Zentrum für Molekulare Biologie der Universität Heidelberg and Deutsches Krebsforschungszentrum, DKFZ-ZMBH Alliance, Im Neuenheimer Feld 282, Heidelberg D-69120, Germany.
FEBS Lett. 2013 Mar 18;587(6):810-7. doi: 10.1016/j.febslet.2013.02.011. Epub 2013 Feb 14.
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.
酿酒酵母的 AAA+ 蛋白 Hsp104 和其对应的大肠杆菌 ClpB 与 Hsp70 伴侣蛋白共同作用以重折叠聚集的蛋白质和片段朊病毒纤维。Hsp104/ClpB 的活性受到 M 结构域与第一个 ATP 酶结构域（AAA-1）相互作用的调节，控制着 ATP 的转换和 Hsp70 的合作。盐酸胍（GdnHCl）抑制 Hsp104/ClpB 的活性，导致朊病毒失活。我们表明，GdnHCl 结合对 Hsp104/ClpB 有双重影响。首先，GdnHCl 增强了 M 结构域/AAA-1 相互作用，将 Hsp104/ClpB 稳定在抑制构象中，并消除了 Hsp70 的合作。其次，GdnHCl 抑制了 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。
