A partially folded structure of amyloid-beta(1-40) in an aqueous environment

Abstract

Aggregation of the Aβ(1-40) peptide is linked to the development of extracellular plaques characteristic of Alzheimer's disease. While previous studies commonly show the Aβ(1-40) is largely unstructured in solution, we show that Aβ(1-40) can adopt a compact, partially folded structure. In this structure (PDB ID: 2LFM), the central hydrophobic region of the peptide forms a 3(10) helix from H13 to D23 and the N- and C-termini collapse against the helix due to the clustering of hydrophobic residues. Helical intermediates have been predicted to be crucial on-pathway intermediates in amyloid fibrillogenesis, and the structure presented here presents a new target for investigation of early events in Aβ(1-40) fibrillogenesis.

Figure 1

H_α-N_H region of a 2D-NOESY spectrum (300 ms, 900 MHz) of Aβ_1-40 in 20 mM potassium phosphate, 50 mM NaCl, pH 7.3 at 288 K. Only the NOEs corresponding to sequential assignment H_αi-N_Hi+1 are labeled.

Figure 2

(A) NOE connectivity plot showing the formation of a 3₁₀ helix for residues H13 to D23 of Aβ_1-40. The strengths of sequential NOEs are indicated by the height of the bars, graded into categories of strong, medium, or weak. (B) Deviations from Hα random coil chemical shift values showing the propensity of Aβ_1-40 to form a helix.

Figure 3

(A) High-resolution NMR structures of Aβ_1-40at 15 °C at pH 7.3 in 50 mM NaCl. (B) A cartoon plot showing the long-range NOEs stabilizing the formation of the hairpin structure and the bends in the N- and C-termini (red lines).

Figure 4

The aromatic region of a 2D-NOESY spectrum showing crosspeaks between F19 and F20 and the C-terminus and F4 and the central helix.