X-RAY-DIFFRACTION FROM INTRANEURONAL PAIRED HELICAL FILAMENTS AND EXTRANEURONAL AMYLOID FIBERS IN ALZHEIMER-DISEASE INDICATES CROSS-BETA CONFORMATION
X-RAY-DIFFRACTION FROM INTRANEURONAL PAIRED HELICAL FILAMENTS AND EXTRANEURONAL AMYLOID FIBERS IN ALZHEIMER-DISEASE INDICATES CROSS-BETA CONFORMATION
复制标题
DOI：
10.1073/pnas.83.2.503
复制
发表时间：
1986-01-01
影响因子：
11.1
通讯作者：
SELKOE, DJ
中科院分区：
文献类型：
--
作者：
KIRSCHNER, DA;ABRAHAM, C;SELKOE, DJ
迄今为止，关于人类神经元内积累的成对螺旋丝（PHF）和阿尔茨海默病神经元间细胞外空间积累的淀粉样纤维结构的信息依赖于薄切片或负染色材料的电子显微镜。为了确定这些异常纤维的蛋白质构象，我们从高度富集PHF的未固定人脑部分和从老年斑中分离的纯化淀粉样蛋白核中获得了x射线衍射图。从两种类型的样品中，无论是湿的还是干的，主要的x射线散射明显是4.76-.ANG的尖锐反射。间距和漫射的一个大约在10.6- 0.ang。间距。这些特性是.beta的特征。-折叠片型蛋白质构象。在PHF组分的双取向干燥球团中，两种反射在彼此成直角时增强，弧在4.76- 0.ang处。间距在光纤方向表示一个十字。构象。从反射的积分宽度我们估计交叉。结晶温度约为80g。在纤维方向长，约40 . ang。厚。这些尺寸对应于大约四个褶片，每个褶片由大约16个与纤维方向垂直的氢键多肽链组成。十字架度量。我们从x射线衍射中发现的PHF和淀粉样纤维的构象与主要的。α形成对比。-螺旋螺旋状大肠杆菌的神经丝构象，它们共享表位，并被认为是由它们派生的。
Information about the structure of the paired helical filaments (PHF) that accumulate within human neurons and the amyloid fibers that accumulate in the extracellular spaces between neurons in Alzheimer disease has so far depended on electron microscopy of thin-sectioned or negatively stained material. To determine the protein conformation of these abnormal fibers, we have obtained x-ray diffraction patterns from unfixed human brain fractions highly enriched in PHF and from purified amyloid cores isolated from senile plaques. The predominant x-ray scatter evident from both types of samples, either wet or dry, is a sharp reflection at 4.76-.ANG. spacing and a diffuse one at about 10.6-.ANG. spacing. These features are characteristic of a .beta.-pleated sheet type of protein conformation. In doubly oriented dried pellets of PHF fractions, the two reflections are accentuated at right angles to each other and the arc at 4.76-.ANG. spacing is in the fiber direction indicating a cross-.beta. conformation. From the integral widths of the reflections we estimate the cross-.beta. crystallite to be about 80 .ANG. long in the fiber direction and about 40 .ANG. thick. These dimensions correspond to approximately four pleated sheets, each of which consists of approximately 16 hydrogen-bonded polypeptide chains running normal to the fiber direction. The cross-.beta. conformation of PHF and amyloid fibers that we have found from x-ray diffraction is in contrast to the predominant .alpha.-helical coiled-coli conformation of the neurofilaments with which they share epitopes and from which they have been postulated to derive.