Dynamics-function relationship in the catalytic domains of N-terminal acetyltransferases

Angèle Abboud,Pierre Bédoucha,Jan Byška,Thomas Arnesen,Nathalie Reuter

doi:10.1016/j.csbj.2020.02.017

Abstract

N-terminal acetyltransferases (NATs) belong to the superfamily of acetyltransferases. They are enzymes catalysing the transfer of an acetyl group from acetyl coenzyme A to the N-terminus of polypeptide chains. N-terminal acetylation is one of the most common protein modifications. To date, not much is known on the molecular basis for the exclusive substrate specificity of NATs. All NATs share a common fold called GNAT. A characteristic of NATs is the β6β7 hairpin loop covering the active site and forming with the α1α2 loop a narrow tunnel surrounding the catalytic site in which cofactor and polypeptide meet and exchange an acetyl group.We investigated the dynamics-function relationships of all available structures of NATs covering the three domains of Life. Using an elastic network model and normal mode analysis, we found a common dynamics pattern conserved through the GNAT fold; a rigid V-shaped groove formed by the β4 and β5 strands and splitting the fold in two dynamical subdomains. Loops α1α2, β3β4 and β6β7 all show clear displacements in the low frequency normal modes. We characterized the mobility of the loops and show that even limited conformational changes of the loops along the low-frequency modes are able to significantly change the size and shape of the ligand binding sites. Based on the fact that these movements are present in most low-frequency modes, and common to all NATs, we suggest that the α1α2 and β6β7 loops may regulate ligand uptake and the release of the acetylated polypeptide.

Highlights

Acetyltransferases are enzymes catalysing the transfer of an acetyl group from the co-factor acetyl-coenzyme A (Ac-CoA) to a substrate
The variety of Na-terminal acetyltransferases (NATs) enables the selective acetylation of a diversity of N-termini of proteins at different localizations in the cell
The GNAT fold shared among all NATs and with other acetyltransferases offers a common scaffold to perform the catalytic activity and fine-tune ligand selectivity

Summary

Introduction

Acetyltransferases are enzymes catalysing the transfer of an acetyl group from the co-factor acetyl-coenzyme A (Ac-CoA) to a substrate. Na-terminal acetyltransferases (NATs) perform N-terminal acetylation of polypeptide chains. NATs acetylate 80–90% of the proteins of the human proteome [1] and N-terminal acetylation has been shown to play a role in various biological processes from protein folding to gene regulation [2]. Dysregulation or mutations of NATs have been linked to several diseases including tumour development [2–5] and initiatives are. ⇑ Corresponding author at: Department of Chemistry, University of Bergen, already undertaken to develop inhibitors targeting the relevant NATs [6]. It consists of a three-layered aba sandwich containing seven b-strands and four a-helices (Fig. 1A).

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