Ageing and vision: Structure, stability and function of lens crystallins
Institute of Biophysics and physical Biochemistry, Universität Regensburg, Ratisbon, Bavaria, Germany Progress in Biophysics and Molecular Biology
(Impact Factor: 2.27).
12/2004; 86(3):407-85. DOI: 10.1016/j.pbiomolbio.2003.11.012
The alpha-, beta- and gamma-crystallins are the major protein components of the vertebrate eye lens, alpha-crystallin as a molecular chaperone as well as a structural protein, beta- and gamma-crystallins as structural proteins. For the lens to be able to retain life-long transparency in the absence of protein turnover, the crystallins must meet not only the requirement of solubility associated with high cellular concentration but that of longevity as well. For proteins, longevity is commonly assumed to be correlated with long-term retention of native structure, which in turn can be due to inherent thermodynamic stability, efficient capture and refolding of non-native protein by chaperones, or a combination of both. Understanding how the specific interactions that confer intrinsic stability of the protein fold are combined with the stabilizing effect of protein assembly, and how the non-specific interactions and associations of the assemblies enable the generation of highly concentrated solutions, is thus of importance to understand the loss of transparency of the lens with age. Post-translational modification can have a major effect on protein stability but an emerging theme of the few studies of the effect of post-translational modification of the crystallins is one of solubility and assembly. Here we review the structure, assembly, interactions, stability and post-translational modifications of the crystallins, not only in isolation but also as part of a multi-component system. The available data are discussed in the context of the establishment, the maintenance and finally, with age, the loss of transparency of the lens. Understanding the structural basis of protein stability and interactions in the healthy eye lens is the route to solve the enormous medical and economical problem of cataract.
Available from: Luciano Saso
- "Several factors including genetic mutations, accumulation of post-translational modifications, environmental stresses and a number of diseases could interrupt the native structure of α-Cry and subsequently compromise its chaperone function. Therefore, under the above mentioned conditions the formation of insoluble protein aggregates in the lenticular tissues eventually leads to blurred vision and cataract incidence   . "
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ABSTRACT: The oxidative stress in eye lens which occurs during inflammation and under chronic hyperglycemia has been already indicated in the pathogenesis of cataract disorders. The aim of this study was to examine structural and functional properties of R12C mutant αA-Crystallin (αA-Cry) in the presence of hydrogen peroxide. The study was done using different spectroscopic techniques and gel mobility shift assay. According to results of our study, H2O2 oxidation strongly compromises the chaperone function of the R12C mutant but not of wild-type αA-Cry. Also, it affects the structural properties of both wild-type and mutant proteins, albeit to different degree. The H2O2 exposure promotes extensive disulfide mediated oligomerization of the R12C mutant but not of the wild-type as revealed by gel mobility shift assay and dynamic light scattering. Moreover, in the presence of hydrogen peroxide, the mutant protein demonstrates severe conformational and protease instability and increased amyloidogenic propensity. The obtained results suggest that incubation of R12C mutant recombinant αA-Cry with hydrogen peroxide accelerates the molecular events which have been already implicated in the pathomechanism of cataract development. Taken together these results suggest that individuals carrying the R12C mutation are at an increased risk to develop early-onset cataract under condition of oxidative stress.
- "The age-related changes affect the interactions of α-, β-, and γcrystallin that play a role in the modulation of lens clarity. The αAcrystallin subunit is more prevalent than the αB subunit, in a ratio of 3:1 to 2:1  . The primary structures of αA-and αB-crystallin subunits exhibit a high degree of sequence similarity between them and to small heat shock proteins (sHSPs) because of the conserved α-crystallin domain in these proteins . "
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ABSTRACT: The demonstration of chaperone-like activity in peptides (mini-chaperones) derived from α-crystallin's chaperone region has generated significant interest in exploring the therapeutic potential of peptide chaperones in diseases of protein aggregation. Recent studies in experimental animals show that mini-chaperones could reach intended targets and alter the disease phenotype. Although mini-chaperones show potential benefits against protein aggregation diseases, they do tend to form aggregates on storage. There is thus a need to fine-tune peptide chaperones to increase their solubility, pharmacokinetics and biological efficacy.
This review summarizes the properties and the potential therapeutic roles of mini-chaperones in protein aggregation diseases and highlights some of the refinements needed to increase the stability and biological efficacy of mini-chaperones while maintaining or enhancing their chaperone-like activity against precipitation of unfolding proteins.
Mini-chaperones suppress the aggregation of proteins, block amyloid fibril formation, stabilize mutant proteins, sequester metal ions and exhibit antiapoptotic properties. Much work must be done to fine-tune mini-chaperones and increase their stability and biological efficacy. Peptide chaperones could have a great therapeutic value in diseases associated with protein aggregation and apoptosis.
Accumulation of misfolded proteins is a primary cause for many age-related diseases, including cataract, macular degeneration and various neurological diseases. Stabilization of native proteins is a logical therapeutic approach for such diseases. Mini- chaperones, with their inherent antiaggregation and antiapoptotic properties, may represent an effective therapeutic molecule to prevent the cascade of protein conformational disorders. Future studies will further uncover the therapeutic potential of mini-chaperones.
Copyright © 2015. Published by Elsevier B.V.
Available from: Jean-Christophe Nebel
- "In the terminal step of differentiation the nucleus become pyknotic and the cell enters proteostasis, retaining the requisite concentration and mixture of crystallins359. The lens, therefore, retains within its refractive index gradient, a chronology of ageing with newly synthesised proteins in peripheral fibre cells and proteins produced during gestation in its centre evolved for longevity and for maintenance of optical function378. "
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ABSTRACT: The crystallins have relatively high refractive increments compared to other proteins. The Greek key motif in βγ-crystallins was compared with that in other proteins, using predictive analysis from a protein database, to see whether this may be related to the refractive increment. Crystallins with Greek keys motifs have significantly higher refractive increments and more salt bridges than other proteins with Greek key domains. Specific amino acid substitutions: lysine and glutamic acid residues are replaced by arginine and aspartic acid, respectively as refractive increment increases. These trends are also seen in S-crystallins suggesting that the primary sequence of crystallins may be specifically enriched with amino acids with appropriate values of refractive increment to meet optical requirements. Comparison of crystallins from five species: two aquatic and three terrestrial shows that the lysine/arginine correlation with refractive increment occurs in all species investigated. This may be linked with formation and maintenance of salt bridges.
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