Abstract
Exposure to ultraviolet radiation (UVR) is a significant risk factor for age-related cataract, a disease of the human lens and the most prevalent cause of blindness in the world. Cataract pathology involves protein misfolding and aggregation of the primary proteins of the lens, the crystallins. Human γD-crystallin (HγD-Crys) is a major γ-crystallin in the nucleus of the human lens. We report here analysis of UVR-induced damage to HγD-Crys in vitro. Irradiation of solutions of recombinant HγD-Crys with UVA/UVB light produced a rise in solution turbidity due to polymerization of the monomeric crystallins into higher molecular weight aggregates. A significant fraction of this polymerized protein was covalently linked. Photoaggregation of HγD-Crys required oxygen and its rate was protein concentration and UVR dose dependent. To investigate the potential roles of individual tryptophan residues in photoaggregation, triple W:F mutants of HγD-Crys were irradiated. Surprisingly, despite reducing UVR absorbing capacity, multiple W:F HγD-Crys mutant proteins photoaggregated more quickly and extensively than wild type. The results reported here are consistent with previous studies that postulated that an energy transfer mechanism between the highly conserved pairs of tryptophan residues in HγD-Crys could be protective against UVR-induced photodamage.
Highlights
Protein misfolding and aggregation are hallmarks of the pathology of many human diseases [1]
The results reported here are consistent with previous studies that postulated that an energy transfer mechanism between the highly conserved pairs of tryptophan residues in HγD
Tryptophan has the highest specific absorption of protein amino acids at 280 nm, and HγD-Crys’ four highly conserved tryptophan residues contribute 51.3% of its absorptivity, the remaining 48.7% coming from its fourteen tyrosines [42, 43]
Summary
Protein misfolding and aggregation are hallmarks of the pathology of many human diseases [1]. Cataract is the leading cause of blindness in the world, projected to affect 20-30 million people in 2020, primarily the elderly, and is associated with misfolding and aggregation of the lens proteins [2]. Despite the widespread prevalence of cataract, the relative contributions of identified risk factors to cataract have not been determined [3]. One of the several risk factors identified is exposure to ultraviolet radiation. Ultraviolet radiation (UVR) is a ubiquitous environmental hazard for life on. The accumulation of UVR-induced DNA lesions leads to mutations, the obstruction of DNA replication, and, if unaddressed, cell death. Several DNA repair pathways have been identified and characterized that target UVR-induced
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