期刊
JOURNAL OF BIOLOGICAL CHEMISTRY
卷 295, 期 2, 页码 458-467出版社
ELSEVIER
DOI: 10.1074/jbc.RA119.008522
关键词
amyloid-beta (AB); amyloid; solid state NMR; protein misfolding; structural biology; oligomer; Alzheimer disease; neurodegeneration; protein aggregation; amylospheroid (ASPD); fibrillization; neurotoxic protein; spherical amyloid assembly (SPA); Abeta42
资金
- National Institutes of Health [U01 GM098033, R01 GM098033]
- JST-Mirai, Japan [JPMJMI17A2]
- Japan Society for the Promotion of Science (SSPS) KAKENHI Grant [17H04055]
- JSPS KAKENHI [JP15K21772]
- Grants-in-Aid for Scientific Research [17H04055] Funding Source: KAKEN
Increasing evidence highlights the central role of neurotoxic oligomers of the 42-residue-long ?-amyloid (A?42) 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 A?42 misfolding, from toxic oligomeric assembly yielding a similar conformation to an AD-associated A?42 oligomer, into a fibril. Transmission EM (TEM) analysis revealed that a spherical amyloid assembly (SPA) of A?42 with a 15.6 ? 2.1-nm diameter forms in a ?30-?m A?42 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 A? oligomer, which had a diameter of 10?15 nm in negative-stain TEM. Solid-state NMR analyses indicated that the SPA structure involves a ?-loop-? motif, which significantly differed from the triple-? motif observed for the A?42 fibril. The comparison of the C-13 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 ?-sheet into in-register parallel ?-sheet during the misfolding. A comparison of the SPA and ASPD C-13 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.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据