An old HAT in human p300/CBP and yeast Rtt109

Abstract

The crystal structure of the human p300 histone acetyltransferase (HAT) domain reveals a familiar α + β fold with unique structural elaborations1 that merit its classification as a third divergent HAT branch alongside the GCN5-related N-acetyltransferase (GNAT) and MYST (MOZ, Ybf2/Sas3, Sas2, Tip60) families.2 Two key departures from the core GNAT/MYST HAT fold - a long unstructured chain (or "flap") overlaying the acetyl-CoA (AcCoA) binding groove, and a four-α-helix "tower" excursion from the main β-sheet - critically contribute to the recognition and presumptive catalytic machinery of p300/CBP HAT enzymes. Kinetic and mutant analysis of this enlarged residue constellation in p300 (which is distinct from functional fingerprints drawn from GNAT or MYST complexes2) led Liu et al.,1 to suggest that p300/CBP works with an unorthodox "hit and run" mechanism that enlists Tyr1467 as the critical catalytic residue. In order to extend the evolutionary testbed for this variant HAT mechanism beyond the thin roll of p300/CBP orthologs, I propose that Rtt109, a novel yeast HAT that has so far eluded classification, is the prototype of a fungal clan of p300-related enzymes that preserve the embellished HAT fold, but further diversify its catalytic options. ©2008 Landes Bioscience.