A structural model for Alzheimer's β-amyloid fibrils based on experimental constraints from solid state NMR
A structural model for Alzheimer's β-amyloid fibrils based on experimental constraints from solid state NMR
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DOI：
10.1073/pnas.262663499
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发表时间：
2002-12-24
影响因子：
11.1
通讯作者：
Tycko, R
中科院分区：
文献类型：
--
作者：
Petkova, AT;Ishii, Y;Tycko, R
我们提出了一个淀粉样蛋白纤维形成的40个残基β-淀粉样蛋白肽与阿尔茨海默氏病（Abeta（1-40）），基于一组实验的限制，从固态NMR光谱的结构模型。该模型还结合了由X射线纤维衍射建立的交叉β结构基序，并满足对Abeta（1-40）原纤维尺寸和电子显微镜测定的质量/长度的约束。Abeta（1-40）的前10个残基在原纤维中结构上是无序的。残基12-24和30-40采用β-链构象并通过分子间氢键形成平行的P-片层。残基25-29含有肽骨架的弯曲，其通过侧链-侧链相互作用使两个β-折叠接触。然后，单个交叉β单元是具有疏水核和一个疏水面的双层β-片层结构。核心中唯一带电的侧链是D23和K28，它们形成盐桥。具有最小单位长度质量和直径的原纤维由两个交叉β单元组成，它们的疏水面并置。
We present a structural model for amyloid fibrils formed by the 40-residue beta-amyloid peptide associated with Alzheimer's disease (Abeta(1-40)), based on a set of experimental constraints from solid state NMR spectroscopy. The model additionally incorporates the cross-beta structural motif established by x-ray fiber diffraction and satisfies constraints on Abeta(1-40) fibril dimensions and mass-per-length determined from electron microscopy. Approximately the first 10 residues of Abeta(1-40) are structurally disordered in the fibrils. Residues 12-24 and 30-40 adopt beta-strand conformations and form parallel p-sheets through intermolecular hydrogen bonding. Residues 25-29 contain a bend of the peptide backbone that brings the two beta-sheets in contact through sidechain-sidechain interactions. A single cross-beta unit is then a double-layered beta-sheet structure with a hydrophobic core and one hydrophobic face. The only charged sidechains in the core are those of D23 and K28, which form salt bridges. Fibrils with minimum mass-per-length and diameter consist of two cross-beta units with their hydrophobic faces juxtaposed.