Ageing and vision: structure, stability and function of lens crystallins.
ABSTRACT 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.
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ABSTRACT: In 2011, the International Commission on Radiological Protection issued a statement on tissue reactions (formerly termed non-stochastic or deterministic effects) to recommend lowering the threshold for cataracts and the occupational equivalent dose limit for the crystalline lens of the eye. Furthermore, this statement was the first to list circulatory disease (cardiovascular and cerebrovascular disease) as a health hazard of radiation exposure and to assign its threshold for the heart and brain. These changes have stimulated various discussions and may have impacts on some radiation workers, such as those in the medical sector. This paper considers emerging issues associated with cataracts and cardiovascular disease. For cataracts, topics dealt with herein include (i) the progressive nature, stochastic nature, target cells and trigger events of lens opacification, (ii) roles of lens protein denaturation, oxidative stress, calcium ions, tumor suppressors and DNA repair factors in cataractogenesis, (iii) dose rate effect, radiation weighting factor, and classification systems for cataracts, and (iv) estimation of the lens dose in clinical settings. Topics for cardiovascular disease include experimental animal models, relevant surrogate markers, latency period, target tissues, and roles of inflammation and cellular senescence. Future research needs are also discussed.Journal of Radiation Research 05/2014; · 1.45 Impact Factor
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ABSTRACT: Abstract Age-related cataract formation is marked by the progressive aggregation of lens proteins. The formation of protein aggregates in the aging lens has been shown to correlate with the progressive accumulation of a range of post-translational crystallin modifications, including oxidation, deamidation, racemization, methylation, acetylation, N- and C-terminal truncations and low molecular weight (LMW) crystallin fragments. We found that an αA-crystallin-derived peptide, αA66-80 (1.8 kDa), is a prominent LMW peptide concentrated in water-insoluble fractions of the aging lens. The peptide has amyloid-like properties and preferentially insolubilizes α-crystallin from lens-soluble fractions. It binds at multiple sites and forms a hydrophobically driven non-covalent complex with α-crystallin to induce α-crystallin aggregation. To define the specific role of the αA66-80 peptide in age-related protein aggregation and cataract formation, it is important to understand the mechanisms by which this peptide acts. We used scanning proline mutagenesis to identify which particular sequences of the peptide drive it to form amyloid-like fibrils and induce α-crystallin aggregation. The secondary structure and the aggregate morphology of the peptides were determined using circular dichroism and transmission electron microscopy, respectively. Peptides were also tested for their ability to induce α-crystallin aggregation. We found that proline replacement of any residue in the sequence FVIFLDV, which corresponds to residues 71-77, led to an absence of both fibril formation and α-crystallin aggregation. The apparently critical role of 71-77 residues in αA66-80 explains their significance in the self-assembly processes of the peptide and further provide insights into the mechanism of peptide-induced aggregation. Our findings may have applications in the design of peptide aggregation inhibitors.Amyloid: the international journal of experimental and clinical investigation: the official journal of the International Society of Amyloidosis 02/2014; · 2.51 Impact Factor
- Progress in Biophysics and Molecular Biology 05/2014; · 2.91 Impact Factor