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09:11
Assays for Validating Histone Acetyltransferase Inhibitors
Published on: August 6, 2020
Catalysis and substrate selection by histone/protein lysine acetyltransferases
Christopher E Berndsen1, John M Denu
1Department of Biomolecular Chemistry, University of Wisconsin-Madison School of Medicine and Public Health, 1300 University Avenue, Madison, WI 53706, USA.
Current Opinion in Structural Biology
|December 6, 2008
Summary
Protein lysine acetyltransferases (HATs) catalyze acetylation via a conserved mechanism. HAT complexes regulate activity, substrate specificity, and targeting, linking cellular metabolism to transcriptional regulation.
Area of Science:
- Biochemistry
- Molecular Biology
- Epigenetics
Background:
- Reversible protein acetylation is regulated by protein lysine acetyltransferases (HATs) and deacetylases.
- Recent structural and mechanistic studies reveal conserved catalytic mechanisms in HATs.
- HATs function in diverse multi-subunit complexes to regulate their activity and specificity.
Purpose of the Study:
- To elucidate the conserved catalytic mechanisms and regulatory strategies of histone acetyltransferases (HATs).
- To investigate how HAT complex formation influences substrate specificity, targeting, and activity.
- To explore the link between cellular metabolic state and transcriptional regulation via HATs.
Main Methods:
- Structural biology techniques to determine HAT complex structures.
- Biochemical assays to analyze acetyl transfer mechanisms and substrate specificity.
- Studies on the Rtt109 HAT and its interaction with histone chaperones.
Main Results:
- HATs utilize a conserved mechanism involving direct substrate attack on enzyme-bound acetyl-CoA.
- Multi-subunit HAT complexes regulate specificity, targeting, and activity.
- The Rtt109 HAT, with histone chaperones, exhibits distinct substrate selection for H3K9, H3K23, and H3K56.
- Some HATs can use alternative acyl-CoAs, suggesting a link to cellular metabolism.
Conclusions:
- HATs employ a conserved catalytic mechanism, with regulation achieved through complex formation.
- Histone chaperones play a critical role in directing HAT substrate specificity.
- The utilization of alternative acyl-CoAs by HATs highlights a connection between cell metabolism and gene expression.
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