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

Abstract

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. As a result, this finding suggests a mechanism for regulating chromatin modification enzyme activity: controlling binding of the modification cosubstrate instead of the histone substrate.

Authors:
 [1];  [2];  [1];  [3];  [4];  [5];  [5];  [5];  [5];  [1]
  1. Pennsylvania State Univ., University Park, PA (United States)
  2. Univ. of Chicago, IL (United States); Grail, Menlo Park, CA (United States)
  3. Pennsylvania State Univ., University Park, PA (United States); Air Force Research Lab., Wright Patterson AFB, OH (United States)
  4. Pennsylvania State Univ., University Park, PA (United States); DesigneRx Pharmaceuticals, Vacaville, CA (United States)
  5. Univ. of Chicago, IL (United States)
Publication Date:
Research Org.:
Argonne National Lab. (ANL), Argonne, IL (United States)
Sponsoring Org.:
National Inst. of Health
OSTI Identifier:
1477118
Grant/Contract Number:  
R01GM088236; R01GM111651; U01GM094588; R01GM072688; U54HG006436
Resource Type:
Journal Article: Accepted Manuscript
Journal Name:
Proceedings of the National Academy of Sciences of the United States of America
Additional Journal Information:
Journal Volume: 115; Journal Issue: 40; Journal ID: ISSN 0027-8424
Publisher:
National Academy of Sciences
Country of Publication:
United States
Language:
ENGLISH
Subject:
59 BASIC BIOLOGICAL SCIENCES; epigenetics; chromatin biology; histone modification; X-ray crystallography

Citation Formats

Sun, Jian, Paduch, Marcin, Kim, Sang-Ah, Kramer, Ryan M., Barrios, Adam F., Lu, Vincent, Luke, Judy, Usatyuk, Svitlana, Kossiakoff, Anthony A., and Tan, Song. Structural basis for activation of SAGA histone acetyltransferase Gcn5 by partner subunit Ada2. United States: N. p., 2018. Web. doi:10.1073/pnas.1805343115.
Sun, Jian, Paduch, Marcin, Kim, Sang-Ah, Kramer, Ryan M., Barrios, Adam F., Lu, Vincent, Luke, Judy, Usatyuk, Svitlana, Kossiakoff, Anthony A., & Tan, Song. Structural basis for activation of SAGA histone acetyltransferase Gcn5 by partner subunit Ada2. United States. doi:10.1073/pnas.1805343115.
Sun, Jian, Paduch, Marcin, Kim, Sang-Ah, Kramer, Ryan M., Barrios, Adam F., Lu, Vincent, Luke, Judy, Usatyuk, Svitlana, Kossiakoff, Anthony A., and Tan, Song. Mon . "Structural basis for activation of SAGA histone acetyltransferase Gcn5 by partner subunit Ada2". United States. doi:10.1073/pnas.1805343115. https://www.osti.gov/servlets/purl/1477118.
@article{osti_1477118,
title = {Structural basis for activation of SAGA histone acetyltransferase Gcn5 by partner subunit Ada2},
author = {Sun, Jian and Paduch, Marcin and Kim, Sang-Ah and Kramer, Ryan M. and Barrios, Adam F. and Lu, Vincent and Luke, Judy and Usatyuk, Svitlana and Kossiakoff, Anthony A. and Tan, Song},
abstractNote = {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. As a result, this finding suggests a mechanism for regulating chromatin modification enzyme activity: controlling binding of the modification cosubstrate instead of the histone substrate.},
doi = {10.1073/pnas.1805343115},
journal = {Proceedings of the National Academy of Sciences of the United States of America},
issn = {0027-8424},
number = 40,
volume = 115,
place = {United States},
year = {2018},
month = {9}
}

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