Aberrant, canavanyl protein formation and the ability to tolerate or utilize L-canavanine

Rosenthal, Gerald A.; Berge, Milan A.; Bleiler, John; Rudd, T. P.

doi:10.1007/bf02143585

Cited by 27 publications

(11 citation statements)

References 20 publications

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“…In addition, we also tested the impact of canavanine on dINSR stability in flies. Incorporation of this non-proteinogenic amino acid leads to aberrantly folded polypeptides and increased proteotoxicity (Dasuri et al., 2011, Rosenthal et al., 1987). Similar to increased oxidative stress, canavanine treatment strongly stabilized dINSR, providing additional support for the correlation between proteotoxic stress and INSR stability (Figure S5E).…”

Section: Resultsmentioning

confidence: 99%

The Ubiquitin Ligase CHIP Integrates Proteostasis and Aging by Regulation of Insulin Receptor Turnover

Tawo

Pokrzywa

Kevei

et al. 2017

Cell

110

149

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SummaryAging is attended by a progressive decline in protein homeostasis (proteostasis), aggravating the risk for protein aggregation diseases. To understand the coordination between proteome imbalance and longevity, we addressed the mechanistic role of the quality-control ubiquitin ligase CHIP, which is a key regulator of proteostasis. We observed that CHIP deficiency leads to increased levels of the insulin receptor (INSR) and reduced lifespan of worms and flies. The membrane-bound INSR regulates the insulin and IGF1 signaling (IIS) pathway and thereby defines metabolism and aging. INSR is a direct target of CHIP, which triggers receptor monoubiquitylation and endocytic-lysosomal turnover to promote longevity. However, upon proteotoxic stress conditions and during aging, CHIP is recruited toward disposal of misfolded proteins, reducing its capacity to degrade the INSR. Our study indicates a competitive relationship between proteostasis and longevity regulation through CHIP-assisted proteolysis, providing a mechanistic concept for understanding the impact of proteome imbalance on aging.

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Section: Resultsmentioning

confidence: 99%

The Ubiquitin Ligase CHIP Integrates Proteostasis and Aging by Regulation of Insulin Receptor Turnover

Tawo

Pokrzywa

Kevei

et al. 2017

Cell

110

149

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“…jack bean ( Canavalia ensiformis ), can discriminate between l ‐arginine and its analogue is indirect. It relies on the observation that jack bean plants injected with radioactive l ‐canavanine do not incorporate the label into their proteins, compared to soybean plants, which do [30]. In a previous study, ‘somewhat indefinite’ conclusions regarding activation of canavanine by the arginyl‐tRNA synthetase from Canavalia ensiformis [17] were reported.…”

Section: Discussionmentioning

confidence: 99%

“…The low discrimination factor achieved by the soybean enzyme leads to efficient canavanylation of tRNA Arg in vitro and incorporation of this allelochemical into proteins in vivo [30,43]. However, the several hundred‐fold discrimination measured for the jack bean enzyme is considerably lower than the factor of 10 4 normally expected from systems that rely on an active proofreading process to correct misrecognized substrates [8].…”

Section: Discussionmentioning

confidence: 99%

Amino acid discrimination by arginyl‐tRNA synthetases as revealed by an examination of natural specificity variants

Igloi

Schiefermayr

2009

The FEBS Journal

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l‐Canavanine occurs as a toxic non‐protein amino acid in more than 1500 leguminous plants. One mechanism of its toxicity is its incorporation into proteins, replacing l‐arginine and giving rise to functionally aberrant polypeptides. A comparison between the recombinant arginyl‐tRNA synthetases from a canavanine producer (jack bean) and from a related non‐producer (soybean) provided an opportunity to study the mechanism that has evolved to discriminate successfully between the proteinogenic amino acid and its non‐protein analogue. In contrast to the enzyme from jack bean, the soybean enzyme effectively produced canavanyl‐tRNAArg when using RNA transcribed from the jack bean tRNAACG gene. The corresponding kcat/KM values gave a discrimination factor of 485 for the jack bean enzyme. The arginyl‐tRNA synthetase does not possess hydrolytic post‐transfer editing activity. In a heterologous system containing either native Escherichia coli tRNAArg or the modification‐lacking E. coli transcript RNA, efficient discrimination between l‐arginine and l‐canavanine by both plant enzymes (but not by the E. coli arginyl‐tRNA synthetase) occurred. Thus, interaction of structural features of the tRNA with the enzyme plays a significant role in determining the accuracy of tRNA arginylation. Of the potential amino acid substrates tested, apart from l‐canavanine, only l‐thioarginine was active in aminoacylation. As it is an equally good substrate for the arginyl‐tRNA synthetase from both plants, it is concluded that the higher discriminatory power of the jack bean enzyme towards l‐canavanine does not necessarily provide increased protection against analogues in general, but appears to have evolved specifically to avoid auto‐toxicity.

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“…There is increasing evidence that structurally aberrant canavanyl proteins exhibit impaired function [4], and this deficiency may be the most important basis for canavanine's antimetabolic properties in insects [4,5].…”

Section: Introductionmentioning

confidence: 99%

“…L-Canavanine, a potentially toxic nonprotein amino acid of leguminous plants [1,2] is readily assimilated into de novo synthesized proteins by organisms sensitive to this arginine analog [3]. There is increasing evidence that structurally aberrant canavanyl proteins exhibit impaired function [4], and this deficiency may be the most important basis for canavanine's antimetabolic properties in insects [4,5].…”

Section: Introductionmentioning

confidence: 99%

Degradation of aberrant proteins by larval tobacco hornworm, Manduca sexta L. (Sphingidae)

Rosenthal

Dahlman

1988

Arch Insect Biochem Physiol

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The tobacco hornworm Manduca sexta (Sphingidae) readily incorporates Lcanavanine, the L-Z-amino-4-(guanidinooxy)butyric acid structural analog of L-arginine, into newly synthesized proteins. As a result, the developing fifthinstar larva produces structurally aberrant canavanyl proteins that can exhibit severely impaired function. This situation is exacerbated by canavanine's ability to stimulate de novo protein synthesis. M. sexta larvae can respond to anomalous protein production by degrading canavanyl proteins nearly five times faster than normal proteins. The proteases of this insect can distinguish between normal and anomalous proteins and thereby avoid destruction of essential macromolecules. Aberrant protein degradative activity is not dependent upon de novo protein synthesis induced by canavanyl proteins.The fat body appears to be the source of proteases that degrade aberrant proteins; degradation is curtailed in the presence of sulfhydryl protease inhibitors as well as inhibitors of trypsin-like activity.

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Aberrant, canavanyl protein formation and the ability to tolerate or utilize L-canavanine

Cited by 27 publications

References 20 publications

The Ubiquitin Ligase CHIP Integrates Proteostasis and Aging by Regulation of Insulin Receptor Turnover

The Ubiquitin Ligase CHIP Integrates Proteostasis and Aging by Regulation of Insulin Receptor Turnover

Amino acid discrimination by arginyl‐tRNA synthetases as revealed by an examination of natural specificity variants

Degradation of aberrant proteins by larval tobacco hornworm, Manduca sexta L. (Sphingidae)

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