Department of Molecular Microbiology and Biotechnology, George S. Wise Faculty of Life Sciences , Tel Aviv University , Tel Aviv 69978 , Israel.
The Raymond and Beverly Sackler School of Physics and Astronomy , Tel Aviv University , Tel Aviv 69978 , Israel.
J Am Chem Soc. 2019 Jan 9;141(1):363-369. doi: 10.1021/jacs.8b10289. Epub 2018 Dec 26.
The ensemble of native, folded state was once considered to represent the global energy minimum of a given protein sequence. More recently, the discovery of the cross-β amyloid state revealed that deeper energy minima exist, often associated with pathogenic, fibrillar deposits, when the concentration of proteins reaches a critical value. Fortunately, a sizable energy barrier impedes the conversion from native to pathogenic states. However, little is known about the structure of the related transition state. In addition, there are indications of polymorphism in the amyloidogenic process. Here, we report the first evidence of the conversion of metastable cross-α-helical crystals to thermodynamically stable cross-β-sheet-like fibrils by a de novo designed heptapeptide. Furthermore, for the first time, we demonstrate at atomic resolution that the flip of a peptide plane from a type I to a type II' turn facilitates transformation to cross-β structure and assembly of a dry steric zipper. This study establishes the potential of a peptide turn, a common protein secondary structure, to serve as a principal gatekeeper between a native metastable folded state and the amyloid state.
天然折叠状态的整体结构曾被认为代表了给定蛋白质序列的全局能量最低点。最近，β-淀粉样蛋白交叉状态的发现揭示了更深的能量最低点的存在，当蛋白质浓度达到临界值时，这些能量最低点通常与致病性纤维状沉积物有关。幸运的是，相当大的能量障碍阻碍了从天然状态向致病状态的转化。然而，关于相关过渡态的结构知之甚少。此外，淀粉样蛋白形成过程中存在多态性的迹象。在这里，我们报告了第一个证据，证明通过从头设计的七肽将亚稳态的交叉α-螺旋晶体转化为热力学稳定的交叉β-片状纤维。此外，我们首次以原子分辨率证明，肽平面从 I 型到 II' 型的翻转有助于转化为交叉β结构，并组装干性位阻拉链。这项研究确立了肽转角（一种常见的蛋白质二级结构）作为天然亚稳态折叠状态和淀粉样蛋白状态之间的主要守门员的潜力。
