A model of threshold behavior reveals rescue mechanisms of bystander proteins in conformational diseases.
A model of threshold behavior reveals rescue mechanisms of bystander proteins in conformational diseases.
复制标题
阈值行为模型揭示了构象疾病中旁观者蛋白的救援机制。
DOI：
10.1016/j.bpj.2011.03.006
复制
发表时间：
2011
影响因子：
3.4
通讯作者：
Schnell,Santiago
中科院分区：
文献类型：
--
作者：
Sandefur,ConnerI;Schnell,Santiago
构象疾病是由于特定蛋白质未能折叠成其正确的功能状态而引起的。错误折叠的蛋白质会导致蛋白质的有毒聚集。构象疾病中的蛋白质错误折叠通常表现出阈值行为，其特征是错误折叠蛋白质的无毒水平和有毒水平之间突然转变。在一些构象疾病中，有证据表明错误折叠的蛋白质与旁观者蛋白质（未折叠的和天然折叠的蛋白质）相互作用，引发错误折叠的表型。在没有错误折叠蛋白质的情况下，这些旁观者异构体将遵循其正常的生理途径。在本文中，我们提出了旁观者和错误折叠蛋白质相互作用的一般机制，我们用它来研究构象疾病中如何触发蛋白质错误折叠的阈值行为。使用内质网的连续流动反应器模型，我们发现旁观者蛋白在内质网中的停留时间或基础错误折叠与旁观者蛋白流入速率的比率的轻微变化可以触发蛋白质错误折叠的阈值行为。我们的分析揭示了构象疾病中拯救旁观者蛋白的三种机制。我们的模型的结果现在可以帮助指导实验以了解阈值行为并制定针对构象疾病调节的治疗策略。
Conformational diseases result from the failure of a specific protein to fold into its correct functional state. The misfolded proteins can lead to the toxic aggregation of proteins. Protein misfolding in conformational diseases often displays a threshold behavior characterized by a sudden shift between nontoxic to toxic levels of misfolded proteins. In some conformational diseases, evidence suggests that misfolded proteins interact with bystander proteins (unfolded and native folded proteins), eliciting a misfolded phenotype. These bystander isomers would follow their normal physiological pathways in absence of misfolded proteins. In this article, we present a general mechanism of bystander and misfolded protein interaction which we have used to investigate how the threshold behavior in protein misfolding is triggered in conformational diseases. Using a continuous flow reactor model of the endoplasmic reticulum, we found that slight changes in the bystander protein residence time in the endoplasmic reticulum or the ratio of basal misfolded to bystander protein inflow rates can trigger the threshold behavior in protein misfolding. Our analysis reveals three mechanisms to rescue bystander proteins in conformational diseases. The results of our model can now help direct experiments to understand the threshold behavior and develop therapeutic strategies targeting the modulation of conformational diseases.