Structural insights into a yeast prion illuminate nucleation and strain diversity
Structural insights into a yeast prion illuminate nucleation and strain diversity
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DOI：
10.1038/nature03679
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发表时间：
2005-06-09
期刊：
影响因子：
64.8
通讯作者：
Lindquist, SL
中科院分区：
文献类型：
--
作者：
Krishnan, R;Lindquist, SL
淀粉样蛋白构象的自我维持变化在正常生物学和疾病中起着至关重要的作用。尽管有大量的研究，淀粉样蛋白的结构和构象转换仍然知之甚少。Sup35的淀粉样蛋白构象异构体是酵母朊病毒（称为[ PSI]）的分子体现，其通过蛋白质折叠中的自我延续变化产生表型的遗传变化。在这里，我们确定Sup35的合作折叠淀粉样蛋白核心的性质，并使用这些信息来研究朊病毒生物学的中心问题。淀粉样蛋白核心的特定片段以“头对头”、“尾对尾”的方式形成分子间接触，但“中央核心”通过分子内接触被隔离。头首先获得生产性的相互作用，这些核组装。淀粉样蛋白核心长度的变化和分子间界面的性质形成了不同朊病毒“株”的结构基础，这些朊病毒“株”在体内产生不同的表型。这些发现解决了酵母朊病毒生物学中的几个问题，并对其他淀粉样蛋白具有广泛的意义。
Self-perpetuating changes in the conformations of amyloidogenic proteins play vital roles in normal biology and disease. Despite intense research, the architecture and conformational conversion of amyloids remain poorly understood. Amyloid conformers of Sup35 are the molecular embodiment of the yeast prion known as [ PSI], which produces heritable changes in phenotype through self-perpetuating changes in protein folding. Here we determine the nature of Sup35' s cooperatively folded amyloid core, and use this information to investigate central questions in prion biology. Specific segments of the amyloid core form intermolecular contacts in a 'Head-to-Head', 'Tail-to-Tail' fashion, but the 'Central Core' is sequestered through intramolecular contacts. The Head acquires productive interactions first, and these nucleate assembly. Variations in the length of the amyloid core and the nature of intermolecular interfaces form the structural basis of distinct prion 'strains', which produce variant phenotypes in vivo. These findings resolve several problems in yeast prion biology and have broad implications for other amyloids.