Covalent modification reactions are marking steps in protein turnover

Stadtman, Earl R.

doi:10.1021/bi00479a001

Cited by 203 publications

(84 citation statements)

References 112 publications

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“…Protein Degradation by the Proteasome-Post-translational modifications decrease the half-life of a range of different proteins by enhancing their rates of degradation, suggesting that they mark proteins for degradation (12). It is generally believed that the degradative mechanisms that enhance protein turnover are important to the maintenance of cellular function.…”

Section: Discussionmentioning

confidence: 99%

“…The dissociation of large protein fragments from the proteasome suggests the opportunity for other cellular protease systems to also be involved in the degradation of cellular proteins (12,54). However, in a number of cases the proteasome has been shown to degrade proteins in a processive manner, involving the release of relatively homogeneous population of small peptides (55)(56)(57).…”

Section: Discussionmentioning

confidence: 99%

“…In contrast, the 20 S proteasome core selectively degrades a range of different oxidized proteins in an ATP-independent manner and has been suggested to represent the primary mechanism in the rapid removal of oxidized proteins after oxidative stress (7)(8)(9)(10)(11). The signal for recognition and degradation of oxidized proteins by the 20 S proteasome is unknown but has been suggested to involve (i) exposure of hydrophobic surfaces after oxidative modification, (ii) recognition of molecular "markers" associated with the oxidative modification of specific amino acid side chains, and (iii) increases in the conformational flexibility of oxidized proteins (12)(13)(14)(15)(16).…”

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confidence: 99%

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Selective Degradation of Oxidized Calmodulin by the 20 S Proteasome

Ferrington

Sun

Murray

et al. 2001

Journal of Biological Chemistry

115

184

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We have investigated the mechanisms that target oxidized calmodulin for degradation by the proteasome. After methionine oxidation within calmodulin, rates of degradation by the 20 S proteasome are substantially enhanced. Mass spectrometry was used to identify the time course of the proteolytic fragments released from the proteasome. Oxidized calmodulin is initially degraded into large proteolytic fragments that are released from the proteasome and subsequently degraded into small peptides that vary in size from 6 to 12 amino acids. To investigate the molecular determinants that result in the selective degradation of oxidized calmodulin, we used circular dichroism and fluorescence spectroscopy to assess oxidant-induced structural changes. There is a linear correlation between decreases in secondary structure and the rate of degradation. Calcium binding or the repair of oxidized calmodulin by methionine sulfoxide reductase induces comparable changes in ␣-helical content and rates of degradation. In contrast, alterations in the surface hydrophobicity of oxidized calmodulin do not alter the rate of degradation by the proteasome, indicating that changes in surface hydrophobicity do not necessarily lead to enhanced proteolytic susceptibility. These results suggest that decreases in secondary structure expose proteolytically sensitive sites in oxidized calmodulin that are cleaved by the proteasome in a nonprocessive manner.Critical to the ability of a cell to reestablish cellular homeostasis after a range of different environmental stresses is the removal of oxidatively modified proteins by the proteasome (1, 2). The proteasome represents approximately 1% of the total cellular protein and is present in the cytosol and nuclei of all mammalian cells in two major forms (i.e. the 20 S and 26 S proteasomes) (3). The 20 S proteasome is a 700-kDa complex with a 10 -20-Å-diameter opening into an internal cavity that provides a sequestered environment for proteolysis. The 26 S proteasome is a 2000-kDa complex containing two 19 S regulatory complexes bound to the 20 S multicatalytic core. The 26 S proteasome is responsible for the degradation of the majority of cellular proteins through an ATP-dependent and ubiquitinmediated pathway (4 -6). In contrast, the 20 S proteasome core selectively degrades a range of different oxidized proteins in an ATP-independent manner and has been suggested to represent the primary mechanism in the rapid removal of oxidized proteins after oxidative stress (7-11). The signal for recognition and degradation of oxidized proteins by the 20 S proteasome is unknown but has been suggested to involve (i) exposure of hydrophobic surfaces after oxidative modification, (ii) recognition of molecular "markers" associated with the oxidative modification of specific amino acid side chains, and (iii) increases in the conformational flexibility of oxidized proteins (12-16).To distinguish which signals are involved in targeting an oxidized protein for degradation by the 20 S proteasome, we have investigated the mech...

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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Selective Degradation of Oxidized Calmodulin by the 20 S Proteasome

Ferrington

Sun

Murray

et al. 2001

Journal of Biological Chemistry

115

184

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“…Degradation of lens crystallins by proteolytic enzymes can damage their highly ordered arrangements. An age-related decrease in the levels or activities of proteases could result in the accumulation of modified proteins (21,22). Although a protein oxidation reaction may convert proteins to forms that are more susceptible to proteolytic degradation, the oxidized forms of some proteins not only are resistant to proteolytic degradation but also may inhibit the ability of some proteases to degrade the oxidized forms of other proteins.…”

mentioning

confidence: 99%

Significance of Interactions of Low Molecular Weight Crystallin Fragments in Lens Aging and Cataract Formation

Santhoshkumar

Udupa

Raju

et al. 2008

Journal of Biological Chemistry

110

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Analysis of aged and cataract lenses shows the presence of increased amounts of crystallin fragments in the high molecular weight aggregates of water-soluble and water-insoluble fractions. However, the significance of accumulation and interaction of low molecular weight crystallin fragments in aging and cataract development is not clearly understood. In this study, 23 low molecular mass (<3.5-kDa) peptides in the urea-soluble fractions of young, aged, and aged cataract human lenses were identified by mass spectroscopy. Two peptides, ␣B-(1-18) (MDIAIHHPWIRRPFFPFH) and ␤A3/A1-(59 -74) (SD(N)AYHIERLMSFRPIC), present in aged and cataract lens but not young lens, and a third peptide, ␥S-(167-178) (SPAVQSFRRIVE) present in all three lens groups were synthesized to study the effects of interaction of these peptides with intact ␣-, ␤-, and ␥-crystallins and alcohol dehydrogenase, a protein used in aggregation studies. Interaction of ␣B-(1-18) and ␤A3/A1-(59 -74) peptides increased the scattering of light by ␤-and ␥-crystallin and alcohol dehydrogenase. The ability of ␣-crystallin subunits to function as molecular chaperones was significantly reduced by interaction with ␣B-(1-18) and ␤A3/ A1-(59 -74) peptides, whereas ␥S peptide had no effect on chaperone-like activity of ␣-crystallin. The ␤A3/A1-(59 -74 peptide caused a 5.64-fold increase in ␣B-crystallin oligomeric mass and partial precipitation. Replacing hydrophobic residues in ␣B-(1-18) and ␤A3/A1-(59 -74) peptides abolished their ability to induce crystallin aggregation and light scattering. Our study suggests that interaction of crystallin-derived peptides with intact crystallins could be a key event in age-related protein aggregation in lens and cataractogenesis.

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“…Firstly, the level of oxidatively modified proteins is determined by their turnover, the rates of generation and degradation. It is known that oxidation renders proteins highly susceptible to proteolytic degradation [6,20,31,32]. Secondly, the introduction of carbonyl groups into proteins is dependent on the oxidant stress and the antioxidant capacity in the ELF.…”

Section: Discussionmentioning

confidence: 99%

Oxidized BAL fluid proteins in patients with interstitial lung diseases

Lenz

Costabel²,

Maier³

1996

Eur Respir J

103

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Oxygen-derived free radicals, released by phagocytic cells, have been postulated to contribute to lung tissue damage. We therefore investigated oxidative damage to proteins from bronchoalveolar lavage fluid (BALF) as an indicator of oxidative stress and to assess antioxidant defences in the lungs.We examined BAL fluids from patients with interstitial lung diseases, such as idiopathic pulmonary fibrosis (IPF, nonsmokers (NS) and smokers (S)), sarcoidosis (SARC, nonsmokers), and asbestosis (ASB, ex-smokers (EXS)). The oxidation of BALF proteins is accompanied by the introduction of carbonyl groups into their amino acid side-chains and can be quantitated by labelling these groups with tritiated borohydride.The total lung content of oxidized proteins recovered by bronchoalveolar lavage (BAL) was 0.3±0.07 nmol carbonyl·mL -1 BALF (mean±SEM) in the NS control group (n=9) and tended to be increased, in the asymptomatic S group (n=8; 0.59± 0.14 nmol·mL -1 ). This parameter was significantly elevated both in IPF-NS (n=14; 0.

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Covalent modification reactions are marking steps in protein turnover

Cited by 203 publications

References 112 publications

Selective Degradation of Oxidized Calmodulin by the 20 S Proteasome

Selective Degradation of Oxidized Calmodulin by the 20 S Proteasome

Significance of Interactions of Low Molecular Weight Crystallin Fragments in Lens Aging and Cataract Formation

Oxidized BAL fluid proteins in patients with interstitial lung diseases

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