Effect of osmolytes and posttranslational modifications on modulating the chaperone function of α-crystallin.

Abstract

Proteins are responsible for a vast majority of various cellular effector processes. α-crystallin is one of the most important proteins in the lens of the eye, which acts as a molecular chaperone that keeps the lens transparent and refractive. α-crystallin is categorized as an intrinsically disordered protein (IDP), devoid of a stable three-dimensional structure, in contrast to conventional globular proteins. Because of its structural flexibility, it can stop denatured proteins from aggregating and building up within the lens over time. α-crystallin's dynamic quaternary structure, which allows it to exist in a variety of oligomeric forms, from dimers to massive assemblies, improves its chaperone function and flexibility. Its intrinsically disordered nature enables it to interact with a variety of client proteins due to its large non-polar and polar residue content and lack of a hydrophobic core. Furthermore, under physiological stress, osmolytes like sorbitol, TMAO, and urea are essential in regulating the stability and function of α-crystallin. Post-translational modifications (PTMs) such as glycation, in which reducing sugars combine with amino groups on the protein to generate advanced glycation end-products, impair α-crystallin's ability to function. These AGEs can cross-link α-crystallin molecules to prevent protein aggregation, changing their structure and decreasing their chaperone action. Because of their raised blood glucose levels, diabetics have an increased chance of developing cataracts as a result of this process. Comprehending how glycation and other PTMs affect α-crystallin is crucial for formulating treatment plans to maintain lens transparency and fight cataracts linked to aging and metabolic disorders.