Differential effects of Phe19 and Phe20 on fibril formation by amyloidogenic peptide Aβ16-22 (Ac-KLVFFAE-NH2)
Differential effects of Phe19 and Phe20 on fibril formation by amyloidogenic peptide Aβ16-22 (Ac-KLVFFAE-NH2)
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DOI：
10.1002/prot.22743
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发表时间：
2010-08-01
影响因子：
2.9
通讯作者：
Kirschner, Daniel A.
中科院分区：
文献类型：
--
作者：
Inouye, Hideyo;Gleason, Katherine A.;Kirschner, Daniel A.
阿尔茨海默病β-淀粉样蛋白中的序列KLVFFAE (A beta 16-22)被认为是核心β-结构，可以作为模板将多肽或分子的其他部分折叠成富含β-折叠的纤维状组件。为了阐明初始折叠过程的机制，我们结合 X 射线纤维/粉末衍射和红外 (IR) 光谱来分析冻干的 A beta 16-22 和含有 F19 和/或 F20 腈探针的溶解/干燥肽。溶解/干燥的野生型 (WT) A β 16-22 和在 F19 (19CN) 或 F20 (20CN) 处含有氰基苯丙氨酸的肽给出了与板状 β 微晶一致的纤维图案，这些纤维图案围绕平行于多肽链方向的轴进行圆柱平均。 WT 和 19CN 组件显示出由板沿肽链方向堆叠而产生的 30 埃周期阵列，而 20CN 组件则缺乏任何此类堆叠。沿肽链方向的电子密度投影表明 WT 和 20CN 具有相似的侧链配置，但 19CN 则不然。这些 X 射线结果和建模表明，在 WT A beta 16-22 的组装中，F19 侧链位于片间空间内，并参与跨片间空间与氨基酸的疏水接触，而位于板表面附近的 F20 侧链对于板间相互作用不太重要，但参与板堆叠。对稀溶液中相同肽的红外观察显示，20CN 中的腈基团比 19CN 中的腈基具有更大程度的氢键，支持了这一解释。蛋白质 2010; 78：2306-2321。 (C) 2010 Wiley-Liss, Inc.
The sequence KLVFFAE (A beta 16-22) in Alzheimer's beta-amyloid is thought to be a core beta-structure that could act as a template for folding other parts of the polypeptide or molecules into fibrillar assemblies rich in beta-sheet. To elucidate the mechanism of the initial folding process, we undertook combined X-ray fiber/powder diffraction and infrared (IR) spectroscopy to analyze lyophilized A beta 16-22 and solubilized/dried peptide containing nitrile probes at F19 and/or F20. Solubilized/dried wild-type (WT) A beta 16-22 and the peptide containing cyanophenylalanine at F19 (19CN) or at F20 (20CN) gave fiber patterns consistent with slab-like beta-crystallites that were cylindrically averaged around the axis parallel to the polypeptide chain direction. The WT and 19CN assemblies showed 30-angstrom period arrays arising from the stacking of the slabs along the peptide chain direction, whereas the 20CN assemblies lacked any such stacking. The electron density projection along the peptide chain direction indicated similar side-chain dispositions for WT and 20CN, but not for 19CN. These X-ray results and modeling imply that in the assembly of WT A beta 16-22 the F19 side chain is localized within the intersheet space and is involved in hydrophobic contact with amino acids across the intersheet space, whereas the F20 side chain localized near the slab surface is less important for the intersheet interaction, but involved in slab stacking. IR observations for the same peptides in dilute solution showed a greater degree of hydrogen bonding for the nitrile groups in 20CN than in 19CN, supporting this interpretation. Proteins 2010; 78:2306-2321. (C) 2010 Wiley-Liss, Inc.