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

• Published in: Proceedings of the National Academy of Sciences - PNAS 2018-10, Vol.115 (40), p.10010-10015
• Main Authors: Sun, Jian, Paduch, Marcin, Kim, Sang-Ah, Kramer, Ryan M., Barrios, Adam F., Lu, Vincent, Luke, Judy, Usatyuk, Svitlana, Kossiakoff, Anthony A., Tan, Song
• Format: Article
• Language: English
• Subjects: Acetyl Coenzyme A - chemistry; Acetyl Coenzyme A - metabolism; Acetylation; Activation; BASIC BIOLOGICAL SCIENCES; Binding; Biological Sciences; Chaperones; Chromatin; chromatin biology; Crystal structure; Crystallization; Crystallography; Crystallography, X-Ray; Enzymatic activity; Enzyme Activation; Enzyme activity; Epigenetics; Gene expression; Histone acetyltransferase; Histone Acetyltransferases - chemistry; Histone Acetyltransferases - metabolism; Histone H3; histone modification; Histones - chemistry; Histones - metabolism; Protein Binding; Protein Domains; Proteins; Saccharomyces cerevisiae - chemistry; Saccharomyces cerevisiae - metabolism; Saccharomyces cerevisiae Proteins - chemistry; Saccharomyces cerevisiae Proteins - metabolism; Substrates; Transcription; Transcription Factors - chemistry; Transcription Factors - metabolism; X-ray crystallography; Yeast
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.1805343115

The Gcn5 histone acetyltransferase (HAT) subunit of the SAGA transcriptional coactivator complex catalyzes acetylation of histone H3 and H2B N-terminal tails, posttranslational modifications associated with gene activation. Binding of the SAGA subunit partner Ada2 to Gcn5 activates Gcn5’s intrinsically weak HAT activity on histone proteins, but the mechanism for this activation by the Ada2 SANT domain has remained elusive. We have employed Fab antibody fragments as crystallization chaperones to determine crystal structures of a yeast Ada2/Gcn5 complex. Our structural and biochemical results indicate that the Ada2 SANT domain does not activate Gcn5’s activity by directly affecting histone peptide binding as previously proposed. Instead, the Ada2 SANT domain enhances Gcn5 binding of the enzymatic cosubstrate acetyl-CoA. This finding suggests a mechanism for regulating chromatin modification enzyme activity: controlling binding of the modification cosubstrate instead of the histone substrate.