N‐terminal modifications of cellular proteins: The enzymes involved, their substrate specificities and biological effects

Abstract

The vast majority of eukaryotic proteins are N-terminally modified by one or more processing enzymes. Enzymes acting on the very first amino acid of a polypeptide include different peptidases, transferases, and ligases. Methionine aminopeptidases excise the initiator methionine leaving the nascent polypeptide with a newly exposed amino acid that may be further modified. N-terminal acetyl-, methyl-, myristoyl-, and palmitoyltransferases may attach an acetyl, methyl, myristoyl, or palmitoyl group, respectively, to the α-amino group of the target protein N-terminus. With the action of ubiquitin ligases, one or several ubiquitin molecules are transferred, and hence, constitute the N-terminal modification. Modifications at protein N-termini represent an important contribution to proteomic diversity and complexity, and are essential for protein regulation and cellular signaling. Consequently, dysregulation of the N-terminal modifying enzymes is implicated in human diseases. We here review the different protein N-terminal modifications occurring co- or post-translationally with emphasis on the responsible enzymes and their substrate specificities.

The world of protein acetylation

“…ACCEPTED MANUSCRIPT 39 Grave's disease is a typical organ-specific autoimmune disease and the most common cause of hyperthyroidism [382]. Also here, a decreased H4 acetylation pattern was observed as well as increased HDAC1 and 2 expression levels [383].…”

“…Indeed, enzyme-independent acetylation has since been demonstrated, and although two potential mitochondrial acetyltransferases have been identified, they cannot account for the observed levels of mitochondrial acetylation. Studies in S. cerevisiae [335] and in various mouse tissues [348] have shown that protein acetylation in mitochondria happens to a very low stoichiometry, in contrast to phosphorylation, a well-established posttranslational regulatory modification, [349] and Nt-acetylation [39]. This suggests that mitochondrial protein acetylation is mainly a non-enzymatic lesion caused by the high concentration of AcCoA and high pH in the mitochondria [176].…”

The Glycolytic Enzyme Triosephosphate Isomerase of Trichomonas vaginalis Is a Surface-Associated Protein Induced by Glucose That Functions as a Laminin- and Fibronectin-Binding Protein

“…In support of this hypothesis, in silico analysis of TvTIM sequences shows that both TvTIM proteins contain putative sites for S-palmitoylation (cluster C) and N-myristoylation; both modifications could be involved in the interaction of the proteins with lipid membranes (54)(55)(56). Additionally, we identified putative sites for phosphorylation (on S and T), which may be important for interactions with other proteins or substrates and N-or O-glycosylation and thus could be relevant for protein secretion (39).…”

Degradation of Serotonin N-Acetyltransferase, a Circadian Regulator, by the N-end Rule Pathway

“…2, C (lanes 6 -9 and 14 -17) and E). S. cerevisiae naa30⌬ cells lack the cognate NatC Nt-acetylase whose substrates include proteins bearing the N-terminal Met-Leu sequence (59,62,63,75,76). S. cerevisiae ubr1⌬ cells lack Ubr1, the E3 Ub ligase (N-recognin) that is essential for the proteolytic activity of the Arg/N-end rule pathway (Fig.…”