Cryo-electron microscopy structure of an SH3 amyloid fibril and model of the molecular packing
Cryo-electron microscopy structure of an SH3 amyloid fibril and model of the molecular packing
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DOI：
10.1093/emboj/18.4.815
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发表时间：
1999-02-15
期刊：
影响因子：
11.4
通讯作者：
Saibil, HR
中科院分区：
文献类型：
--
作者：
Jiménez, JL;Guijarro, JL;Saibil, HR
淀粉样蛋白原纤维是错误折叠蛋白质的集合，与阿尔茨海默病和海绵状脑病等病理状况有关。在淀粉样蛋白疾病中，一组不同的正常可溶性蛋白质自组装形成不溶性原纤维，x射线纤维衍射研究表明，由各种蛋白质形成的原纤维的原丝核都含有交叉-支架。线垂直于纤维轴，片平行于纤维轴。我们已经确定了淀粉样纤维的三维结构，由磷脂酰肌醇-3'-激酶的SH3结构域形成，使用低温电子显微镜和25埃分辨率的图像处理。其结构为两对原丝缠绕在空心核上的双螺旋结构，螺旋交叉重复约为600埃，轴向亚基重复约为27埃。原生SH3结构域过于紧凑，无法适应原纤维的密度，必须展开，以淀粉样蛋白的形式采用更长的、更薄的形状。这种20x40埃的原丝只能容纳一对相互堆叠的扁平β -片，其股间扭曲很小。我们提出了一个多肽包装模型，作为理解淀粉样原纤维结构的基础。
Amyloid fibrils are assemblies of misfolded proteins and are associated with pathological conditions such as Alzheimer's disease and the spongiform encephalopathies, In the amyloid diseases, a diverse group of normally soluble proteins self-assemble to form insoluble fibrils, X-ray fibre diffraction studies have shown that the protofilament cores of fibrils formed from the various proteins all contain a cross-beta-scaffold, with beta-strands perpendicular and beta-sheets parallel to the fibre axis. We have determined the three-dimensional structure of an amyloid fibril, formed by the SH3 domain of phosphatidylinositol-3'-kinase, using cryo-electron microscopy and image processing at 25 Angstrom resolution. The structure is a double helix of two protofilament pairs wound around a hollow core, with a helical crossover repeat of similar to 600 Angstrom and an axial subunit repeat of similar to 27 Angstrom. The native SH3 domain is too compact to fit into the fibril density, and must unfold to adopt a longer, thinner shape in the amyloid form. The 20x40-Angstrom protofilaments can only accommodate one pair of flat beta-sheets stacked against each other, with very little inter-strand twist. We propose a model for the polypeptide packing as a basis for understanding the structure of amyloid fibrils in general.