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Review
. 2015 Jul;15(14):2385-401.
doi: 10.1002/pmic.201400619. Epub 2015 Jun 16.

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

Sylvia Varland  1 , Camilla Osberg  1   2 , Thomas Arnesen  1   2
Affiliations
Review

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

Sylvia Varland et al. Proteomics. 2015 Jul.

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.

Keywords: Acetylation; Cell biology; N-terminal; Protein modification; Substrate specificity; α-amino group.

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Figures

Figure 1
Figure 1
Structural formulae of major N-terminal protein modifications. The N-terminal α-amino group is (usually) positively charged at neutral pH. The chemical character of protein N-termini can be modified by, for example: acetylation, propionylation, methylation, myristoylation, palmitoylation or ubiquitylation (attachment shown in red). The responsible enzymes and their respective donor molecules are listed. NATs, N-terminal acetyltransferases; NPTs, N-terminal propionyltransferases; NTMTs, N-terminal methyltransferases; NMTs, N-terminal myristoyltransferases; PATs, Palmitoylacyltransferases; CoA, Coenzyme A; ⊕ denotes permanent positive charge.
Figure 2
Figure 2
Substrate specificity of N-terminal modifying enzymes. Proteins are synthesized with an initiator methionine (iMet). The iMet can remain at the N-terminus (blue) or be removed by MetAPs (yellow). A retained iMet can undergo Nt-acetylation (red) by one of four NATs (NatB/NatC/NatE/NatF), depending upon the subsequent amino acid (listed). Following iMet removal, the N-terminal amino acid residue can become Nt-acetylated, Nt-myristoylated, Nt-palmitoylated or Nt-methylated (green). It is not known whether Nt-ubiquitylation (grey) takes place on iMet and/or the exposed amino acid residue following iMet removal. A consensus sequence for Nt-ubiquitylation has not been established. *For Met-Asp and Met-Glu of mammalian cytoplasmic β-actin and γ-actin, respectively, iMet excision is catalyzed by an unidentified aminopeptidase. †Asp and Glu of mammalian cytoplasmic β-actin and γ-actin, respectively, are Nt-acetylated by Naa10. ǂCys is post-translationally Nt-palmitoylated after generation of protein neo-N-termini by endopeptidases.
Figure 3
Figure 3
Overview of co- and post-translational N-terminal modifications. Co-translational protein modifications (left) taking place on the ribosomes include iMet excision, Nt-acetylation, Nt-propionylation, Nt-myristoylation or Nt-palmitoylation. Post-translational modifications (right) include Nt-methylation, Nt-palmitoylation or Nt-acetylation. Regarding Nt-ubiquitylation, it is uncertain whether it is a co- or post-translational event. Listed in relation to each modification are the responsible enzymes. The arrows are weighed according to the presumed extent of the individual modifications.*Preceding post-translational Nt-palmitoylation of Cys, a signal sequence is removed by endopeptidases thus generating neo-N-termini. †The case of mammalian cytoplasmic β-actin and γ-actin (Met-Asp and Met-Glu, respectively) involves co-translational Nt-acetylation of iMet, presumably by NatB, followed by post-translational Ac-iMet excision by an unknown aminopeptidase and finally Nt-acetylation by Naa10.
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