure And Chemistry Of The Human P300/Cbp And Yeast Rtt109 Histone Acetyltransferase

Histone actyltransferase (HAT) enzymes form a superfamily of proteins that transfer an acetyl group from the acetyl-coenzyme A (Ac-CoA) cofactor to the epsilon amino group of histone or sometimes non-histone proteins to promote gene activation. Paradoxally, despite the similar chemistry carried out by these enzymes, and their structurally related core regions, they fall into subfamilies with very limited to no sequence homology, structurally divergent core flanking regions and they use divergent mechanisms for catalysis. Four well studied HAT families include Gcn5/PCAF, MYST, p300/CBP and Rtt109. Although the structure and chemistry of the evolutionarily conserved Gcn5/PCAF and MYST HATs have been previously characterized, the metazoan-specific p300/CBP and fungal-specific Rtt109 have only recently been characterized at the structural and chemical levels. These recent studies provide new insights into the ancestral relationship between HATs and their functions and point to a common HAT ancestor 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 will also be discussed.