Structure and Interactions of Conformational Intermediates in gamma-D Crystallin Aggregation, and Their Targeting for Cataract Prevention

γ-D 晶状体蛋白聚集中构象中间体的结构和相互作用及其预防白内障的靶向作用

基本信息

  • 批准号:
    10401812
  • 负责人:
  • 金额:
    $ 40.39万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2020
  • 资助国家:
    美国
  • 起止时间:
    2020-05-01 至 2025-04-30
  • 项目状态:
    未结题

项目摘要

PROJECT ABSTRACT Cataracts result from progressive aggregation of eye lens crystallin proteins. Severity of age-onset cataract has been linked to specific post-translational modifications in crystallins that accumulate during aging. Two important classes of cataract-associated modifications are oxidation of Trp residues to more hydrophilic products and oxidation of Cys residues to generate disulfide bonds. Our prior research has revealed a crucial synergy between the two. The W42Q variant of human γD crystallin (a Trp oxidation mimic) and the W42R congenital-cataract variant, are destabilized but well folded and soluble under reducing conditions, yet formation of a non-native internal disulfide bond (Cys32-Cys41) kinetically traps them in a partially unfolded conformational intermediate, generating rapid and robust aggregation at physiologically relevant temperature, pH, and concentration in vitro. We have developed a rapid, atomistic Monte-Carlo modeling method, with a knowledge-based statistical potential, that is uniquely suited for the study of conformational intermediates, including in multiple polypeptide chains as they simultaneously unfold to reveal new protein-protein interactions. We have already applied this method to γD crystallin and its variants to predict not only the structure of the aggregation-prone intermediate but also, for the first time, an atomistic model of the aggregated state. Experimentally, we recently discovered a novel oxidoreductase activity in human γD crystallin and demonstrated that native-state disulfides in WT can be transferred to generate the non-native, aggregation-promoting disulfide in W42Q. We found an even more surprising WT/mutant interaction – domain interface stealing – that allows WT to catalyze mutants’ aggregation even in the presence of an abundant external disulfide source. We will now (1) investigate the physical principles, kinetics, and evolutionary and disease implications of the novel interface stealing interaction by a combined computational, biochemical, and proteolysis/mass spectrometry approach we are now developing; and (2) distinguish among atomistic models for the aggregation precursor and the aggregated state and (3) apply these newly refined atomistic models to rationally design structure-based peptide inhibitors of the aggregation process. Although our studies have focused on the W42Q/R variants, other cataract-associated variants (V75D, L5S) appear to behave quite similarly. Moreover, both the native and the non-native disulfide we identified as culprits in aggregation processes have been entirely supported by tissue proteomics of aged and cataractous human lenses in the absence of any genetic mutation. We will therefore test the hypothesis that many mutations or post- translational modifications converge on few conformational intermediates that determine aggregation. We will generalize the detailed mechanistic and structural picture of aggregation to other γ-crystallins and other cataract- associated variants testing whether human γC and γS crystallins are also redox-active and capable of interface stealing. A more general understanding of the synergy between structural destabilization and redox chemistry in cataract will improve design of aggregation inhibitors testable on existing genetic mouse models of cataract.
项目摘要

项目成果

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EUGENE I SHAKHNOVICH其他文献

EUGENE I SHAKHNOVICH的其他文献

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{{ truncateString('EUGENE I SHAKHNOVICH', 18)}}的其他基金

Biophysical foundations of evolutionary dynamics
进化动力学的生物物理学基础
  • 批准号:
    10633124
  • 财政年份:
    2021
  • 资助金额:
    $ 40.39万
  • 项目类别:
Biophysical foundations of evolutionary dynamics
进化动力学的生物物理学基础
  • 批准号:
    10452241
  • 财政年份:
    2021
  • 资助金额:
    $ 40.39万
  • 项目类别:
Biophysical foundations of evolutionary dynamics
进化动力学的生物物理基础
  • 批准号:
    10413808
  • 财政年份:
    2021
  • 资助金额:
    $ 40.39万
  • 项目类别:
Structure and Interactions of Conformational Intermediates in gamma-D Crystallin Aggregation, and Their Targeting for Cataract Prevention
γ-D 晶状体蛋白聚集中构象中间体的结构和相互作用及其预防白内障的靶向作用
  • 批准号:
    10608130
  • 财政年份:
    2020
  • 资助金额:
    $ 40.39万
  • 项目类别:
Study of phenotypic and fitness effects of non-functional protein interactions in
非功能性蛋白质相互作用的表型和适应度效应研究
  • 批准号:
    8912519
  • 财政年份:
    2014
  • 资助金额:
    $ 40.39万
  • 项目类别:
Study of Biological Evolution of Structure and Function in Proteins
蛋白质结构和功能的生物进化研究
  • 批准号:
    8624697
  • 财政年份:
    2004
  • 资助金额:
    $ 40.39万
  • 项目类别:
Evolutionary study of structure-function relationship
结构-功能关系的进化研究
  • 批准号:
    6773025
  • 财政年份:
    2004
  • 资助金额:
    $ 40.39万
  • 项目类别:
Realistic protein folding with hydrophobic potentials
具有疏水潜力的真实蛋白质折叠
  • 批准号:
    6844886
  • 财政年份:
    2004
  • 资助金额:
    $ 40.39万
  • 项目类别:
Predictive biophysical models of evolution
进化的预测生物物理模型
  • 批准号:
    9234799
  • 财政年份:
    2004
  • 资助金额:
    $ 40.39万
  • 项目类别:
Evolutionary study of structure-function relationship
结构-功能关系的进化研究
  • 批准号:
    6874497
  • 财政年份:
    2004
  • 资助金额:
    $ 40.39万
  • 项目类别:

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