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. 2012 Jun 29;287(27):22822-6.
doi: 10.1074/jbc.M112.367474. Epub 2012 May 15.

Solid-state NMR reveals a close structural relationship between amyloid-β protofibrils and oligomers

Holger A Scheidt  1 , Isabel Morgado, Daniel Huster
Affiliations

Solid-state NMR reveals a close structural relationship between amyloid-β protofibrils and oligomers

Holger A Scheidt et al. J Biol Chem. .

Abstract

We have studied tertiary contacts in protofibrils and mature fibrils of amyloid-β (Aβ) peptides using solid-state NMR spectroscopy. Although intraresidue contacts between Glu-22 and Ile-31 were found in Aβ protofibrils, these contacts were completely absent in mature Aβ fibrils. This is consistent with the current models of mature Aβ fibrils. As these intramolecular contacts have also been reported in Aβ oligomers, our measurements suggest that Aβ protofibrils are structurally more closely related to oligomers than to mature fibrils. This suggests that some structural alterations have to take place on the pathway from Aβ oligomers/protofibrils to mature fibrils, in agreement with a model that suggests a conversion of intramolecular hydrogen-bonded structures of Aβ oligomers to the intermolecular stabilized mature fibrils (Hoyer, W., Grönwall, C., Jonsson, A., Ståhl, S., and Härd, T. (2008) Proc. Natl. Acad. Sci. U.S.A. 105, 5099-5104).

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Figures

FIGURE 1.
FIGURE 1.
Molecular structures of Aβ(1–40) oligomers (A; Protein Data Bank code 2OTK (15)) and mature Aβ fibrils (B; Ref. and I. Bertini, personal communication). Glu-22 and Ile-31 are shown in their molecular structure. For Aβ protofibrils, no molecular structure is available so far.
FIGURE 2.
FIGURE 2.
Aliphatic region of the covariance-processed 13C-13C correlation spectra (by proton-driven spin diffusion with a mixing time of 600 ms) for B10AP-stabilized Aβ protofibrils (A) and mature Aβ fibrils (B). The major correlations inside one and the same amino acid for Glu-22 (dashed blue lines) and Ile-31 (dashed black lines) are highlighted. Interresidue cross-peaks between Glu-22 and Ile-31 in A and the lack of these cross-peaks in B are marked with red boxes.
FIGURE 3.
FIGURE 3.
Slices through the Cα (A) and Cβ (B) peaks of Glu-22 for B10AP-stabilized Aβ protofibrils (red) and mature Aβ fibrils (black) of the covariance-processed proton-driven spin diffusion spectra. Interresidue cross-peaks between Glu-22 and Ile-31 are highlighted by the arrows.
FIGURE 4.
FIGURE 4.
C-H order parameters for Glu-22 and Ile-31 in B10AP-stabilized Aβ protofibrils (light gray bars) and mature Aβ fibrils (dark gray bars).
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