Krishnan Rajaraman, Lindquist Susan L
Whitehead Institute for Biomedical Research, 9 Cambridge Center, Cambridge, Massachusetts 02142, USA.
Nature. 2005 Jun 9;435(7043):765-72. doi: 10.1038/nature03679.
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.
淀粉样蛋白构象的自我延续性变化在正常生物学和疾病中起着至关重要的作用。尽管进行了深入研究，但淀粉样蛋白的结构和构象转换仍知之甚少。Sup35的淀粉样构象是酵母朊病毒[PSI]的分子体现，它通过蛋白质折叠的自我延续性变化产生可遗传的表型变化。在这里，我们确定了Sup35协同折叠的淀粉样核心的性质，并利用这些信息来研究朊病毒生物学中的核心问题。淀粉样核心的特定片段以“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。头部首先获得有效的相互作用，这些相互作用引发组装。淀粉样核心长度的变化和分子间界面的性质构成了不同朊病毒“菌株”的结构基础，这些菌株在体内产生变异表型。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。
