Functional Elements in Alpha Crystallin Chaperone

描述（由申请人提供）：白内障是致盲的主要原因， 世界大多数白内障的发展是由于年龄相关的 眼透镜蛋白的修饰和聚集。晶体蛋白 占成人透镜蛋白质的近40%。尽管有 对过去的深入研究，α-晶体蛋白的结构-功能 还没有被完全理解。近十年前， α-晶体蛋白被发现，但我们还没有完全了解 分子伴侣活性的分子机制。也有越来越多的证据 支持β-和γ-晶状体蛋白与α-晶状体蛋白的相互作用 在老化的镜片中，这种相互作用部分归因于 α-晶状体蛋白的伴侣活性。了解α-晶体蛋白 结构和分子机制的伴侣作用将使我们能够 确定白内障形成的机制，并设计方法来延迟/阻止白内障的发生。 过程 我们研究的总体目标是深入了解α-晶体蛋白 结构-功能和理解透镜蛋白的分子机制 聚合来我们一直在研究α-晶体蛋白的性质， 一段时间在未来的五年里，我们建议1）确定亚基 使用合成方法在α A-和α B-晶体蛋白中的识别位点 其中一系列连续的重叠肽包括α A-和 将测试α B-晶体蛋白的识别序列，2）继续 研究充分表征在α A和α B中的伴侣位点， α B-晶体蛋白和3）研究α-晶体蛋白伴侣蛋白的作用 在透镜晶体蛋白聚集中的活性。

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.