Publication details

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



Year of publication 2020
Type Article in Periodical
Magazine / Source Computational and Structural Biology Journal
MU Faculty or unit

Faculty of Informatics

Keywords Acetylation; Ligand specificity; N-terminal acetyltransferases; Normal modes analysis; Protein dynamics
Description 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 beta6beta7 hairpin loop covering the active site and forming with the alpha1alpha2 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 beta4 and beta5 strands and splitting the fold in two dynamical subdomains. Loops alpha1alpha2, beta3beta4 and beta6beta7 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 alpha1alpha2 and beta6beta7 loops may regulate ligand uptake and the release of the acetylated polypeptide.

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