A molecular model of Alzheimer amyloid β-peptide fibril formation

被引:334
作者
Tjernberg, LO
Callaway, DJE
Tjernberg, A
Hahne, S
Lilliehöök, C
Terenius, L
Thyberg, J
Nordstedt, C
机构
[1] Karolinska Hosp, Dept Clin Neurosci, Sect Drug Dependence Res, Lab Biochem & Mol Pharmacol, S-17176 Stockholm, Sweden
[2] Picower Inst Med Res, Manhasset, NY 11030 USA
[3] Pharmacia & Upjohn Inc, Dept Struct Chem, Mass Spectrometr Sect, S-11287 Stockholm, Sweden
[4] Karolinska Inst, Med Nobel Inst, Dept Cell & Mol Biol, S-17177 Stockholm, Sweden
关键词
D O I
10.1074/jbc.274.18.12619
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
Polymerization of the amyloid beta (A beta) peptide into protease-resistant fibrils is a significant step in the pathogenesis of Alzheimer's disease. It has not been possible to obtain detailed structural information about this process with conventional techniques because the peptide has limited solubility and does not form crystals. In this work, we present experimental results leading to a molecular level model for fibril formation. Systematically selected A beta-fragments containing the A beta(16-20) sequence, previously shown essential for A beta-A beta binding, were incubated in a physiological buffer. Electron microscopy revealed that the shortest fibril-forming sequence was A beta(14-23). Substitutions in this decapeptide impaired fibril formation and deletion of the decapeptide from A beta(1-42) inhibited fibril formation completely. All studied peptides that formed fibrils also formed stable dimers and/or tetramers, Molecular modeling of A beta(14-23) oligomers in an antiparallel beta-sheet conformation displayed favorable hydrophobic interactions stabilized by salt bridges between all charged residues. We propose that this decapeptide sequence forms the core of A beta-fibrils, with the hydrophobic C terminus folding over this core. The identification of this fundamental sequence and the implied molecular model could facilitate the design of potential inhibitors of amyloidogenesis.
引用
收藏
页码:12619 / 12625
页数:7
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