Radically Different Amyloid Conformations Dictate the Seeding Specificity of a Chimeric Sup35 Prion
Radically Different Amyloid Conformations Dictate the Seeding Specificity of a Chimeric Sup35 Prion
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DOI：
10.1016/j.jmb.2011.02.025
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发表时间：
2011-04-22
影响因子：
5.6
通讯作者：
Weissman, Jonathan S.
中科院分区：
文献类型：
--
作者：
Foo, Catherine K.;Ohhashi, Yumiko;Weissman, Jonathan S.
朊病毒生物学的一个显著特征是，相同的朊病毒蛋白可以错误折叠成一种以上的感染性构象，而这些构象反过来又导致具有不同表型的可遗传朊病毒株。酵母朊病毒[PSI（+）]是研究菌株构象变化如何影响跨物种传播的强大系统。我们以前已经建立了一个嵌合体的酿酒酵母（SC）和白色念珠菌（CA）Sup 35朊病毒域可以跨越SC/CA物种屏障的应变依赖性的方式。在体外，单体嵌合体转化为朊病毒（淀粉样蛋白）形式可以通过SC或CA Sup 35淀粉样蛋白纤维接种，产生两种菌株：Chim[SC]和Chim[CA]。这些菌株具有其起源物种的“分子记忆”，因为Chim[SC]优先接种SC Sup 35的转化，反之亦然。为了研究这种物种特异性是如何构象编码的，我们使用酰胺交换和有限的蛋白水解来探测这两种菌株的结构。我们发现Chim [SC]和Chim[CA]的淀粉样蛋白核心主要分别局限于SC衍生和CA衍生的残基。此外，嵌合体即使在缺失构成Chim[SC]核心的SC残基时也能够繁殖Chim[CA]构象。因此，这两种菌株具有非重叠和模块化的淀粉样蛋白核心，其决定了朊病毒种子的生长面上是否存在SC或CA残基。这些观察结果建立了构象如何决定朊病毒传播的特异性，并证明了淀粉样蛋白错误折叠的显著可塑性。(C)2011爱思唯尔有限公司保留所有权利。
A remarkable feature of prion biology is that the same prion protein can misfold into more than one infectious conformation, and these conformations in turn lead to distinct heritable prion strains with different phenotypes. The yeast prion [PSI(+)] is a powerful system for studying how changes in strain conformation affect cross-species transmission. We have previously established that a chimera of the Saccharomyces cerevisiae (SC) and Candida albicans (CA) Sup35 prion domains can cross the SC/CA species barrier in a strain-dependent manner. In vitro, the conversion of the monomeric chimera into the prion (amyloid) form can be seeded by either SC or CA Sup35 amyloid fibers, resulting in two strains: Chim[SC] and Chim[CA]. These strains have a "molecular memory" of their originating species in that Chim[SC] preferentially seeds the conversion of SC Sup35, and vice versa. To investigate how this species specificity is conformationally encoded, we used amide exchange and limited proteolysis to probe the structures of these two strains. We found that the amyloid cores of Chim [SC] and Chim[CA] are predominantly confined to the SC-derived and CA-derived residues, respectively. In addition, the chimera is able to propagate the Chim[CA] conformation even when the SC residues comprising the Chim[SC] core were deleted. Thus, the two strains have non-overlapping and modular amyloid cores that determine whether SC or CA residues are presented on the growing face of the prion seed. These observations establish how conformations determine the specificity of prion transmission and demonstrate a remarkable plasticity to amyloid misfolding. (C) 2011 Elsevier Ltd. All rights reserved.