Effect of Oxidized βB3-Crystallin Peptide on Lens β<sub>L</sub>-Crystallin: Interaction with βB2-Crystallin

Udupa, E. G. Padmanabha; Sharma, K. Krishna

doi:10.1167/iovs.05-0031

Cited by 16 publications

(18 citation statements)

References 45 publications

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“…Based on our earlier study [36] and the data presented here, it appears that binding of the αA-(66-80) peptide to α-crystallin increases the hydrophobicity of the α-crystallin–peptide complex (Figure 3), with a concomitant gain of function, leading to the additional binding of α-, β- and γ-crystallins to form HMW complexes (Figures 2B, 4 and S5) that precipitate rapidly. We believe that the peptide binds to α-crystallin subunits, at multiple sites, as in the case of βA3/A1-(102-117) peptide binding to αB-crystallin [35], to bring about conformational change sufficient to increase the overall hydrophobicity of the complex above that of native protein.…”

Section: Discussionsupporting

confidence: 51%

αA-Crystallin Peptide 66SDRDKFVIFLDVKHF80 Accumulating in Aging Lens Impairs the Function of α-Crystallin and Induces Lens Protein Aggregation

2011

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BackgroundThe eye lens is composed of fiber cells that are filled with α-, β- and γ-crystallins. The primary function of crystallins is to maintain the clarity of the lens through ordered interactions as well as through the chaperone-like function of α-crystallin. With aging, the chaperone function of α-crystallin decreases, with the concomitant accumulation of water-insoluble, light-scattering oligomers and crystallin-derived peptides. The role of crystallin-derived peptides in age-related lens protein aggregation and insolubilization is not understood.Methodology/Principal FindingsWe found that αA-crystallin-derived peptide, 66 SDRDKFVIFLDVKHF 80, which accumulates in the aging lens, can inhibit the chaperone activity of α-crystallin and cause aggregation and precipitation of lens crystallins. Age-related change in the concentration of αA-(66-80) peptide was estimated by mass spectrometry. The interaction of the peptide with native crystallin was studied by multi-angle light scattering and fluorescence methods. High molar ratios of peptide-to-crystallin were favourable for aggregation and precipitation. Time-lapse recordings showed that, in the presence of αA-(66-80) peptide, α-crystallin aggregates and functions as a nucleus for protein aggregation, attracting aggregation of additional α-, β- and γ-crystallins. Additionally, the αA-(66-80) peptide shares the principal properties of amyloid peptides, such as β-sheet structure and fibril formation.Conclusions/SignificanceThese results suggest that crystallin-derived peptides such as αA-(66-80), generated in vivo, can induce age-related lens changes by disrupting the structure and organization of crystallins, leading to their insolubilization. The accumulation of such peptides in aging lenses may explain a novel mechanism for age-related crystallin aggregation and cataractogenesis.

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Section: Discussionsupporting

confidence: 51%

αA-Crystallin Peptide 66SDRDKFVIFLDVKHF80 Accumulating in Aging Lens Impairs the Function of α-Crystallin and Induces Lens Protein Aggregation

2011

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“…In vitro oxidized crystallin peptides were shown in our previous studies to interact with lens crystallins and to influence their aggregation and light scattering (27)(28)(29). The present study investigated whether in vivo found crystallin fragments interact with lens crystallins and produce similar effects on aggregation and light scattering.…”

Section: Groupmentioning

confidence: 85%

“…Although it is hypothesized that cataract develops as a result of the improper interaction of crystallin fragments generated by proteolysis (17), the mechanism by which crystallin fragments initiate or influence the process of lens protein aggregation to form high molecular weight aggregates is not clear. Earlier, we showed that in vitro oxidized crystallin peptides enhance the aggregation of ␤ L -crystallin and ␥-crystallin and also exhibit an anti-chaperonelike property (27)(28)(29). Peptide interactions with lens proteins and the aggregation-facilitating nature of lens peptides may be important in age-related cataract formation, where lens proteins undergo incomplete proteolysis and peptide fragments tend to accumulate.…”

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confidence: 98%

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

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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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“…In support of this hypothesis, it was shown that trypsin digestion of in vitro oxidized b-crystallin generates a peptide that has anti-chaperone activity [185]. The oxidized peptide binding enhanced the aggregation of denaturing bL- and g-crystallins [186, 187]. The potential role of in vivo- generated crystallin fragments in masking the chaperone activity was investigated using both synthetic a-crystallin fragments and crystallin fragments isolated from aged human lenses [36].…”

Section: Role Of Crystallins In Lens Transparency and Lens Opacitymentioning

confidence: 99%

Lens aging: Effects of crystallins

Sharma

Santhoshkumar

2009

Biochimica et Biophysica Acta (BBA) - General Subjects

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280

234

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The primary function of the eye lens is to focus light on the retina. The major proteins in the lensa, b, and g-crystallins-are constantly subjected to age-related changes such as oxidation, deamidation, truncation, glycation, and methylation. Such age-related modifications are cumulative and affect crystallin structure and function. With time, the modified crystallins aggregate, causing the lens to increasingly scatter light on the retina instead of focusing light on it and causing the lens to lose its transparency gradually and become opaque. Age-related lens opacity, or cataract, is the major cause of blindness worldwide. We review deamidation, and glycation that occur in the lenses during aging keeping in mind the structural and functional changes that these modifications bring about in the proteins. In addition, we review proteolysis and discuss recent observations on how crystallin fragments generated in vivo, through their anti-chaperone activity may cause crystallin aggregation in aging lenses. We also review hyperbaric oxygen treatment induced guinea pig and 'humanized' ascorbate transporting mouse models as suitable options for studies on age-related changes in lens proteins.

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Effect of Oxidized βB3-Crystallin Peptide on Lens β_L-Crystallin: Interaction with βB2-Crystallin

Abstract: Oxidized betaB3-peptide interacts with betaB2-crystallin and enhances its aggregation and precipitation. Peptide-induced aggregation and increased hydrophobicity of the lens crystallin at 37 degrees C are relevant to crystallin aggregation in the aging lenses.

Cited by 16 publications

References 45 publications

αA-Crystallin Peptide 66SDRDKFVIFLDVKHF80 Accumulating in Aging Lens Impairs the Function of α-Crystallin and Induces Lens Protein Aggregation

αA-Crystallin Peptide 66SDRDKFVIFLDVKHF80 Accumulating in Aging Lens Impairs the Function of α-Crystallin and Induces Lens Protein Aggregation

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

Lens aging: Effects of crystallins

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Effect of Oxidized βB3-Crystallin Peptide on Lens βL-Crystallin: Interaction with βB2-Crystallin

Abstract: Oxidized betaB3-peptide interacts with betaB2-crystallin and enhances its aggregation and precipitation. Peptide-induced aggregation and increased hydrophobicity of the lens crystallin at 37 degrees C are relevant to crystallin aggregation in the aging lenses.

Cited by 16 publications

References 45 publications

αA-Crystallin Peptide 66SDRDKFVIFLDVKHF80 Accumulating in Aging Lens Impairs the Function of α-Crystallin and Induces Lens Protein Aggregation

αA-Crystallin Peptide 66SDRDKFVIFLDVKHF80 Accumulating in Aging Lens Impairs the Function of α-Crystallin and Induces Lens Protein Aggregation

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

Lens aging: Effects of crystallins

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Effect of Oxidized βB3-Crystallin Peptide on Lens β_L-Crystallin: Interaction with βB2-Crystallin