Importance of Eye Lens α-Crystallin Heteropolymer with 3:1 αA to αB Ratio: Stability, Aggregation, and Modifications

Chaperone-like activity (CLA) of alpha-crystallin is essential not only for the maintenance of eye lens transparency but also in the biology of other tissues. Eye lens alpha-crystallin is a heteropolymer composed of two homologous subunits, alpha A and alpha B, and in most vertebrates they are present in a ratio of 3:1. The structural and functional significance of this specific ratio of alpha-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 alpha B-crystallin has greater CLA, under stress conditions such as elevated temperatures alpha-crystallin heteropolymer with 3:1 alpha A to alpha B ratio displayed higher CLA (Srinivas et al., Biochem. J., 2008, 414, 453 460). Herein, we provide a rationale for the existence of alpha-crystallin heteropolymer with 3:1 alpha A to alpha B ratio in terms of structural stability, aggregation pattern, and susceptibility to posttranslational modifications that could explain the importance of the heteropolymer of alpha-crystallin in the eye lens. We demonstrate that alpha A-crystallin is not only more stable but also imparts stability to the heteropolymer by preventing the aggregation of alpha B-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 alpha A subunit is substantiated by using a heteropolymer with mutant (F71L) alpha A-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. (C) 2010 IUBMB IUBMB Life, 62(9): 693-702, 2010