Chaperone-supervised conversion of prion protein to its protease-resistant form
Chaperone-supervised conversion of prion protein to its protease-resistant form
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DOI：
10.1073/pnas.94.25.13938
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发表时间：
1997-12-09
影响因子：
11.1
通讯作者：
Lindquist, S
中科院分区：
文献类型：
--
作者：
DebBurman, SK;Raymond, GJ;Lindquist, S
传染性海绵状脑病（TSE）是哺乳动物神经系统的致命性感染性疾病。TSE的一个标志是细胞蛋白PrPC转化为疾病相关的PrPSc（以瘙痒症命名，这是第一种已知的TSE）。PrPC是蛋白酶敏感的、单体的、去污剂可溶的，并且主要是α-螺旋; PrPSc是蛋白酶抗性的、聚合的、去污剂不溶的，并且富含β-折叠。“仅蛋白质”假说假定PrPSc是感染性TSE因子，其直接将宿主编码的PrPC转化为新鲜的PrPSc，损害神经元并产生新的感染因子。为了深入了解PrP的构象转变，我们测试了几种蛋白伴侣的能力，这些蛋白伴侣监督不同wag中蛋白质的构象转变，以影响PrPC向其蛋白酶抗性状态的转化，在不存在预先存在的PrPSc的情况下，没有影响转化，在其存在下，只有两种，GroEL和Hsp 104（热休克蛋白104）对转化有显著影响，两者均促进转化，但两种分子伴侣的转化反应特点不同，而化学分子伴侣则抑制转化。我们的研究结果提供了新的机制的性质PrP转换的见解，并提供了一套新的工具，研究TSE发病机制的过程。
Transmissible spongiform encephalopathies (TSEs) are lethal, infectious disorders of the mammalian nervous system. A TSE hallmark is the conversion of the cellular protein PrPC to disease-associated PrPSc (named for scrapie, the first known TSE). PrPC is protease-sensitive, monorneric, detergent soluble, and primarily alpha-helical; PrPSc is protease-resistant, polymerized, detergent insoluble, and rich in beta-sheet. The ''protein-only'' hypothesis posits that PrPSc is the infectious TSE agent that directly converts host-encoded PrPC to fresh PrPSc, harming neurons and creating new agents of infection. To gain insight on the conformational transitions of PrP, we tested the ability of several protein chaperones, which supervise the conformational transitions of proteins in diverse wags, to affect conversion of PrPC to its protease-resistant state, None affected conversion in the absence of pre-existing PrPSc, In its presence, only two, GroEL and Hsp104 (heat shock protein 104), significantly affected conversion, Both promoted it, but the reaction characteristics of conversions sith the two chaperones were distinct, In contrast, chemical chaperones inhibited conversion. Our findings provide new mechanistic insights into nature of PrP conversions, and provide a new set of tools for studying the process underlying TSE pathogenesis.