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

Abstract

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. © 2010 IUBMB IUBMB Life, 62(9): 693–702, 2010