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首页> 外文期刊>Journal of Molecular Biology >A single destabilizing mutation (F9S) promotes concerted unfolding of an entire globular domain in gammaS-crystallin.
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A single destabilizing mutation (F9S) promotes concerted unfolding of an entire globular domain in gammaS-crystallin.

机译：单个失稳突变（F9S）促进了γS-晶状体蛋白中整个球状结构域的一致展开。

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摘要

Conformational change and aggregation of native proteins are associated with many serious age-related and neurological diseases. gammaS-Crystallin is a highly stable, abundant structural component of vertebrate eye lens. A single F9S mutation in the N-terminal domain of mouse gammaS-crystallin causes the severe Opj cataract, with disruption of cellular organization and appearance of fibrillar structures in the lens. Although the mutant protein has a near-native fold at room temperature, significant increases in hydrogen/deuterium exchange rates were observed by NMR for all the well-protected beta-sheet core residues throughout the entire N-terminal domain of the mutant protein, resulting in up to a 3.5-kcal/mol reduction in the free energy of the folding/unfolding equilibrium. No difference was detected for the C-terminal domain. At a higher temperature, this effect further increases to allow for a much more uniform exchange rate among the N-terminal core residues and those of the least well-structured surface loops. This suggests a concerted unfolding intermediate of the N-terminal domain, while the C-terminal domain stays intact. Increasing concentrations of guanidinium chloride produced two transitions for the Opj mutant, with an unfolding intermediate at approximately 1 M guanidinium chloride. The consequence of this partial unfolding, whether by elevated temperature or by denaturant, is the formation of thioflavin T staining aggregates, which demonstrated fibril-like morphology by atomic force microscopy. Seeding with the already unfolded protein enhanced the formation of fibrils. The Opj mutant protein provides a model for stress-related unfolding of an essentially normally folded protein and production of aggregates with some of the characteristics of amyloid fibrils.
机译：天然蛋白质的构象变化和聚集与许多严重的年龄相关和神经系统疾病有关。 gammaS-Crystallin是脊椎动物晶状体的高度稳定，丰富的结构成分。小鼠γS-晶状体蛋白N末端结构域中的单个F9S突变会导致严重的Opj白内障，破坏细胞组织和晶状体中纤维状结构的出现。尽管突变蛋白在室温下具有近乎自然的折叠，但是通过NMR发现，在突变蛋白的整个N端结构域中，所有受到良好保护的β-sheet核心残基的氢/氘交换速率均显着增加。折叠/展开平衡的自由能最多降低3.5kcal / mol。 C端结构域未检测到差异。在更高的温度下，这种作用会进一步增强，以使N末端核心残基与结构最不完善的表面环的残基之间的交换速率更加均匀。这暗示了N端结构域的一致的展开中间物，而C端结构域保持完整。浓度增加的氯化胍产生了Opj突变体的两个转变，在约1M的氯化胍上有一个展开的中间体。无论是通过升高的温度还是通过变性剂，这种部分展开的结果是形成了硫代黄素T染色聚集体，通过原子力显微镜显示了原纤维状的形态。用已经展开的蛋白质播种可增强原纤维的形成。 Opj突变蛋白提供了一个模型，用于与应力相关的基本折叠蛋白的解折叠以及具有淀粉样原纤维某些特征的聚集体的产生。

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