Molecular wear and tear leads to terminal marking and the unstable isoforms of aging

Gracy, Robert W.; Talent, John M.; Zvaigzne, Anita I.

doi:10.1002/(sici)1097-010x(199809/10)282:1/2<18::aid-jez5>3.0.co;2-q

Cited by 41 publications

(19 citation statements)

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“…Finally, analysis of protein function within protein complexes revealed that catalytic subunits turnover faster than their regulatory counterparts (Figure 2D), suggesting that their direct involvement in enzymatic reactions may cause faster attrition and thus require faster replacement (Gracy et al, 1998). To experimentally test that proteins have faster turnover when are actively used, we conducted two experiments in which we tuned protein activity in a pathway-specific manner and measured changes in turnover rates.…”

Section: Resultsmentioning

confidence: 99%

“…While an association between protein activity and turnover had not been suggested on previous proteomic studies, protein-centric studies had linked protein activity to faster attrition and turnover rates in diverse enzyme families. These studies suggest a mechanism in which catalysis and ligand binding cause conformational changes that promote protein modifications (deamidation, oxidation and/or ubiquitination) that destabilize the protein (Goldberg and Boches, 1982; Gracy et al, 1998; Harris et al, 1999). …”

Section: Discussionmentioning

confidence: 99%

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Determinants and Regulation of Protein Turnover in Yeast

2017

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SUMMARY Protein turnover maintains the recycling needs of the proteome and its malfunction has been linked to aging and age-related diseases. However, not all proteins turnover equally and the factors that contribute to accelerate or slow down turnover are mostly unknown. We measured turnover rates for 3,160 proteins in exponentially growing yeast and analyzed their dependence on physical, functional, and genetic properties. We found that functional characteristics including protein localization, complex membership, and connectivity, have greater effect on turnover than sequence elements. We also found that protein turnover and mRNA turnover are correlated. Analysis under nutrient perturbation and osmotic stress revealed that protein turnover highly depends on cellular state, and is faster when proteins are being actively used. Finally, stress-induced changes in protein and transcript abundance correlated with changes in protein turnover. This study provides a resource of protein turnover rates and principles to understand the recycling needs of the proteome under basal conditions and perturbation.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Determinants and Regulation of Protein Turnover in Yeast

2017

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“…About 30% of cytosolic proteins contain a KFERQ-motif, suggesting that, in theory, this would be the subset of proteins degraded through CMA during mild oxidative stress ( Figure 1A). However, a very intriguing idea proposed by Gracy et al, 1998 is that some amino acid modifications, such as deamidation and oxidation, could result in the generation of KFERQ-like containing motifs in proteins previously lacking this sequence. As other targeting motifs, the KFERQ-like motif is degenerate, resulting from the combination of a basic, a hydrophobic and an acid residue with a fourth basic or hydrophobic residue, flanked on either side by a glutamine.…”

Section: Discussionmentioning

confidence: 99%

Activation of Chaperone-mediated Autophagy during Oxidative Stress

Kiffin

Christian

Knecht

et al. 2004

MBoC

556

524

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Oxidatively damaged proteins accumulate with age in almost all cell types and tissues. The activity of chaperonemediated autophagy (CMA), a selective pathway for the degradation of cytosolic proteins in lysosomes, decreases with age. We have analyzed the possible participation of CMA in the removal of oxidized proteins in rat liver and cultured mouse fibroblasts. Added to the fact that CMA substrates, when oxidized, are more efficiently internalized into lysosomes, we have found a constitutive activation of CMA during oxidative stress. Oxidation-induced activation of CMA correlates with higher levels of several components of the lysosomal translocation complex, but in particular of the lumenal chaperone, required for substrate uptake, and of the lysosomal membrane protein (lamp) type 2a, previously identified as a receptor for this pathway. In contrast with the well characterized mechanism of CMA activation during nutritional stress, which does not require de novo synthesis of the receptor, oxidation-induced activation of CMA is attained through transcriptional up-regulation of lamp2a. We conclude that CMA is activated during oxidative stress and that the higher activity of this pathway under these conditions, along with the higher susceptibility of the oxidized proteins to be taken up by lysosomes, both contribute to the efficient removal of oxidized proteins. INTRODUCTIONAccumulation of oxidized protein is a common feature of aged cells (Dunlop et al., 2002;Grune et al., 2001Grune et al., , 2002bStadtman, 2001). Many physiological and pathological processes lead to the generation of free radicals and consequent damage of intracellular components, including proteins. In most of these oxidative events, damaged proteins are removed from the cell through degradation by proteases (Dunlop et al., 2002). The activity of different intracellular proteolytic systems decreases with age (Terman, 1995;Cuervo and Dice, 1998a;Friguet et al., 2000;Carrard et al., 2002;Donati et al., 2001;Merker et al., 2001;Friguet, 2002;Keller et al., 2002;Ward, 2002), and this impaired activity is considered responsible for the deficient removal of oxidized proteins in old organisms (Grune, 2000;Merker and Grune, 2000;Dunlop et al., 2002;Szweda et al., 2002).The susceptibility of oxidized proteins to proteases changes with the duration and degree of oxidative damage (Dunlop et al., 2002;Mehlhase and Grune, 2002). Thus, mild oxidation induces partial protein unfolding and facilitates proteolytic cleavage (Grune et al., 1995. However, persistent or extensive oxidative damage usually promotes protein aggregation, due to the exposure of patches of hydrophobic amino acids. Once a protein aggregates, it becomes less susceptible to proteolytic cleavage (Hoff et al., 1993;Davies, 2001;Demasi and Davies, 2003). Kinetics of degradation of oxidized proteins in vitro have been analyzed using different types of proteases (Merker and Grune, 2000;Dunlop et al., 2002;Szweda et al., 2002). One of the most extensively analyzed protease in this respect has be...

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“…However, taking into account that the CMA-targeting motif is not sequence-linked, but it depends primarily on the physical properties of the constituent amino acids, it has been proposed that oxidation could convert a non-targeting motif into a CMA-targeting motif by modifying one or more of the amino acid residues (Gracy et al, 1998). Experimental evidence supporting this possibility is still missing.…”

Section: Cma and Oxidative Stressmentioning

confidence: 99%

Autophagy as a cell-repair mechanism: Activation of chaperone-mediated autophagy during oxidative stress

Kaushik

Cuervo

2006

Molecular Aspects of Medicine

134

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Proper removal of oxidized proteins is an important determinant of success when evaluating the ability of cells to handle oxidative stress. The ubiquitin/proteasome system has been considered the main responsible mechanism for the removal of oxidized proteins, as it can discriminate between normal and altered proteins, and selectively target the last ones for degradation. A possible role for lysosomes, the other major intracellular proteolytic system, in the removal of oxidized proteins has been often refused, mostly on the basis of the lack of selectivity of this system. Although most of the degradation of intracellular components in lysosomes (autophagy) takes place through "in bulk" sequestration of complete cytosolic regions, selective targeting of proteins to lysosomes for their degradation is also possible via what is known as chaperone-mediated autophagy (CMA). In this work, we review recent evidence supporting the participation of CMA in the clearance of oxidized proteins in the forefront of the cellular response to oxidative stress. The consequences of an impairment in CMA activity, observed during aging and in some age-related disorders, are also discussed.

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Molecular wear and tear leads to terminal marking and the unstable isoforms of aging

Cited by 41 publications

References 50 publications

Determinants and Regulation of Protein Turnover in Yeast

Determinants and Regulation of Protein Turnover in Yeast

Activation of Chaperone-mediated Autophagy during Oxidative Stress

Autophagy as a cell-repair mechanism: Activation of chaperone-mediated autophagy during oxidative stress

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