Functional Elements in Alpha Crystallin Chaperone

描述(申请人提供)：白内障是致盲的主要原因 整个世界。大多数白内障的发生是由于年龄相关的 眼晶状体蛋白质的修饰和聚集。α-结晶蛋白 占成人晶状体蛋白质的近40%。尽管有 对过去的密集研究，α-晶体蛋白的结构和功能 还没有完全被理解。近十年前，像监护人一样的活动 α-晶状体蛋白被发现，但我们还没有完全了解 伴侣活性的分子机制。也有越来越多的证据表明 支持β-和γ-晶体蛋白与α-晶体蛋白的相互作用 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-晶状体蛋白 结构和其伴侣作用的分子机制将使我们能够 明确白内障的发生机制，并设计出延缓/阻止白内障的方法。 进程。 我们研究的总体目标是深入了解α-结晶 晶状体蛋白的结构与功能及其分子机制的研究 聚合。我们一直在研究α-晶状体蛋白的性质 过段时间吧。在接下来的五年里，我们建议1)确定亚基 用合成方法识别αA和αB晶体蛋白中的识别位点 其中围绕αA的一系列连续重叠的多肽-和 将测试α-晶体蛋白的识别序列，2)继续 全面描述αA和αA中的伴侣位点的研究 α-晶体蛋白和3)研究α-晶体蛋白伴侣的作用 晶状体晶体蛋白聚集的活性。

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.