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The structural basis of yeast prion strain variants

机译：酵母病毒菌株变异体的结构基础

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摘要

Among the many surprises to arise from studies of prion biology, perhaps the most unexpected is the strain phenomenon whereby a single protein can misfold into structurally distinct, infectious states that cause distinguishable phenotypes. Similarly, proteins can adopt a spectrum of conformations in non-infectious diseases of protein folding; some are toxic and others are well tolerated. However, our understanding of the structural differences underlying prion strains and how these differences alter their physiological impact remains limited. Here we use a combination of solution NMR, amide hydrogen/deuterium (H/D) exchange and mutagenesis to study the structural differences between two strain conformations, termed Sc4 and Sc37 (ref. 5), of the yeast Sup35 prion. We find that these two strains have an overlapping amyloid core spanning most of the Gln/Asn-rich first 40 amino acids that is highly protected from H/D exchange and very sensitive to mutation. These features indicate that the cores are composed of tightly packed β-sheets possibly resembling 'steric zipper' structures revealed by X-ray crystallography of Sup35-derived peptides. The stable structure is greatly expanded in the Sc37 conformation to encompass the first 70 amino acids, revealing why this strain shows increased fibre stability and decreased ability to undergo chaperone-mediated replication. Our findings establish that prion strains involve large-scale conformational differences and provide a structural basis for understanding a broad range of functional studies, including how conformational changes alter the physiological impact of prion strains.
机译：在病毒生物学研究中出现的许多惊喜中，也许最出乎意料的是菌株现象，即一种蛋白质可以错误折叠成结构不同的，传染性的状态，从而导致可区分的表型。类似地，蛋白质在蛋白质折叠的非传染性疾病中可以采用一系列构象。有些是有毒的，而另一些则耐受良好。但是，我们对underlying病毒株基础结构差异以及这些差异如何改变其生理影响的理解仍然有限。在这里，我们结合使用溶液NMR，酰胺氢/氘（H / D）交换和诱变来研究酵母Sup35 ion病毒的两个菌株构象，分别称为Sc4和Sc37（参考文献5）之间的结构差异。我们发现这两个菌株具有重叠的淀粉样蛋白核心，涵盖了大多数富含Gln / Asn的前40个氨基酸，该核心受到高度保护，不受H / D交换的影响，并且对突变非常敏感。这些特征表明核心由紧密堆积的β-折叠组成，该β-折叠可能类似于Sup35衍生肽的X射线晶体学揭示的“立体拉链”结构。稳定的结构在Sc37构象中得到了极大扩展，以涵盖前70个氨基酸，从而揭示了该菌株为何显示出更高的纤维稳定性，并降低了伴侣介导的复制能力。我们的发现表明病毒菌株涉及大规模的构象差异，并为理解广泛的功能研究（包括构象变化如何改变病毒菌株的生理影响）提供了结构基础。

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  • 来源
    《Nature》 |2007年第7159期|p.233-237|共5页
  • 作者

    Brandon H. Toyama; Mark J. S. Kelly; John D. Gross; Jonathan S. Weissman;

  • 作者单位

    Howard Hughes Medical Institute, Department of Cellular and Molecular Pharmacology University of California San Francisco and California Institute for Quantitative Biomedical Research, San Francisco, California 94158-2542, USA;

  • 收录信息 美国《科学引文索引》(SCI);美国《工程索引》(EI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类 自然科学总论;
  • 关键词

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