Importance of eye lens α-crystallin heteropolymer with 3:1 αA to αB ratio: stability, aggregation, and modifications

Chaperone-like activity (CLA) of α-crystallin is essential not only for the maintenance of eye lens transparency but also in the biology of other tissues. Eye lens α-crystallin is a heteropolymer composed of two homologous subunits, αA and αB, and in most vertebrates they are present in a ratio of 3:1. The structural and functional significance of this specific ratio of α-crystallin subunits is of considerable interest in understanding its role in the eye lens transparency. Previously, we have shown that although at physiologically relevant conditions αB-crystallin has greater CLA, under stress conditions such as elevated temperatures α-crystallin heteropolymer with 3:1 αA to αB ratio displayed higher CLA (Srinivas et al., Biochem. J., 2008, 414, 453 - 460). Herein, we provide a rationale for the existence of α-crystallin heteropolymer with 3:1 αA to αB ratio in terms of structural stability, aggregation pattern, and susceptibility to posttranslational modifications that could explain the importance of the heteropolymer of α-crystallin in the eye lens. We demonstrate that αA-crystallin is not only more stable but also imparts stability to the heteropolymer by preventing the aggregation of αB-crystallin at higher temperatures by using differential scanning calorimetry, size-exclusion chromatography, and denaturant-induced unfolding methods. Further, the physiological significance of heteropolymer with higher proportion of αA subunit is substantiated by using a heteropolymer with mutant (F71L) αA-crystallin and the susceptibility of 3:1 heteropolymer to glycation-induced modifications. Thus, the existence of 3:1 heteropolymer might be vital for the eye lens transparency under diverse conditions to prevent cataract.