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首页> 外文期刊>Journal of Molecular Biology >Kinetic control in protein folding for light chain amyloidosis and the differential effects of somatic mutations
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Kinetic control in protein folding for light chain amyloidosis and the differential effects of somatic mutations

机译：轻链淀粉样变性蛋白折叠的动力学控制和体细胞突变的差异作用

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Light chain amyloidosis is a devastating disease where immunoglobulin light chains form amyloid fibrils, resulting in organ dysfunction and death. Previous studies have shown a direct correlation between the protein thermodynamic stability and the propensity for amyloid formation for some proteins involved in light chain amyloidosis. Here we investigate the effect of somatic mutations on protein stability and in vitro fibril formation of single and double restorative mutants of the protein AL-103 compared to the wild-type germline control protein. A scan rate dependence and hysteresis in the thermal unfolding and refolding was observed for all proteins. This indicates that the unfolding/refolding reaction is kinetically determined with different kinetic constants for unfolding and refolding even though the process remains experimentally reversible. Our structural analysis of AL-103 and AL-103 delP95aIns suggests a kinetic coupling of the unfolding/refolding process with cis-trans prolyl isomerization. Our data reveal that the deletion of proline 95a (AL-103 delP95aIns), which removes the trans-cis di-proline motif present in the patient protein AL-103, results in a dramatic increment in the thermodynamic stability and a significant delay in fibril formation kinetics with respect to AL-103. Fibril formation is pH dependent; all proteins form fibrils at pH 2; reactions become slower and more stochastic as the pH increases up to pH 7. Based on these results, we propose that, in addition to thermodynamic stability, kinetic stability (possibly influenced by the presence of cis proline 95a) plays a major role in the AL-103 amyloid fibril formation process.
机译：轻链淀粉样变性病是一种破坏性疾病，其中免疫球蛋白轻链形成淀粉样蛋白原纤维，导致器官功能障碍和死亡。先前的研究表明，蛋白质热力学稳定性与某些轻链淀粉样变性相关蛋白质的淀粉样形成倾向之间存在直接关系。在这里，我们研究了体突变对蛋白稳定性以及与野生型种系对照蛋白相比，蛋白AL-103的单个和双重恢复性突变体的体外原纤维形成的影响。对于所有蛋白质，观察到热解折叠和复折叠中的扫描速率依赖性和滞后性。这表明，即使该过程保持实验上可逆的，该解折叠/重折叠反应还是通过动力学上不同的动力学常数确定的。我们对AL-103和AL-103 delP95aIns的结构分析表明，解折叠/折叠过程与顺-反脯氨酰异构化之间存在动力学耦合。我们的数据表明，脯氨酸95a（AL-103 delP95aIns）的缺失会删除患者蛋白AL-103中存在的反式顺式双脯氨酸基序，从而导致热力学稳定性急剧增加，并显着延迟原纤维形成关于AL-103的形成动力学。原纤维的形成与pH有关;所有蛋白质在pH 2时均形成原纤维;随着pH升高至pH 7，反应变得越来越慢，并且更加随机。基于这些结果，我们建议，除了热力学稳定性外，动力学稳定性（可能受顺式脯氨酸95a的影响）在AL中也起着重要作用。 -103淀粉样蛋白原纤维的形成过程。

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