Age‐dependent deamidation of αB‐crystallin

Groenen, Patricia J.T.A.; Dongen, M.J.P. van; Voorter, Christina E.M.; Bloemendal, H.; Jong, Wilfried W. de

doi:10.1016/0014-5793(93)81113-e

Cited by 48 publications

(28 citation statements)

References 35 publications

(6 reference statements)

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“…[13][14][15][16][17][18][19] When a peptide or protein is deamidated, its molecular weight increases by 0.98 Da at each site. 20 In this project, we first analyzed a tryptic peptide, AVHLPSGG-QYK, derived from cS crystallin that appeared on the basis of LC/MS investigation, to show age-dependent deamidation.…”

Section: Resultsmentioning

confidence: 99%

Age‐dependent deamidation of glutamine residues in human γS crystallin: Deamidation and unstructured regions

2012

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Human aging is associated with the deterioration of long-lived proteins. Gradual cumulative modifications to the life-long proteins of the lens may ultimately be responsible for the pronounced alterations to the optical and physical properties that characterize lenses from older people. cS crystallin, a major human lens protein, is known to undergo several age-dependent changes. Using proteomic techniques, a site of deamidation involving glutamine 92 has been characterized and its time course established. The proportion of deamidation increased from birth to teen-age years and then plateaud. Deamidation at this site increased again in the eighth decade of life. There was no significant difference in the extent of deamidation between cataract and age-matched normal lenses. Gln92 is located in the linker region between the two domains, and the introduction of a negative charge at this site may alter the interaction between the two regions of the protein. Gln170, which is located in another unstructured part of cS crystallin, showed a similar deamidation profile to that of Gln92. As the other Gln residues in b-sheet regions of cS crystallin appear to remain as amides, modification of Gln92 and Gln170 thus conforms to a pattern whereby deamidation is localized to the unstructured regions of long-lived proteins.

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Section: Resultsmentioning

confidence: 99%

Age‐dependent deamidation of glutamine residues in human γS crystallin: Deamidation and unstructured regions

2012

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“…One manner in which proteins can be marked for degradation is via deamidation [155][156][157]. Acting as a "molecular clock" during physiological conditions, there is suggestion that deamidation may also signal proteolysis with pathogenesis [158,159]. Several studies on individual proteins have shown a significant role for protein deamidation in pathogenesis, including the deamidation of Asp 146 in a B-crystalline, which has been significantly correlated with cataractogenesis [158,159].…”

Section: Mitochondrial Signalingmentioning

confidence: 99%

“…Acting as a "molecular clock" during physiological conditions, there is suggestion that deamidation may also signal proteolysis with pathogenesis [158,159]. Several studies on individual proteins have shown a significant role for protein deamidation in pathogenesis, including the deamidation of Asp 146 in a B-crystalline, which has been significantly correlated with cataractogenesis [158,159]. Proteomics has been used to show that deamidated proteins undergo differential modifications with I/R injury, where fragmentation of deamidated myosin light chain 2 (MLC-2) resulted from ROS generation during reperfusion [88], whilst deami-dated a B-crystalline decreased during the preceding ischemia [160], suggesting further differential proteolysis.…”

Section: Mitochondrial Signalingmentioning

confidence: 99%

Mitochondria: A mirror into cellular dysfunction in heart disease

White

Edwards

Cordwell

et al. 2008

Proteomics Clinical Apps

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Cardiovascular (CV) disease is the single most significant cause of morbidity and mortality worldwide. The emerging global impact of CV disease means that the goals of early diagnosis and a wider range of treatment options are now increasingly pertinent. As such, there is a greater need to understand the molecular mechanisms involved and potential targets for intervention. Mitochondrial function is important for physiological maintenance of the cell, and when this function is altered, the cell can begin to suffer. Given the broad range and significant impacts of the cellular processes regulated by the mitochondria, it becomes important to understand the roles of the proteins associated with this organelle. Proteomic investigations of the mitochondria are hampered by the intrinsic properties of the organelle, including hydrophobic mitochondrial membranes; high proportion of basic proteins (pI greater than 8.0); and the relative dynamic range issues of the mitochondria. For these reasons, many proteomic studies investigate the mitochondria as a discrete subproteome. Once this has been achieved, the alterations that result in functional changes with CV disease can be observed. Those alterations that lead to changes in mitochondrial function, signaling and morphology, which have significant implications for the cardiomyocyte in the development of CV disease, are discussed.

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“…Thus, crystallins accumulate modifications due to environmental and metabolic damage during an individual's entire lifetime. This makes the lens an easily accessible tissue to study the effects of post-translational modifications on protein unfolding and aggregation.The major post-translational modifications in lenses are truncation, methylation, oxidation, disulfide bond formation, advanced glycation end-products and deamidation (3)(4)(5)(6)(7)(8)(9)(10)(11)(12). Of these AUTHOR EMAIL ADDRESS lampik@ohsu.edu.…”

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confidence: 99%

Deamidation Alters the Structure and Decreases the Stability of Human Lens βΑ3-Crystallin

et al. 2007

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According to the World Health Organization, cataracts account for half of the blindness in the world, with the majority occurring in developing countries. A cataract is a clouding of the lens of the eye due to light scattering of precipitated lens proteins or aberrant cellular debris. The major proteins in the lens are crystallins and they are extensively deamidated during aging and cataracts. Deamidation has been detected at the domain and monomer interfaces of several crystallins during aging.The purpose of this study was to determine the effects of two potential deamidation sites at the predicted interface of the βA3-crystallin dimer on its structure and stability. The glutamine residues at the reported in vivo deamidation sites of Q180 in the C-terminal domain and at the homologous site Q85 in the N-terminal domain were substituted with glutamic acid residues by site-directed mutagenesis. Far UV and near UV circular dichroism spectroscopy indicated that there were subtle differences in the secondary structure and more notable differences in the tertiary structure of the mutant proteins compared to wild type βA3-crystallin. The Q85E/Q180E mutant also was more susceptible to enzymatic digestion, suggesting increased solvent accessibility. These structural changes in the deamidated mutants led to decreased stability during unfolding in urea and increased precipitation during heat-denaturation. When simulating deamidation at both residues, there was a further decrease in stability and loss of cooperativity. However, multiangle-light scattering and quasielastic light scattering experiments showed that dimer formation was not disrupted, nor did higherorder oligomers form. These results suggest that introducing charges at the predicted domain interface in the βA3 homodimer may contribute to the insolubilization of lens crystallins or favor other, more stable, crystallin subunit interactions.Cataracts account for half of all blindness according to the World Health Organization (1). The greatest incidence is in developing countries. A cataract is opacity within the lens of the eye due to scattering of light by precipitated proteins or by aberrant cellular debris. The major proteins within the lens belong to the α and β/γ-crystallin families. Protein concentrations can reach 400 mg/mL and above in the center of the lens, and it is their ordered packing that is necessary for transparency (2). There is an extremely low rate of turnover of crystallins in differentiated lens cells. Thus, crystallins accumulate modifications due to environmental and metabolic damage during an individual's entire lifetime. This makes the lens an easily accessible tissue to study the effects of post-translational modifications on protein unfolding and aggregation.The major post-translational modifications in lenses are truncation, methylation, oxidation, disulfide bond formation, advanced glycation end-products and deamidation (3)(4)(5)(6)(7)(8)(9)(10)(11)(12). Of these AUTHOR EMAIL ADDRESS lampik@ohsu.edu. NIH Public Access Author M...

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Age‐dependent deamidation of αB‐crystallin

Cited by 48 publications

References 35 publications

Age‐dependent deamidation of glutamine residues in human γS crystallin: Deamidation and unstructured regions

Age‐dependent deamidation of glutamine residues in human γS crystallin: Deamidation and unstructured regions

Mitochondria: A mirror into cellular dysfunction in heart disease

Deamidation Alters the Structure and Decreases the Stability of Human Lens βΑ3-Crystallin

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