Post-translational arginylation of ornithine decarboxylase from rat hepatocytes

Kopitz, Jürgen; Rist, Beate; Bohley, Peter

doi:10.1042/bj2670343

Cited by 40 publications

(20 citation statements)

References 38 publications

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“…The N-terminal addition of arginine is a posttranslational modification of proteins that has been postulated to result in a rapid degradation of proteins by the ubiquitin pathway (Ferber and Ciechanover, 1987) or in a ubiquitinindependent way (Kopitz et al, 1990;Hayashi and Murakami, 1995). In the present study using hyperthermia as stress model, we found an increase in the in vitro [ 14 C]-arginine incorporation at 3 hr of recovery, which is accompanied by the characteristic increase of the stress marker hsp70 (Schlesinger, 1994).…”

Section: Discussionmentioning

confidence: 47%

“…However, arginylation is not always the signal for the binding of ubiquitin. One welldocumented exception is the enzyme ornithine decarboxylase (ODC), which is posttranslationally arginylated (Kopitz et al, 1990) and is specifically degraded in a ubiquitin-independent way (Hayashi and Murakami, 1995). On the other hand, it has being reported that angiotensine II loses up to 80% of its activity when it is arginylated (Soffer, 1975), which indicates that there may be other functions for this posttranslational modification.…”

Section: Introductionmentioning

confidence: 96%

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Posttranslational arginylation of soluble rat brain proteins after whole body hyperthermia

et al. 1999

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We have previously reported the posttranslational addition of [14C]-arginine in the N-terminus of several soluble rat brain proteins. One of these proteins was identified as the microtubule-associated protein, the stable tubule only polypeptide (STOP). However, despite the fact that the biological significance of arginylation is not completely understood, some evidence associates it with proteolysis via the ubiquitin pathway. Since this degradative via is exacerbated as a response to stress, we studied in vitro the posttranslational [14C]-arginylation of cytosolic brain proteins of rats subjected to hyperthermia in vivo. Immediately after subjecting the animals to hyperthermia, a minor reduction (16%) in the acceptor capacity of [14C]-arginine into proteins was observed in comparison with animals maintained at 28 degrees C. However, in the animals allowed to recover for 3 h, an increase (46%) in the arginylation was observed concomitantly with a significant accumulation of the heat shock protein (70 kDa; hsp 70) when compared to the control animals. These findings suggest that the posttranslational arginylation of proteins participate in the heat shock response. The STOP protein of the soluble brain fraction of control animals, which in Western blot appears as a doublet band (125 and 130 kDa, respectively), is seen, after the hyperthermic treatment, as a single band of 125 kDa. The amount of 125 kDa protein, as well as the in vitro incorporation of [14C]-arginine, increases after hyperthermia in comparison with control animals. Following hyperthermic treatment, we observed a decrease in the amount of in vivo [35S]-methionine-labeled brain proteins. We speculate that, as observed for STOP protein, the increase in the degradation of protein that occurs in hyperthermia, would produce an increase in the amount of arginine acceptor proteins.

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Section: Discussionmentioning

confidence: 47%

Section: Introductionmentioning

confidence: 96%

Posttranslational arginylation of soluble rat brain proteins after whole body hyperthermia

et al. 1999

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“…Tri-peptide Glu-Val-Phe can inhibit arginylation by acting as a substrate mimic that saturates ATE1, making it unavailable for arginyl transfer to its natural targets [8], however this peptide acts only at high concentrations and is not very effective in biological assays [8, 9]. Bifunctional phenylarsenoxide was shown to inhibit ATE1 through interaction with reactive Cys residues in the critical positions within the molecule [10], however this inhibitor is not only toxic but relatively non-specific, since it exerts its effect similarly on all proteins whose activity is dependent on reactive Cys groups.…”

Section: Introductionmentioning

confidence: 99%

Small molecule inhibitors of arginyltransferase regulate arginylation-dependent protein degradation, cell motility, and angiogenesis

Saha

Wang

Buckley

et al. 2012

Biochemical Pharmacology

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Posttranslational arginylation mediated by arginyltransferase (ATE1) is an emerging major regulator of embryogenesis and cell physiology. Impairments of ATE1 are implicated in congenital heart defects, obesity, cancer, and neurodegeneration making this enzyme an important therapeutic target, whose potential has been virtually unexplored. Here we report the development of a biochemical assay for identification of small molecule inhibitors of ATE1 and application of this assay to screen a library of 3280 compounds. Our screen identified two compounds which specifically affect ATE1-regulated processes in vivo, including tannic acid, which has been previously shown to inhibit protein degradation and angiogenesis and to act as a therapeutic agent in heart disease and cancer. Our data suggest that these actions of tannic acid are mediated by its direct effect on ATE1, which regulates protein degradation and angiogenesis in vivo.

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“…Recently, Kopitz et al (19) reported that a short-lived enzyme, ornithine decarboxylase, could be arginylated in extracts from rat hepatocytes by an endogenous Arg-tRNAprotein transferase, and furthermore, that the in vivo degradation of ornithine decarboxylase in hepatocytes could be partially suppressed by the tripeptide Glu-Val-Phe, a substrate of Arg-tRNA-protein transferase. While still indirect, these results suggest that ornithine decarboxylase is a substrate of the N-end rule pathway that bears a secondary or a tertiary destabilizing amino-terminal residue.…”

Section: Od6wmentioning

confidence: 99%

Inhibition of the N-end rule pathway in living cells.

Baker

Varshavsky

1991

Proc. Natl. Acad. Sci. U.S.A.

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The N-end rule relates the metabolic stability of a protein to the identity of its amino-terminal residue.Previous work, using amino acid derivatives such as dipeptides to inhibit N-end rule-mediated protein degradation in an extract from mammalian reticulocytes, has demonstrated the existence of specific N-end-recogniing proteins in this in vitro system. We now show that these nontoxic amino acid derivatives, when added to growing cells of the yeast Saccharomyces cerevisiae, are able to inhibit the degradation of proteins by the N-end rule pathway in vivo. Moreover, this inhibition is shown to be selective for the two distinct classes of destabilizing amino-terminal residues in substrates of the N-end rule pathway.At least some proteins are short-lived in vivo because they contain sequences (degradation signals) that make these proteins substrates of specific proteolytic pathways. An essential component ofone degradation signal is the protein's amino-terminal residue (1). This degradation signal is manifested as the N-end rule, which relates the metabolic stability of a protein to the identity of its amino-terminal residue (1-8).Similar but distinct versions of the N-end rule operate in mammals (2, 5, 8-11), yeast (1-5, 7, 12), and bacteria (J. Tobias and A.V., unpublished results). The N-end rule-based degradation signal in eukaryotes comprises a destabilizing amino-terminal residue and a specific internal lysine residue (1)(2)(3)(4)(5)8). The set of destabilizing amino-terminal residues is organized hierarchically. Specifically, amino-terminal Asp and Glu (and Cys in mammalian reticulocytes) are secondary destabilizing residues in that they are destabilizing through their ability to be conjugated to Arg, aprimary destabilizing residue (1, 5-7). Amino-terminal Asn and Gln are tertiary destabilizing residues in that they are destabilizing through their ability to be converted, via selective deamidation, into the secondary destabilizing residues Asp and Glu (5).Previous work (1) has predicted the existence of "N-endrecognizing" proteins that select potential proteolytic substrates by binding to their amino-terminal residues. N-endrecognizing proteins have recently been detected in an in vitro ubiquitin-dependent proteolytic system derived from mammalian reticulocytes, and identified as the E3 proteins that were previously shown to bind proteolytic substrates prior to their ubiquitination by a subset of ubiquitinconjugating (E2) enzymes (5, 9, 10, 12, 13). Three distinct types of E3 activity have been detected in the reticulocytederived in vitro system by using assays based on selective inhibition of the degradation of specific proteins by dipeptides bearing different destabilizing amino-terminal residues. The type I E3 activity is specific for the positively charged destabilizing amino-terminal residues Arg, Lys, and His (5, 9). The type II activity is specific for the bulky hydrophobic destabilizing amino-terminal residues Phe, Trp, Tyr, and Leu (and lie in yeast) (5, 9). The type III activity is specif...

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Post-translational arginylation of ornithine decarboxylase from rat hepatocytes

Cited by 40 publications

References 38 publications

Posttranslational arginylation of soluble rat brain proteins after whole body hyperthermia

Posttranslational arginylation of soluble rat brain proteins after whole body hyperthermia

Small molecule inhibitors of arginyltransferase regulate arginylation-dependent protein degradation, cell motility, and angiogenesis

Inhibition of the N-end rule pathway in living cells.

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