title: Structural basis for acyl-group discrimination by human Gcn5L2.
abstract: Gcn5 is a conserved acetyltransferase that regulates transcription by acetylating the N-terminal tails of histones. Motivated by recent studies identifying a chemically diverse array of lysine acyl modifications in vivo, the acyl-chain specificity of the acetyltransferase human Gcn5 (Gcn5L2) was examined. Whereas Gcn5L2 robustly catalyzes lysine acetylation, the acyltransferase activity of Gcn5L2 becomes progressively weaker with increasing acyl-chain length. To understand how Gcn5 discriminates between different acyl-CoA molecules, structures of the catalytic domain of human Gcn5L2 bound to propionyl-CoA and butyryl-CoA were determined. Although the active site of Gcn5L2 can accommodate propionyl-CoA and butyryl-CoA without major structural rearrangements, butyryl-CoA adopts a conformation incompatible with catalysis that obstructs the path of the incoming lysine residue and acts as a competitive inhibitor of Gcn5L2 versus acetyl-CoA. These structures demonstrate how Gcn5L2 discriminates between acyl-chain donors and explain why Gcn5L2 has weak activity for acyl moieties that are larger than an acetyl group.
authors.affiliation: Department of Biophysics and Biophysical Chemistry, Johns Hopkins University School of Medicine, 725 North Wolfe Street, Baltimore, MD 21205, USA.
authors.forename: Alison E
authors.initials: AE
authors.lastname: Ringel
authors.affiliation: Department of Biophysics and Biophysical Chemistry, Johns Hopkins University School of Medicine, 725 North Wolfe Street, Baltimore, MD 21205, USA.
authors.forename: Cynthia
authors.initials: C
authors.lastname: Wolberger
mesh_terms: D000107:Acetylation; D000214:Acyl Coenzyme A / Q000378:metabolism; D018360:Crystallography, X-Ray; D006801:Humans; D008958:Models, Molecular; D011487:Protein Conformation; D013379:Substrate Specificity; D050880:p300-CBP Transcription Factors / Q000737:chemistry* / Q000378:metabolism*; D000099224:p300-CBP-Associated Factor
chemical_list: D000214:Acyl Coenzyme A; D050880:p300-CBP Transcription Factors; D000099224:p300-CBP-Associated Factor; C024343:butyryl-coenzyme A; C009061:propionyl-coenzyme A
keywords: Gcn5; acyltransferase; butyryl-CoA; histone acetyltransferase; propionyl-CoA