Functional Elements in Alpha Crystallin Chaperone

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DESCRIPTION (provided by applicant): Cataract is a major cause of blindness in the world. A majority of the cataracts develop due to the age-related modifications and aggregation of the eye lens proteins. Alpha-crystallin accounts for nearly 40 percent of the adult lens proteins. In spite of the intense investigations of the past, the structure-function of alpha-crystallin is not fully understood. Nearly a decade ago the chaperone-like activity of alpha-crystallin was discovered but we are yet to fully understand the molecular mechanism of chaperone activity. There is also growing evidence supporting the interaction of beta- and gamma-crystallins with alpha-crystallin in aging lenses and this interaction has been attributed in part to the chaperone activity of alpha-crystallin. Understanding the alpha-crystallin structure and the molecular mechanism of its chaperone action will enable us to define the mechanisms of cataractogenesis and devise methods to delay/stop the process. The overall goal of our research is to get an insight to alpha-crystallin structure-function and understand the molecular mechanism of lens protein aggregation. We have been investigating the properties of alpha-crystallin for some time. During the next five years we propose to 1) dertermine the subunit recognition sites in alphaA- and alphaB-crystallins using a synthetic approach where a series of consecutive overlapping peptides encompassing alphaA- and alphaB-crystallins will be tested for recognition sequences, 2) continue the studies to fully characterize the chaperone-sites in both alphaA- and alphaB-crystallins and 3) investigate the role of alpha-crystallin chaperone activity in the aggregation of lens crystallins.