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New protein tricks from an old enzyme

NATsDec. 18, 2012 — Small chemical groups are commonly attached to proteins in order to control their activity, localization, and stability. In eukaryotic cells, most proteins are modified at their N-termini by an acetyl group. N-terminal acetylation involves the transfer of an acetyl moiety from acetyl coenzyme A to the α-amino group of the first amino acid residue of a protein and is catalyzed by N-terminal acetyltransferases (NATs) [see TIBS April 2012]. The NATs have been linked to cancer development [see Oncogene March 2012] and most recently a NAT-mutation was found to be the cause of a lethal syndrome [see AJHG June 2011].

ARTICLE ABSTRACT


Protein N-Terminal acetyltransferases act as N-Terminal propionyltransferases in vitro and in vivo 

N-terminal acetylation (Nt-acetylation) is a highly abundant protein modification in eukaryotes catalysed by N-terminal acetyltransferases (NATs), which transfer an acetyl group from acetyl coenzyme A to the alpha amino group of a nascent polypeptide. Nt-acetylation has emerged as an important protein modifier, steering protein degradation, protein complex formation and protein localization. Very recently, it was reported that some human proteins could carry a propionyl group at their N-terminus. Here, we investigated the generality of N-terminal propionylation by analysing its proteome-wide occurrence in yeast and we identified 10 unique in vivo Nt-propionylated N-termini. Furthermore, by performing differential N-terminome analysis of a control yeast strain (yNatA), a yeast NatA deletion strain (yNatA△) or a yeast NatA deletion strain expressing human NatA (hNatA), we were able to demonstrate that in vivo Nt-propionylation of several proteins, displaying a NatA type substrate specificity profile, depended on the presence of either yeast or human NatA. Furthermore, in vitro Nt-propionylation assays using synthetic peptides, propionyl coenzyme A, and either purified human NATs or immunoprecipitated human NatA, clearly demonstrated that NATs are Nt-propionyltransferases (NPTs) per se. We here demonstrate for the first time that Nt-propionylation can occur in yeast and thus is an evolutionarily conserved process, and that the NATs are multifunctional enzymes acting as NPTs in vivo and in vitro, in addition to their main role as NATs, and their potential function as lysine acetyltransferases (KATs) and non-catalytic regulators.

Now researchers from the Department of Molecular Biology, University of Bergen, and Ghent University (VIB) have revealed that a related protein modification, N-terminal propionylation, is conserved among eukaryotes. Interestingly, the NATs were uncovered to also be responsible for this newly discovered modification by transferring a propionyl-moiety from propionyl coenzyme A to various proteins. These results are now presented in Molecular & Cellular Proteomics. Thus, the NATs now emerge as multifunctional enzymes with a broad and diverse impact on the eukaryotic proteomes.