Structural basis for acyl-group discrimination by human Gcn5L2

Alison E. Ringel, Cynthia Wolberger

Research output: Contribution to journalArticle

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.Structures of human Gcn5L2 bound to propionyl-CoA and butyryl-CoA show how the active site accommodates different acyl modifications and explain why butyryl-CoA acts as a competitive inhibitor.

Original languageEnglish (US)
Pages (from-to)841-848
Number of pages8
JournalActa Crystallographica Section D: Structural Biology
Volume72
Issue number7
DOIs
StatePublished - 2016

Keywords

  • acyltransferase
  • butyryl-CoA
  • Gcn5
  • histone acetyltransferase
  • propionyl-CoA

ASJC Scopus subject areas

  • Structural Biology

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