Ohhashi Yumiko, Ito Kazuki, Toyama Brandon H, Weissman Jonathan S, Tanaka Motomasa
Tanaka Research Unit, RIKEN Brain Science Institute, Wako, Saitama, Japan.
Nat Chem Biol. 2010 Mar;6(3):225-230. doi: 10.1038/nchembio.306. Epub 2010 Jan 17.
Aggregation-prone proteins often misfold into multiple distinct amyloid conformations that dictate different physiological impacts. Although amyloid formation is triggered by a transient nucleus, the mechanism by which an initial nucleus is formed and allows the protein to form a specific amyloid conformation has been unclear. Here we show that, before fiber formation, the prion domain (Sup35NM, consisting of residues 1-254) of yeast prion Sup35, the [PSI(+)] protein determinant, forms oligomers in a temperature-dependent, reversible manner. Mutational and biophysical analyses revealed that 'non-native' aromatic interactions outside the amyloid core drive oligomer formation by bringing together different Sup35NM monomers, which specifically leads to the formation of highly infectious strain conformations with more limited amyloid cores. Thus, transient non-native interactions in the initial nucleus are pivotal in determining the diversity of amyloid conformations and resulting prion strain phenotypes.
易于聚集的蛋白质常常错误折叠成多种不同的淀粉样蛋白构象，这些构象决定了不同的生理影响。尽管淀粉样蛋白的形成是由一个瞬时核引发的，但初始核形成并使蛋白质形成特定淀粉样蛋白构象的机制尚不清楚。在这里，我们表明，在纤维形成之前，酵母朊病毒Sup35（即[PSI(+)]蛋白决定因子）的朊病毒结构域（Sup35NM，由1-254位残基组成）以温度依赖的、可逆的方式形成寡聚体。突变和生物物理分析表明，淀粉样蛋白核心之外的“非天然”芳香族相互作用通过聚集不同的Sup35NM单体来驱动寡聚体形成，这特别导致形成具有更有限淀粉样蛋白核心的高传染性菌株构象。因此，初始核中的瞬时非天然相互作用对于决定淀粉样蛋白构象的多样性以及由此产生的朊病毒菌株表型至关重要。
