The effect of small molecules in modulating the chaperone activity of αB-crystallin against ordered and disordered protein aggregation
The effect of small molecules in modulating the chaperone activity of αB-crystallin against ordered and disordered protein aggregation
复制标题
DOI：
10.1111/j.1742-4658.2008.06257.x
复制
发表时间：
2008-03-01
期刊：
影响因子：
5.4
通讯作者：
Carver, John A.
中科院分区：
文献类型：
--
作者：
Ecroyd, Heath;Carver, John A.
蛋白质聚集可以通过无序或有序的机制进行，后者与淀粉样原纤维的形成有关，淀粉样原纤维的形成与许多使人衰弱的疾病有关，包括阿尔茨海默病、帕金森病和克雅氏病。小热休克蛋白 (sHsps)，例如 α B-晶状体蛋白，充当伴侣以防止蛋白质聚集，并被认为在预防蛋白质错误折叠疾病中发挥关键作用。在这项研究中，我们探索了精氨酸和胍等小分子影响 α B-晶状体蛋白的伴侣活性以对抗无序（无定形）和有序（淀粉样原纤维）形式的蛋白质聚集的潜力。这些添加剂的效果高度依赖于发生聚集的靶蛋白。重要的是，我们的结果表明，在精氨酸和类似的带正电荷的化合物（例如赖氨酸和胍）存在的情况下，αB-晶状体蛋白对疾病相关淀粉样原纤维形成蛋白α-突触核蛋白A53T聚集的伴侣作用增强。因此，我们的结果表明，靶蛋白特性在控制小分子对 sHsps 伴侣作用的影响方面发挥着关键作用。值得注意的是，调节 sHsps 活性的小分子可能提供一种机制来保护细胞免受与某些蛋白质错误折叠疾病相关的有毒蛋白质聚集的影响。
Protein aggregation can proceed via disordered or ordered mechanisms, with the latter being associated with amyloid fibril formation, which has been linked to a number of debilitating conditions including Alzheimer's, Parkinson's and Creutzfeldt-Jakob diseases. Small heat-shock proteins (sHsps), such as alpha B-crystallin, act as chaperones to prevent protein aggregation and are thought to play a key role in the prevention of protein-misfolding diseases. In this study, we have explored the potential for small molecules such as arginine and guanidine to affect the chaperone activity of alpha B-crystallin against disordered (amorphous) and ordered (amyloid fibril) forms of protein aggregation. The effect of these additives is highly dependent upon the target protein undergoing aggregation. Importantly, our results show that the chaperone action of alpha B-crystallin against aggregation of the disease-related amyloid fibril forming protein alpha-synucleinA53T is enhanced in the presence of arginine and similar positively charged compounds (such as lysine and guanidine). Thus, our results suggest that target protein identity plays a critical role in governing the effect of small molecules on the chaperone action of sHsps. Significantly, small molecules that regulate the activity of sHsps may provide a mechanism to protect cells from the toxic protein aggregation that is associated with some protein-misfolding diseases.