Solid state NMR reveals a pH-dependent antiparallel β-sheet registry in fibrils formed by a β-amyloid peptide

被引:271
作者
Petkova, AT
Buntkowsky, G
Dyda, F
Leapman, RD
Yau, WM
Tycko, R [1 ]
机构
[1] NIDDKD, Chem Phys Lab, NIH, Bethesda, MD 20892 USA
[2] Free Univ Berlin, Dept Chem, D-14195 Berlin, Germany
[3] NIDDKD, Mol Biol Lab, NIH, Bethesda, MD 20892 USA
[4] NIH, Div Bioengn & Phys Sci, Off Res Serv, Bethesda, MD 20892 USA
基金
美国国家卫生研究院;
关键词
amyloid fibrils; hydrogen bond registry; antiparallel beta-sheets; solid state NMR; Alzheimer's disease;
D O I
10.1016/j.jmb.2003.10.044
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
We report solid state nuclear magnetic resonance (NMR) measurements that probe the supramolecular organization of beta-sheets in the cross-beta motif of amyloid fibrils formed by residues 11-25 of the beta-amyloid peptide associated with Alzheimer's disease (Abeta(11-25)). Fibrils were prepared at pH 7.4 and pH 2.4. The solid state NMR data indicate that the central hydrophobic segment of Abeta(11-25) (sequence LVFFA) adopts a beta-strand conformation and participates in antiparallel beta-sheets at both pH values, but that the registry of intermolecular hydrogen bonds is pH-dependent. Moreover, both registries determined for Abeta(11-25) fibrils are different from the hydrogen bond registry in the antiparallel beta-sheets of Abeta(16-22) fibrils at pH 7.4 determined in earlier solid state NMR studies. In all three cases, the hydrogen bond registry is highly ordered, with no detectable "registry-shift" defects. These results suggest that the supramolecular organization of beta-sheets in amyloid fibrils is determined by a sensitive balance of multiple side-chain-side-chain interactions. Recent structural models for Abeta(11-25) fibrils based on X-ray fiber diffraction data are inconsistent with the solid state NMR data at both pH values. (C) 2003 Elsevier Ltd. All rights reserved.
引用
收藏
页码:247 / 260
页数:14
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