Crystal structure of the histone acetyltransferase Hpa2: A tetrameric member of the Gcn5-related N-acetyltransferase superfamily

We report the crystal structure of the yeast protein Hpa2 in complex with a cetyl coenzyme A (AcCoA) at 2.4 Angstrom resolution and without cofactor at 2.9 Angstrom resolution. Hpa2 is a member of the Gcn5-related N-acetyltran sferase (GNAT) superfamily, a family of enzymes with diverse substrates inc luding histones, other proteins, arylalkylamines and aminoglycosides. In vi tro, Hpa2 is able to acetylate specific lysine residues of histones H3 and H4 with a preference for Lys14 of histone H3. Hpa2 forms a stable dimer in solution and forms a tetramer upon binding AcCoA. The crystal structure rev eals that the Hpa2 tetramer is stabilized by base-pair interactions between the adenine moieties of the bound AcCoA molecules. These base-pairs repres ent a novel method of stabilizing an oligomeric protein structure. Comparis on of the structure of Hpa2 with those of other GNAT superfamily members il lustrates a remarkably conserved fold of the catalytic domain of the GNAT f amily even though members of this family share low levels of sequence homol ogy. This comparison has allowed us to better define the borders of the fou r sequence motifs that characterize the GNAT family, including a motif that is not discernable in histone acetyltransferases by sequence comparison al one. We discuss implications of the Hpa2 structure for the catalytic mechan ism of the GNAT enzymes and the opportunity for multiple histone tail modif ication created by the tetrameric Hpa2 structure. (C) 1999 Academic Press.