Structural basis for activation of SAGA histone acetyltransferase Gcn5 by partner subunit Ada2

Significance Regulating gene expression is critical to the normal function of a biological cell, and misregulation of gene expression often leads to a diseased cell. In eukaryotic cells, DNA genetic information is wrapped around histone proteins into chromatin. Modification of histone proteins with the acetyl chemical group (i.e., acetylation) is an important mechanism for activating gene expression. Our biochemical and structural studies of the Gcn5 histone acetyltransferase and its partner protein Ada2 explain how Ada2 activates Gcn5’s enzymatic activity without directly contacting the histone substrate, as previously proposed. Instead, Ada2 indirectly influences binding of the enzyme cofactor acetyl-CoA, a mechanism not previously observed for histone modification enzymes.