Laboratory for Protein Conformation Diseases, RIKEN Brain Science Institute, Wako, 351-0198 Saitama, Japan.
Department of Applied Chemistry, Tokyo University of Science, Shinjuku-ku, 162-8601 Tokyo, Japan.
Proc Natl Acad Sci U S A. 2018 Mar 6;115(10):2389-2394. doi: 10.1073/pnas.1715483115. Epub 2018 Feb 21.
Self-propagating β-sheet-rich fibrillar protein aggregates, amyloid fibers, are often associated with cellular dysfunction and disease. Distinct amyloid conformations dictate different physiological consequences, such as cellular toxicity. However, the origin of the diversity of amyloid conformation remains unknown. Here, we suggest that altered conformational equilibrium in natively disordered monomeric proteins leads to the adaptation of alternate amyloid conformations that have different phenotypic effects. We performed a comprehensive high-resolution structural analysis of Sup35NM, an N-terminal fragment of the Sup35 yeast prion protein, and found that monomeric Sup35NM harbored latent local compact structures despite its overall disordered conformation. When the hidden local microstructures were relaxed by genetic mutations or solvent conditions, Sup35NM adopted a strikingly different amyloid conformation, which redirected chaperone-mediated fiber fragmentation and modulated prion strain phenotypes. Thus, dynamic conformational fluctuations in natively disordered monomeric proteins represent a posttranslational mechanism for diversification of aggregate structures and cellular phenotypes.
自传播的β-折叠丰富的纤维状蛋白聚集体，即淀粉样纤维，通常与细胞功能障碍和疾病有关。不同的淀粉样纤维构象决定了不同的生理后果，如细胞毒性。然而，淀粉样纤维构象多样性的起源仍然未知。在这里，我们提出，天然无序单体蛋白构象平衡的改变导致了不同淀粉样纤维构象的适应，这些构象具有不同的表型效应。我们对 Sup35NM 进行了全面的高分辨率结构分析，Sup35NM 是酵母 Sup35 朊病毒蛋白的 N 端片段，尽管其整体呈无序构象，但单体 Sup35NM 仍具有潜在的局部紧凑结构。当隐藏的局部微观结构被遗传突变或溶剂条件放松时，Sup35NM 会采用一种截然不同的淀粉样纤维构象，这种构象重新定向了伴侣介导的纤维断裂，并调节了朊病毒株的表型。因此，天然无序单体蛋白的动态构象波动代表了聚集结构和细胞表型多样化的一种翻译后机制。
