| Abstract: | Abstract: We have proposed that amyloid fibrils contain subunits (protofibrils) that are formed from β-strands wound into continuous 2–3 nm-diameter β-helices. Subsequent lateral aggregation of the β-helices to form the widely observed 5–12 nm-diameter fibrils could be promoted by hydrophobic residues on the exterior of the postulated β-helix. A number of short peptide fragments of the amyloid-β (Aβ) proteins, such as Aβ34–42 LMVGGVVIA], the nine-residue, carboxyl-terminal portion of Aβ1–42, can also form amyloid fibrils. In the present study, it was found that a β-helix formed from Aβ34–42 accounts for features suggested by published rotational resonance solid-state NMR data, including an anomalous conformation about the Gly-37–Gly-38 region and exaggerated pleating. An analogue of Aβ34–42 was synthesized in which the hydrophobic groups on the exterior of the postulated β-helix were replaced with glutamates, giving LEVGGVEIE. The analogue was completely soluble at pH 7, but at pH 2.5 it produced 2–2.5 nm-diameter fibrils which did not associate into larger-diameter bundles. The results of this study support the proposal that amyloid fibrils are formed from β-helical subunits. |
