Polymorphism of Alzheimer's Aβ17-42 (p3) oligomers: The importance of the turn location and its conformation

Yifat Miller, Buyong Ma, Ruth Nussinov

Research output: Contribution to journalArticlepeer-review

Abstract

17-42 (so-called p3) amyloid is detected in vivo in the brains of individuals with Alzheimer's disease or Down's syndrome. We investigated the polymorphism of Aβ17-42 oligomers based on experimental data from steady-state NMR measurements, electron microscopy, two-dimensional hydrogen exchange, and mutational studies, using all-atom moleculardynamics simulation with explicit solvent. We assessed the structural stability and the populations. Our results suggest that conformational differences in the U-turn of Aβ17-42 lead to polymorphism in β-sheet registration and retention of an ordered β-strand organization at the termini. Further, although the parallel Aβ17-42 oligomer organization is the most stable of the conformers investigated here, different antiparallel Aβ17-42 organizations are also stable and compete with the parallel architectures, presenting a polymorphic population. In this study we propose that 1), the U-turn conformation is the primary factor leading to polymorphism in the assembly of Aβ17-42 oligomers, and is also coupled to oligomer growth; and 2), both parallel Aβ17-42 oligomers and an assembly of Aβ17-42 oligomers that includes both parallel and antiparallel organizations contribute to amyloid fibril formation. Finally, since a U-turn motif generally appears in amyloids formed by full proteins or long fragments, and since to date these have been shown to exist only in parallel architectures, our results apply to a broad range of oligomers and fibrils.

Original languageEnglish
Pages (from-to)1168-1177
Number of pages10
JournalBiophysical Journal
Volume97
Issue number4
DOIs
StatePublished - 19 Aug 2009

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