Modifications of Small Heat Shock Proteins in the Lens

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Alpha-crystallin and heat shock protein-27 (Hsp27), the two small heat shock proteins (Hsps) found in the lens are thought to protect lens proteins from the stress, such as, oxidation and ultra violet light. In addition to functioning as chaperone proteins, they are versatile anti-apoptotic proteins. In the lens methylglyoxal (MGO) is produced as a metabolic by-product during glycolysis and its concentration is at least 20 times higher than in plasma. Lenses from diabetics have far greater MGO concentrations than lenses from nondiabetic individuals. MGO readily reacts with lysine, arginine and cysteine residues in proteins to form stable adducts, several of which have been identified in the human lens. Our recent studies on MGO modifications provided the surprising results that MGO-modification enhances the chaperone function of sHsps. Our most recent studies demonstrate that cataractous lenses contain high levels of phosphorylated Hsp27 (pHsp27) and pHsp27 is highly susceptible for modification by MGO. We also found MGO-modified alpha-crystallin is a better anti-apoptotic protein than the native unmodified protein. These intriguing observations prompted us to examine further on the MGO-induced structural alterations in sHsps, and to determine how such alterations change their functions. We have four aims. In aim 1, we will examine in detail the structural changes resulting from exposure of sHsps to MGO. We will focus on arginine residues, because these are the most vulnerable to modification by MGO. In aim 2, we will determine how MGO-induced modifications alter the anti-apoptotic functions of sHsps. In aim 3, we will study the impact of MGO-induced modifications on the interaction of sHsps with other lens proteins. Finally, in aim 4, we will determine whether MGO-modification of sHsps influence their transportation into the nucleus during increased cellular stress. These studies will improve our understanding of the interplay between sHsps and metabolic pathways, and they will help us to define the role of sHsps in apoptosis of lens epithelial cells and the implications for cataract formation.