UCLA-DOE Institute for Genomics and Proteomics, The Howard Hughes Medical Institute, Molecular Biology Institute and Molecular Biology Institute, University of California, Los Angeles, CA 90095, USA.
Proc Natl Acad Sci U S A. 2012 Dec 18;109(51):20913-8. doi: 10.1073/pnas.1218792109. Epub 2012 Dec 3.
Although aberrant protein aggregation has been conclusively linked to dozens of devastating amyloid diseases, scientists remain puzzled about the molecular features that render amyloid fibrils or small oligomers toxic. Here, we report a previously unobserved type of amyloid fibril that tests as cytotoxic: one in which the strands of the contributing β-sheets are out of register. In all amyloid fibrils previously characterized at the molecular level, only in-register β-sheets have been observed, in which each strand makes its full complement of hydrogen bonds with the strands above and below it in the fibril. In out-of-register sheets, strands are sheared relative to one another, leaving dangling hydrogen bonds. Based on this finding, we designed out-of-register β-sheet amyloid mimics, which form both cylindrin-like oligomers and fibrils, and these mimics are cytotoxic. Structural and energetic considerations suggest that out-of-register fibrils can readily convert to toxic cylindrins. We propose that out-of-register β-sheets and their related cylindrins are part of a toxic amyloid pathway, which is distinct from the more energetically favored in-register amyloid pathway.
虽然异常蛋白聚集与数十种破坏性淀粉样疾病有明确关联，但科学家仍不清楚导致淀粉样纤维或小寡聚体有毒的分子特征。在这里，我们报告了一种以前未观察到的具有细胞毒性的淀粉样纤维类型：其中β-折叠链的链不在同一位置。在以前在分子水平上表征的所有淀粉样纤维中，只观察到了同构β-折叠，其中每个链都与其在纤维中的上下链形成完整的氢键。在非同构折叠中，链相对于彼此被剪断，留下悬垂的氢键。基于这一发现，我们设计了非同构β-折叠淀粉样模拟物，它们既可以形成类似圆柱蛋白的寡聚体，也可以形成纤维，而这些模拟物具有细胞毒性。结构和能量方面的考虑表明，非同构纤维很容易转化为有毒的圆柱蛋白。我们提出，非同构β-折叠及其相关的圆柱蛋白是一种毒性淀粉样途径的一部分，该途径与更具能量优势的同构淀粉样途径不同。
