Cryo-EM structures of amyloid-β filaments with the Arctic mutation (E22G) from human and mouse brains.
Cryo-EM structures of amyloid-β filaments with the Arctic mutation (E22G) from human and mouse brains.
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DOI：
10.1007/s00401-022-02533-1
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发表时间：
2023-03
影响因子：
12.7
通讯作者：
中科院分区：
文献类型：
--
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北极突变，编码淀粉样前体蛋白（APP）基因中的E693 G [淀粉样蛋白-β（Aβ）中的E22 G]，导致显性遗传性阿尔茨海默病。在这里，我们报告了来自先前描述的北极突变病例（Aβ PParc 1）额叶皮质的Aβ细丝的高分辨率冷冻电镜结构。大多数丝由两对不相同的原丝组成，所述原丝包含残基V12-V40（人北极折叠A）和E11-G37（人北极折叠B）。其亚结构（残基F20-G37）与I型和II型Aβ42的折叠相同。当与野生型Aβ42细丝的结构相比时，人类北极褶皱中存在细微的构象变化，因为在G22处缺少侧链，这可能会加强突变Aβ分子之间的氢键并促进细丝形成。还存在少数II型Aβ42细丝，以及tau配对螺旋细丝。此外，我们报告了来自小鼠敲入系AppNL−G−F的具有北极突变的Aβ细丝的冷冻电镜结构。大多数的原丝由两个相同的突变原丝组成，从D1延伸到G37（AppNL−G−F鼠北极折叠）。在少数细丝中，两个二聚体折叠以反平行方式彼此包装。AppNL−G−F小鼠北极褶皱不同于人类北极褶皱，但共享一些子结构。在线版本包含补充材料，可通过10.1007/s 00401 -022-02533-1获得。
The Arctic mutation, encoding E693G in the amyloid precursor protein (APP) gene [E22G in amyloid-β (Aβ)], causes dominantly inherited Alzheimer’s disease. Here, we report the high-resolution cryo-EM structures of Aβ filaments from the frontal cortex of a previously described case (AβPParc1) with the Arctic mutation. Most filaments consist of two pairs of non-identical protofilaments that comprise residues V12–V40 (human Arctic fold A) and E11–G37 (human Arctic fold B). They have a substructure (residues F20–G37) in common with the folds of type I and type II Aβ42. When compared to the structures of wild-type Aβ42 filaments, there are subtle conformational changes in the human Arctic folds, because of the lack of a side chain at G22, which may strengthen hydrogen bonding between mutant Aβ molecules and promote filament formation. A minority of Aβ42 filaments of type II was also present, as were tau paired helical filaments. In addition, we report the cryo-EM structures of Aβ filaments with the Arctic mutation from mouse knock-in line AppNL−G−F. Most filaments are made of two identical mutant protofilaments that extend from D1 to G37 (AppNL−G−F murine Arctic fold). In a minority of filaments, two dimeric folds pack against each other in an anti-parallel fashion. The AppNL−G−F murine Arctic fold differs from the human Arctic folds, but shares some substructure. The online version contains supplementary material available at 10.1007/s00401-022-02533-1.
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DOI：
10.1107/s2059798319016577
发表时间：
2020-02-01
影响因子：
2.2
作者：
Scheres, Sjors H. W.
通讯作者：
Scheres, Sjors H. W.
影响因子：
25
作者：
Nilsberth, C;Westlind-Danielsson, A;Lannfelt, L
通讯作者：
Lannfelt, L
影响因子：
16.2
作者：
GOEDERT, M;SPILLANTINI, MG;CROWTHER, RA
通讯作者：
CROWTHER, RA
影响因子：
3
作者：
He, Shaoda;Scheres, Sjors H. W.
通讯作者：
Scheres, Sjors H. W.
影响因子：
48
作者：
Bepler, Tristan;Morin, Andrew;Berger, Bonnie
通讯作者：
Berger, Bonnie