Mechanism of Hsp104/ClpB inhibition by prion curing Guanidinium hydrochloride
Mechanism of Hsp104/ClpB inhibition by prion curing Guanidinium hydrochloride
复制标题
DOI：
10.1016/j.febslet.2013.02.011
复制
发表时间：
2013-03-18
期刊：
影响因子：
3.5
通讯作者：
Mogk, Axel
中科院分区：
文献类型：
--
作者：
Kummer, Eva;Oguchi, Yuki;Mogk, Axel
酿酒酵母AAA+蛋白Hsp104及其大肠杆菌对应蛋白ClpB与Hsp70伴侣蛋白合作，重组聚集蛋白并使朊蛋白原纤维片段化。Hsp104/ClpB活性受m结构域与第一ATP酶结构域（AAA-1）的相互作用调控，控制ATP的周转和Hsp70的配合。盐酸胍（GdnHCl）抑制Hsp104/ClpB活性，导致朊病毒固化。我们发现GdnHCl结合对Hsp104/ClpB具有双重作用。首先，GdnHCl加强了m结构域/AAA-1的相互作用，使Hsp104/ClpB稳定在一个受抑制的构象中，并取消了Hsp70的合作。其次，GdnHCl抑制AAA-1的连续ATP转换。这些发现为GdnHCl治疗朊病毒提供了机制基础。(C) 2013年欧洲生化学会联合会。Elsevier b.v.版权所有。
The Saccharomyces cerevisiae AAA+ protein Hsp104 and its Escherichia coli counterpart ClpB cooperate with Hsp70 chaperones to refold aggregated proteins and fragment prion fibrils. Hsp104/ClpB activity is regulated by interaction of the M-domain with the first ATPase domain ( AAA-1), controlling ATP turnover and Hsp70 cooperation. Guanidinium hydrochloride ( GdnHCl) inhibits Hsp104/ClpB activity, leading to prion curing. We show that GdnHCl binding exerts dual effects on Hsp104/ClpB. First, GdnHCl strengthens M-domain/AAA-1 interaction, stabilizing Hsp104/ClpB in a repressed conformation and abrogating Hsp70 cooperation. Second, GdnHCl inhibits continuous ATP turnover by AAA-1. These findings provide the mechanistic basis for prion curing by GdnHCl. (C) 2013 Federation of European Biochemical Societies. Published by Elsevier B. V. All rights reserved.