Blake C, Serpell L
Laboratory of Molecular Biophysics, University of Oxford, Rex Richard's Building, South Parks Road, Oxford, OX1 3QU, England.
Structure. 1996 Aug 15;4(8):989-98. doi: 10.1016/s0969-2126(96)00104-9.
Amyloid diseases, which include Alzheimer's disease and the transmissible spongiform encephalopathies, are characterized by the extracellular deposition of abnormal protein fibrils derived from soluble precursor proteins. Although different precursors seem to generate similar fibrils, no adequate molecular structure of amyloid fibrils has been produced using modern techniques. Knowledge of the fibril structure is essential to understanding the molecular mechanism of amyloid formation and could lead to the development of agents to inhibit or reverse the process.
The structure of amyloid fibrils from patients with familial amyloidotic polyneuropathy (FAP), which are derived from transthyretin (TTR) variants, has been investigated by fibre diffraction methods using synchrotron radiation. For the first time a significant high-angle diffraction pattern has been observed showing meridional reflections out to 2 A resolution. This pattern was fully consistent with the previously reported cross-beta structure for the fibril, but also reveals a new large scale fibre repeat of 115 A. We interpret this pattern as that of a repeating unit of 24 beta strands, which form a complete helical turn of beta sheet about an axis parallel to the fibre axis. This structure has not been observed previously. We have built a model of the protofilament of the FAP amyloid fibril based on this interpretation, composed of four beta sheets related by a single helix axis coincident with the fibre axis, and shown that it is consistent with the observed X-ray data.
This work suggests that amyloid fibrils have a novel molecular structure consisting of beta sheets extended in regular helical twists along the length of the fibre. This implies that the polypeptide chains in the fibres are hydrogen-bonded together along the entire length of the fibres, thereby accounting for their great stability. The proposed structure of the FAP fibril requires a TTR building block that is structurally different from the native tetramer. This is likely to be either a monomer or dimer with reorganized or truncated beta sheets, suggesting that amyloid formation may require significant structural change in precursor proteins.
淀粉样疾病，包括阿尔茨海默病和传染性海绵状脑病，其特征是由可溶性前体蛋白衍生而来的异常蛋白原纤维在细胞外沉积。尽管不同的前体似乎能产生相似的原纤维，但利用现代技术尚未得出淀粉样原纤维的适当分子结构。原纤维结构的知识对于理解淀粉样形成的分子机制至关重要，并且可能会促成抑制或逆转该过程的药物的开发。
利用同步辐射的纤维衍射方法研究了来自家族性淀粉样多神经病（FAP）患者的淀粉样原纤维的结构，这些原纤维源自转甲状腺素蛋白（TTR）变体。首次观察到显著的高角度衍射图谱，显示出分辨率达2埃的子午线反射。该图谱与先前报道的原纤维的交叉β结构完全一致，但同时也揭示了一个新的115埃的大规模纤维重复结构。我们将此图谱解释为由24条β链组成的重复单元的图谱，这些β链围绕平行于纤维轴的轴形成一个完整的β折叠螺旋圈。这种结构以前未曾观察到。基于这一解释，我们构建了FAP淀粉样原纤维原丝的模型，该模型由通过与纤维轴重合的单个螺旋轴相关的四个β折叠组成，并表明它与观察到的X射线数据一致。
这项工作表明，淀粉样原纤维具有一种新颖的分子结构，由沿着纤维长度以规则螺旋扭曲延伸的β折叠组成。这意味着纤维中的多肽链在纤维的整个长度上通过氢键结合在一起，从而解释了它们的高度稳定性。所提出的FAP原纤维结构需要一个在结构上不同于天然四聚体的TTR构建模块。这很可能是一个具有重组或截短的β折叠的单体或二聚体，表明淀粉样形成可能需要前体蛋白发生显著的结构变化。
