Research Article: Structural basis for acyl-group discrimination by human Gcn5L2

Date Published: July 01, 2016

Publisher: International Union of Crystallography

Author(s): Alison E. Ringel, Cynthia Wolberger.

http://doi.org/10.1107/S2059798316007907

Abstract

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.

Partial Text

Lysine acetylation is an abundant post-translational modification (Weinert et al., 2011 ▸; Choudhary et al., 2009 ▸) that changes the overall size and charge of the modified residue. Several classes of enzymes are known to catalyze site-specific lysine acetylation (Roth et al., 2001 ▸; Yang, 2004 ▸; Marmorstein & Trievel, 2009 ▸), many of which localize to the nucleus and modify lysine residues on histones (Lee & Workman, 2007 ▸). These enzymes are collectively referred to as either histone acetyltransferases (HATs) or lysine (K) acetyltransferases (KATs), the latter to reflect their ability to acetylate non­histone substrates (Glozak et al., 2005 ▸). KATs are divided into several main families based on both structural similarity and the presence of sequence conservation within their catalytic domains (Marmorstein & Trievel, 2009 ▸). Although different KAT families employ distinct kinetic mechanisms to catalyze acetyl transfer, they all share a common dependence on the nucleotide cofactor acetyl-CoA as an acetyl donor (Berndsen & Denu, 2008 ▸).

We have determined crystal structures that describe how Gcn5 accommodates propionyl-CoA in its active site and provide a structural mechanism that explains our biochemical data showing that human Gcn5 discriminates between different acyl-CoA molecules. Since unsaturated acyl chains greater than three C atoms in length (propyl groups) cannot fit into the active site of Gcn5, butyryl-CoA binds in a conformation that is incompatible with catalysis. The butyryl-CoA C3 and C4 atoms occupy the channel for the incoming lysine (Fig. 3 ▸d), which prevents the peptide substrate from accessing the active-site cleft of Gcn5. We further show that butyryl-CoA is a competitive inhibitor versus acetyl-CoA for human Gcn5 (Fig. 5 ▸c), raising the question as to whether fluctuating levels of acyl-CoA molecules in cells may regulate the activity of Gcn5.

 

Source:

http://doi.org/10.1107/S2059798316007907

 

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