chjapernas

Abstract

α-Crystallin is a member of the small heat-shock protein (sHSP) family and consists of two subunits, αA- and αB-. Both αA- and αB-crystallin act as chaperones and anti-apoptotic proteins.Previous studies have identified the peptide 70KFVIFLDVKHFSPEDLTVK88 in αA-crystallin and the peptide 73DRFSVNLDVKHFSPEELKVK92 in αB-crystallin as mini-chaperones. In the human lens, lysine70 (K70)of αA- and K92 of αB- (in the mini-chaperone sequences) are acetylated. In this study, we investigated the cellular effects of the unmodified and acetyl mini-chaperones. The αA- and αB-crystallinpeptides inhibited stress-induced aggregation of four client proteins, and the acetyl peptides were more effective than the native peptides against three of the client proteins. Both the acetyl and nativecrystallin peptides inhibited stress-induced apoptosis in two mammalian cell types, and this property was directly related to the inhibition of cytochrome-C release from mitochondria and the activityof caspase-3 and -9. In organ-cultured rat lenses, the peptides inhibited calcimycin-induced epithelial cell apoptosis. Intraperitoneal injection of the peptides inhibited cataract development inselenite-treated rats, which was accompanied by inhibition of oxidative stress, protein insolubilization and caspase activity in the lens. These inhibitory effects were more pronounced for acetyl peptidesthan native peptides. A scrambled αA-crystallin peptide produced no such effects. The results suggest that the α-crystallin chaperone peptides could be used as therapeutic agents to treat cataractsand diseases in which protein aggregation and apoptosis are contributing factors.
Las mutaciones con pérdida de sentido (missense) representan la causa más común de muchas enfermedades genéticasincluyendo la deficiencia de cistationina beta-sintasa (CBS). Muchas de estas mutaciones dan lugar a proteínas mal plegadas, que carecen de función biológica. La presencia de chaperonas químicas a veces...