Center for Cancer Research Nanobiology Program, National Cancer Institute, Frederick, MD 21702, USA.
Proc Natl Acad Sci U S A. 2010 Aug 10;107(32):14128-33. doi: 10.1073/pnas.1004704107. Epub 2010 Jul 26.
Recent cryoEM density maps of Abeta(42) fibrils obtained at low pH revealed two protofilaments winding around a hollow core raising the question if such tubular structures also exist at physiological pH. Based on the cryoEM measurements and on NMR data, we probe amyloid fibril organizations corresponding to the observed cryoEM density map. Our study demonstrates that the tubular Abeta(42) fibril models exist at both acidic and physiological pH; however, the relative populations of the polymorphic models shift with pH. At acidic pH, the hollow core model exhibits higher population than the other models; at physiological pH, although it is less populated compared to the other models, structurally, it is stable and represents 8% of the population. We observe that only models with C termini facing the external surface of the fibril retain the hollow core under acidic and physiological conditions with dimensions similar to those observed by cryoEM; on the other hand, the hydrophobic effect shrinks the tubular cavity in the alternative organization. The existence of the hollow core fibril at physiological pH emphasizes the need to examine toxic effects of minor oligomeric species with unique organizations.
最近在低 pH 值下获得的 Abeta(42) 纤维的冷冻电镜密度图显示出两个原纤维围绕着一个中空核心缠绕，这引发了一个问题，即在生理 pH 值下是否也存在这种管状结构。基于冷冻电镜测量和 NMR 数据，我们探测了与观察到的冷冻电镜密度图相对应的淀粉样纤维组织。我们的研究表明，管状 Abeta(42) 纤维模型存在于酸性和生理 pH 值下；然而，多态模型的相对群体随 pH 值而变化。在酸性 pH 值下，中空核心模型的群体比其他模型更高；在生理 pH 值下，尽管与其他模型相比，它的群体较少，但在结构上是稳定的，占群体的 8%。我们观察到，只有 C 末端面向纤维外表面的模型在酸性和生理条件下保留中空核心，其尺寸与冷冻电镜观察到的相似；另一方面，疏水作用会使替代构象中的管状腔缩小。在生理 pH 值下存在中空核心纤维强调了需要检查具有独特组织的少量寡聚体的毒性作用。
