NMR-based site-resolved profiling of β-amyloid misfolding reveals structural transitions from pathologically relevant spherical oligomer to fibril
| Autor: | Yoshitaka Ishii, Minako Hoshi, Isamu Matsuda, Yiling Xiao, Masafumi Inoue, Tomoya Sasahara |
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| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
Conformational change Amyloid Protein Folding Protein aggregation Fibril Biochemistry Oligomer Protein Structure Secondary 03 medical and health sciences chemistry.chemical_compound Alzheimer Disease Humans Molecular Biology Nuclear Magnetic Resonance Biomolecular Amyloid beta-Peptides 030102 biochemistry & molecular biology Cell Biology Peptide Fragments 030104 developmental biology Structural biology Solid-state nuclear magnetic resonance chemistry Protein Structure and Folding Biophysics Protein folding |
| Zdroj: | J Biol Chem |
| ISSN: | 1083-351X |
| Popis: | Increasing evidence highlights the central role of neurotoxic oligomers of the 42-residue-long β-amyloid (Aβ42) in Alzheimer's disease (AD). However, very limited information is available on the structural transition from oligomer to fibril, particularly for pathologically relevant amyloids. To the best of our knowledge, we present here the first site-specific structural characterization of Aβ42 misfolding, from toxic oligomeric assembly yielding a similar conformation to an AD-associated Aβ42 oligomer, into a fibril. Transmission EM (TEM) analysis revealed that a spherical amyloid assembly (SPA) of Aβ42 with a 15.6 ± 2.1-nm diameter forms in a ∼30-μm Aβ42 solution after a ∼10-h incubation at 4 °C, followed by a slow conversion into fibril at ∼180 h. Immunological analysis suggested that the SPA has a surface structure similar to that of amylospheroid (ASPD), a patient-derived toxic Aβ oligomer, which had a diameter of 10–15 nm in negative-stain TEM. Solid-state NMR analyses indicated that the SPA structure involves a β-loop-β motif, which significantly differed from the triple-β motif observed for the Aβ42 fibril. The comparison of the (13)C chemical shifts of SPA with those of the fibril prepared in the above conditions and interstrand distance measurements suggested a large conformational change involving rearrangements of intermolecular β-sheet into in-register parallel β-sheet during the misfolding. A comparison of the SPA and ASPD (13)C chemical shifts indicated that SPA is structurally similar to the ASPD relevant to AD. These observations provide insights into the architecture and key structural transitions of amyloid oligomers relevant for AD pathology. |
| Databáze: | OpenAIRE |
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