Molecular, Cellular, and Physiological Significance of N-Terminal Acetylation

Aksnes, Henriette; Hole, Kristine; Arnesen, Thomas

doi:10.1016/bs.ircmb.2015.01.001

Cited by 96 publications

(90 citation statements)

References 139 publications

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“…One branch, called the Ac/N-end rule pathway, targets proteins for degradation through their N ␣ -terminally acetylated (Nt-acetylated) residues (Fig. 1B) (5,6,13,36,56,70,71). Degradation signals and E3 Ub ligases of the Ac/N-end rule pathway are called Ac/N-degrons and Ac/N-recognins, respectively.…”

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confidence: 99%

Analyzing N-terminal Arginylation through the Use of Peptide Arrays and Degradation Assays

Wadas

Piatkov

Brower

et al. 2016

Journal of Biological Chemistry

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N␣ -terminal arginylation (Nt-arginylation) of proteins is mediated by the Ate1 arginyltransferase (R-transferase), a component of the Arg/N-end rule pathway. This proteolytic system recognizes proteins containing N-terminal degradation signals called N-degrons, polyubiquitylates these proteins, and thereby causes their degradation by the proteasome. The definitively identified ("canonical") residues that are Nt-arginylated by R-transferase are N-terminal Asp, Glu, and (oxidized) Cys. Over the last decade, several publications have suggested (i) that Ate1 can also arginylate non-canonical N-terminal residues; (ii) that Ate1 is capable of arginylating not only ␣-amino groups of N-terminal residues but also ␥-carboxyl groups of internal (non-N-terminal) Asp and Glu; and (iii) that some isoforms of Ate1 are specific for substrates bearing N-terminal Cys residues. In the present study, we employed arrays of immobilized 11-residue peptides and pulse-chase assays to examine the substrate specificity of mouse R-transferase. We show that amino acid sequences immediately downstream of a substrate's canonical (Nt-arginylatable) N-terminal residue, particularly a residue at position 2, can affect the rate of Nt-arginylation by R-transferase and thereby the rate of degradation of a substrate protein. We also show that the four major isoforms of mouse R-transferase have similar Nt-arginylation specificities in vitro, contrary to the claim about the specificity of some Ate1 isoforms for N-terminal Cys. In addition, we found no evidence for a significant activity of the Ate1 R-transferase toward previously invoked non-canonical N-terminal or internal amino acid residues. Together, our results raise technical concerns about earlier studies that invoked non-canonical arginylation specificities of Ate1.The N-end rule pathway is a set of intracellular proteolytic systems whose unifying feature is the ability to recognize and polyubiquitylate proteins containing N-terminal (Nt) 2 degradation signals called N-degrons, thereby causing the processive degradation of these proteins by the proteasome (Fig. 1, A and B) (1-13). Recognition components of the N-end rule pathway are called N-recognins. In eukaryotes, N-recognins are E3 ubiquitin (Ub) ligases that can target N-degrons. Some N-recognins contain several substrate-binding sites and thereby can recognize (bind to) not only N-degrons but also specific internal (non-N-terminal) degradation signals (Fig. 1A) (14 -18). The main determinant of a protein's N-degron is either an unmodified or chemically modified N-terminal residue. Another determinant of an N-degron is an internal Lys residue(s). It functions as a site of protein polyubiquitylation, is often engaged stochastically (in competition with other "eligible" lysines), and tends to be located in a conformationally disordered region (2,9,19,20). Bacteria also contain the N-end rule pathway, but Ub-independent versions of it (21-26).Regulated degradation of proteins and their natural fragments by the N-end rule pathway has been s...

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confidence: 99%

Analyzing N-terminal Arginylation through the Use of Peptide Arrays and Degradation Assays

Wadas

Piatkov

Brower

et al. 2016

Journal of Biological Chemistry

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“…The complementarity of the two N-end rule pathways should be taken into consideration in studies performed in the absence of NATs; for example, some earlier studies of substrate subcellular localization [2]. The NAT substrates under investigation may shift from Ac/N-end to Arg/N-end rule mediated degradation, thus it should be clarified whether the lack of Nt-acetylation causes loss of membrane localization, or increased degradation, or both.…”

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confidence: 99%

“…In humans and other mammals, Nt-acetylation is catalyzed by six N-terminal acetyltransferases (NATs), NatA-NatF. Numerous studies found functional implications of Nt-acetylation [2], including modulation of subcellular localization and proteinprotein interactions. Hwang and Varshavsky made a breakthrough in this field by showing that an Nt-acetyl group can decrease the half-life of a protein, thereby suggesting a fundamental function of Nt-acetylation [3].…”

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(Hyper)tension release by N-terminal acetylation

Aksnes

Drazic

Arnesen

2015

Trends in Biochemical Sciences

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“…N-terminal acetylation is an irreversible process that typically occurs during protein synthesis and involves the transfer of an acetyl group from acetyl coenzyme A to the α-amino group of a protein's first amino acid, as catalysed by N-terminal acetyltransferases (NATs) 8 . The functional changes induced by N-terminal acetylation can be highly variable but can be broadly categorized into subcellular localization, protein interactions and complex formation, protein folding, and perhaps the most well-known, protein degradation with regard to the N-end rule 9,10,11 . The N-end rule pathway targets proteins for ubiquitin-mediated degradation based on their N-terminal residue and the PTM status of this residue.…”

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Novel IEF Peptide Fractionation Method Reveals a Detailed Profile of N-Terminal Acetylation in Chemotherapy-Responsive and -Resistant Ovarian Cancer Cells

et al. 2016

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Molecular, Cellular, and Physiological Significance of N-Terminal Acetylation

Cited by 96 publications

References 139 publications

Analyzing N-terminal Arginylation through the Use of Peptide Arrays and Degradation Assays

Analyzing N-terminal Arginylation through the Use of Peptide Arrays and Degradation Assays

(Hyper)tension release by N-terminal acetylation

Novel IEF Peptide Fractionation Method Reveals a Detailed Profile of N-Terminal Acetylation in Chemotherapy-Responsive and -Resistant Ovarian Cancer Cells

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