Capturing intermediate structures of Alzheimer's β-amyloid, Aβ(1-40), by solid-state NMR spectroscopy

摘要: Molecular structures of diffusible amyloid intermediates, commonly observed in misfolding proteins into fibrils, have attracted broad interest because the intermediates may be potent neurotoxins responsible for diseases such as Alzheimer's disease (AD) and intermediate provide an experimental basis defining pathway. However, owing to intrinsically unstable noncrystalline nature systems, traditional approaches X-ray crystallography solution NMR been ineffective elucidating molecular-level intermediates. We present a novel approach using solid-state (SSNMR) that permitted first site-resolved structural measurement species fibril formation 40-residue beta-amyloid peptide, Abeta(1-40). In this approach, we combined detection conformation morphology changes by fluorescence spectroscopy electron microscopy quantitative examination freeze-trapped SSNMR. The results initial evidence spherical 15-30 nm diameter exists prior Abeta(1-40) involves well-ordered beta-sheets C-terminal hydrophobic core regions. SSNMR-based presented here could applied diverse proteins.