Centre of Medical Biotechnology, Faculty of Biology, University Duisburg-Essen, Essen, Germany.
Department of Structural Biochemistry, Max Planck Institute Molecular Physiology, Dortmund, Germany.
Nat Chem Biol. 2015 Nov;11(11):862-9. doi: 10.1038/nchembio.1931. Epub 2015 Oct 5.
Excessive aggregation of proteins has a major impact on cell fate and is a hallmark of amyloid diseases in humans. To resolve insoluble deposits and to maintain protein homeostasis, all cells use dedicated protein disaggregation, protein folding and protein degradation factors. Despite intense recent research, the underlying mechanisms controlling this key metabolic event are not well understood. Here, we analyzed how a single factor, the highly conserved serine protease HTRA1, degrades amyloid fibrils in an ATP-independent manner. This PDZ protease solubilizes protein fibrils and disintegrates the fibrillar core structure, allowing productive interaction of aggregated polypeptides with the active site for rapid degradation. The aggregate burden in a cellular model of cytoplasmic tau aggregation is thus reduced. Mechanistic aspects of ATP-independent proteolysis and its implications in amyloid diseases are discussed.
蛋白质的过度聚集对细胞命运有重大影响，是人类淀粉样变疾病的标志。为了解决不溶性沉积物并维持蛋白质的体内平衡，所有细胞都使用专用的蛋白解聚、蛋白折叠和蛋白降解因子。尽管最近的研究非常深入，但控制这一关键代谢事件的潜在机制还不是很清楚。在这里，我们分析了单一因子——高度保守的丝氨酸蛋白酶 HTRA1 如何以不依赖 ATP 的方式降解淀粉样纤维。这种 PDZ 蛋白酶可溶解蛋白纤维并破坏纤维核心结构，使聚集多肽与活性位点进行有效相互作用，从而快速降解。因此，细胞质 tau 聚集的细胞模型中的聚集体负担减少。讨论了不依赖 ATP 的蛋白水解的机制方面及其在淀粉样变疾病中的意义。
