Role of deamidation in human beta-crystallin structure

脱酰胺在人 β-晶状体蛋白结构中的作用

• 批准号: 8288836
• 负责人: KIRSTEN Jeanne LAMPI
• 金额: $ 29.27万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-08-01 至 2015-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8288836
• 关键词: Age; Aging; Alzheimer' s Disease; Arts; Blindness; Cataract; Collaborations; Crystalline Lens; Crystallins; Defect; Deuterium; Disease; Future; Goals; Government; Grant; Healthcare Systems; Heavy Drinking; Human; Hydrogen; In Vitro; Lead; Life; Life Style; Light; Mass Spectrum Analysis; Measures; Methods; Modification; Molecular Chaperones; Molecular Weight; Post-Translational Protein Processing; Predisposition; Presbyopia; Proteins; Recording of previous events; Reporting; Research; Resolution; Retina; Role; Site; Structure; Testing; Therapeutic Agents; Zebrafish; age related; aged; base; beta-Crystallins; deamidation; in vivo; in vivo Model; innovation; lens; lens transparency; prevent; protein aggregation; public health relevance; research study

The overall goal of our research is to determine the role of deamidation in the lens. During the last grant cycle, we convincingly demonstrated that deamidation led to soluble aggregates, destabilized b-crystallins, altered interactions between b-subunits, and increased the a-crystallin needed to chaperone b-crystallins. These results suggest a mechanism for deamidation-induced insolubilization of crystallins and strongly support that deamidation contributes directly to cataract formation. Based on our findings, we hypothesize that deamidation decreases crystallin stability leading to aggregation that eventually triggers cataract formation. Experiments in Aim 1 will identify potentially relevant deamidations in the lens. Next, we will determine if deamidations previously identified to cause aggregation or decrease stability directly lead to cataract formation by using an in vivo model. Experiments in Aim 2 will determine the mechanism by which deamidation triggers aggregation, by identifying altered interactions within b-crystallins and with the a-chaperone. Numerous deamidation sites exist in the b-crystallins. The proposed experiments are innovative in that they will distinguish between functionally relevant sites and those that are detrimental, using state-of-the art approaches to directly test the role of deamidation in vivo. Future studies will screen for agents that prevent crystallin aggregation.

我们研究的总体目标是确定脱氨酸在镜头中的作用。 在上一个赠款周期中，我们令人信服地证明了脱氨酸导致 可溶性聚集体，不稳定的B-晶状体，改变了B-亚基之间的相互作用， 并增加了伴侣B-晶状体所需的A-晶状体。这些结果表明 脱氨酸诱导的晶体不溶化和强烈支持的机制 该脱氨基直接导致白内障形成。 根据我们的发现，我们假设脱氨降低了结晶蛋白 稳定性导致聚集最终触发白内障的形成。 AIM 1中的实验将识别镜头中潜在相关的脱氨化。接下来，我们 将确定是否先前确定的脱氨液会导致聚集或减少 稳定性通过使用体内模型直接导致白内障形成。实验 AIM 2将确定脱氨酸触发聚集的机制， 识别B-晶状体内部和与A-Chaperone中的变化相互作用。 B-晶状体中存在许多脱氨酸位点。提出的实验是 创新的是，他们将区分与功能相关的站点和那些网站 有害，采用最先进的方法直接测试脱氨酸的作用 体内。未来的研究将筛选防止结晶蛋白聚集的药物。

项目成果

New focus on alpha-crystallins in retinal neurodegenerative diseases.

• DOI: 10.1016/j.exer.2010.11.008
• 发表时间: 2011-02
• 期刊: EXPERIMENTAL EYE RESEARCH
• 影响因子: 3.4
• 作者: Fort, Patrice E.;Lampi, Kirsten J.
• 通讯作者: Lampi, Kirsten J.