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基本情報
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タイトル | Sarkosyl-extracted AppNL-G-F Abeta42 fibril structure (Methoxy-X04-labelled mice) | |||||||||
![]() | CryoEM map for extracted AppNLGF Abeta42 fibril after MOX04 labelling | |||||||||
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![]() | Amyloid / fibril / helical / cross-beta / beta amyloid / PROTEIN FIBRIL / ex vivo / arctic mutant / alzheimers disease | |||||||||
機能・相同性 | ![]() regulation of epidermal growth factor-activated receptor activity / cytosolic mRNA polyadenylation / collateral sprouting in absence of injury / microglia development / regulation of synapse structure or activity / regulation of Wnt signaling pathway / Formyl peptide receptors bind formyl peptides and many other ligands / axo-dendritic transport / synaptic assembly at neuromuscular junction / signaling receptor activator activity ...regulation of epidermal growth factor-activated receptor activity / cytosolic mRNA polyadenylation / collateral sprouting in absence of injury / microglia development / regulation of synapse structure or activity / regulation of Wnt signaling pathway / Formyl peptide receptors bind formyl peptides and many other ligands / axo-dendritic transport / synaptic assembly at neuromuscular junction / signaling receptor activator activity / axon midline choice point recognition / smooth endoplasmic reticulum calcium ion homeostasis / astrocyte activation involved in immune response / regulation of spontaneous synaptic transmission / mating behavior / NMDA selective glutamate receptor signaling pathway / ciliary rootlet / Lysosome Vesicle Biogenesis / PTB domain binding / Golgi-associated vesicle / neuron remodeling / Insertion of tail-anchored proteins into the endoplasmic reticulum membrane / positive regulation of amyloid fibril formation / positive regulation of G2/M transition of mitotic cell cycle / Deregulated CDK5 triggers multiple neurodegenerative pathways in Alzheimer's disease models / nuclear envelope lumen / COPII-coated ER to Golgi transport vesicle / suckling behavior / dendrite development / presynaptic active zone / modulation of excitatory postsynaptic potential / regulation of peptidyl-tyrosine phosphorylation / TRAF6 mediated NF-kB activation / Advanced glycosylation endproduct receptor signaling / neuromuscular process controlling balance / The NLRP3 inflammasome / regulation of presynapse assembly / transition metal ion binding / negative regulation of long-term synaptic potentiation / regulation of multicellular organism growth / negative regulation of neuron differentiation / ECM proteoglycans / intracellular copper ion homeostasis / smooth endoplasmic reticulum / positive regulation of T cell migration / spindle midzone / Purinergic signaling in leishmaniasis infection / protein serine/threonine kinase binding / positive regulation of chemokine production / clathrin-coated pit / forebrain development / Notch signaling pathway / neuron projection maintenance / positive regulation of protein metabolic process / positive regulation of calcium-mediated signaling / astrocyte activation / ionotropic glutamate receptor signaling pathway / positive regulation of glycolytic process / response to interleukin-1 / cholesterol metabolic process / positive regulation of mitotic cell cycle / extracellular matrix organization / adult locomotory behavior / axonogenesis / platelet alpha granule lumen / trans-Golgi network membrane / positive regulation of peptidyl-threonine phosphorylation / positive regulation of interleukin-1 beta production / learning / dendritic shaft / positive regulation of long-term synaptic potentiation / Mitochondrial protein degradation / central nervous system development / locomotory behavior / endosome lumen / positive regulation of JNK cascade / Post-translational protein phosphorylation / synapse organization / microglial cell activation / regulation of long-term neuronal synaptic plasticity / TAK1-dependent IKK and NF-kappa-B activation / visual learning / neuromuscular junction / positive regulation of non-canonical NF-kappaB signal transduction / recycling endosome / cognition / G2/M transition of mitotic cell cycle / Golgi lumen / positive regulation of inflammatory response / neuron cellular homeostasis / positive regulation of interleukin-6 production / cellular response to amyloid-beta / endocytosis / Regulation of Insulin-like Growth Factor (IGF) transport and uptake by Insulin-like Growth Factor Binding Proteins (IGFBPs) / serine-type endopeptidase inhibitor activity / positive regulation of peptidyl-serine phosphorylation / positive regulation of tumor necrosis factor production / neuron projection development / cell-cell junction / synaptic vesicle 類似検索 - 分子機能 | |||||||||
生物種 | ![]() ![]() | |||||||||
手法 | らせん対称体再構成法 / クライオ電子顕微鏡法 / 解像度: 3.2 Å | |||||||||
![]() | Wilkinson M / Leistner C / Burgess A / Goodfellow S / Deuchars S / Ranson NA / Radford SE / Frank RAW | |||||||||
資金援助 | ![]()
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![]() | ![]() タイトル: The in-tissue molecular architecture of β-amyloid pathology in the mammalian brain. 著者: Conny Leistner / Martin Wilkinson / Ailidh Burgess / Megan Lovatt / Stanley Goodbody / Yong Xu / Susan Deuchars / Sheena E Radford / Neil A Ranson / René A W Frank / ![]() 要旨: Amyloid plaques composed of Aβ fibrils are a hallmark of Alzheimer's disease (AD). However, the molecular architecture of amyloid plaques in the context of fresh mammalian brain tissue is unknown. ...Amyloid plaques composed of Aβ fibrils are a hallmark of Alzheimer's disease (AD). However, the molecular architecture of amyloid plaques in the context of fresh mammalian brain tissue is unknown. Here, using cryogenic correlated light and electron tomography we report the in situ molecular architecture of Aβ fibrils in the App familial AD mouse model containing the Arctic mutation and an atomic model of ex vivo purified Arctic Aβ fibrils. We show that in-tissue Aβ fibrils are arranged in a lattice or parallel bundles, and are interdigitated by subcellular compartments, extracellular vesicles, extracellular droplets and extracellular multilamellar bodies. The Arctic Aβ fibril differs significantly from an earlier App fibril structure, indicating a striking effect of the Arctic mutation. These structural data also revealed an ensemble of additional fibrillar species, including thin protofilament-like rods and branched fibrils. Together, these results provide a structural model for the dense network architecture that characterises β-amyloid plaque pathology. | |||||||||
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画像 | ![]() | 91.5 KB | ||
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その他 | ![]() ![]() | 56.6 MB 56.7 MB | ||
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-検証レポート
文書・要旨 | ![]() | 954.5 KB | 表示 | ![]() |
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文書・詳細版 | ![]() | 954 KB | 表示 | |
XML形式データ | ![]() | 12.4 KB | 表示 | |
CIF形式データ | ![]() | 14.6 KB | 表示 | |
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-関連構造データ
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リンク
EMDBのページ | ![]() ![]() |
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「今月の分子」の関連する項目 |
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マップ
ファイル | ![]() | ||||||||||||||||||||
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注釈 | CryoEM map for extracted AppNLGF Abeta42 fibril after MOX04 labelling | ||||||||||||||||||||
ボクセルのサイズ | X=Y=Z: 0.94 Å | ||||||||||||||||||||
密度 |
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対称性 | 空間群: 1 | ||||||||||||||||||||
詳細 | EMDB XML:
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-添付データ
-ハーフマップ: halfmap2
ファイル | emd_16019_half_map_1.map | ||||||||||||
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注釈 | halfmap2 | ||||||||||||
投影像・断面図 |
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密度ヒストグラム |
-ハーフマップ: halfmap1
ファイル | emd_16019_half_map_2.map | ||||||||||||
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注釈 | halfmap1 | ||||||||||||
投影像・断面図 |
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密度ヒストグラム |
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試料の構成要素
-全体 : Sarkosyl-extracted AppNL-G-F Abeta42 fibril
全体 | 名称: Sarkosyl-extracted AppNL-G-F Abeta42 fibril |
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要素 |
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-超分子 #1: Sarkosyl-extracted AppNL-G-F Abeta42 fibril
超分子 | 名称: Sarkosyl-extracted AppNL-G-F Abeta42 fibril / タイプ: complex / ID: 1 / 親要素: 0 / 含まれる分子: all 詳細: Fibrils purified from mouse brain labelled with Methoxy-X04 |
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由来(天然) | 生物種: ![]() ![]() |
分子量 | 理論値: 4.441 kDa/nm |
-分子 #1: Amyloid-beta precursor protein
分子 | 名称: Amyloid-beta precursor protein / タイプ: protein_or_peptide / ID: 1 詳細: Humanised Abeta42 from App^NL-G-F mice with arctic mutation (E22G) コピー数: 10 / 光学異性体: LEVO |
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由来(天然) | 生物種: ![]() ![]() |
分子量 | 理論値: 4.448025 KDa |
配列 | 文字列: DAEFRHDSGY EVHHQKLVFF AGDVGSNKGA IIGLMVGGVV IA UniProtKB: Amyloid-beta precursor protein |
-実験情報
-構造解析
手法 | クライオ電子顕微鏡法 |
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![]() | らせん対称体再構成法 |
試料の集合状態 | filament |
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試料調製
緩衝液 | pH: 7.4 構成要素:
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グリッド | モデル: C-flat-1.2/1.3 / 材質: COPPER / メッシュ: 300 / 支持フィルム - 材質: CARBON / 支持フィルム - トポロジー: HOLEY / 前処理 - タイプ: PLASMA CLEANING / 前処理 - 時間: 60 sec. | |||||||||
凍結 | 凍結剤: ETHANE / チャンバー内湿度: 90 % / チャンバー内温度: 277 K / 装置: FEI VITROBOT MARK IV / 詳細: 6s blot. | |||||||||
詳細 | Sarkosyl-insoluble fibrils from App^NL-G-F mouse brain labelled with Methoxy-X04 |
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電子顕微鏡法
顕微鏡 | FEI TITAN KRIOS |
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特殊光学系 | エネルギーフィルター - 名称: TFS Selectris / エネルギーフィルター - スリット幅: 10 eV |
撮影 | フィルム・検出器のモデル: FEI FALCON IV (4k x 4k) 撮影したグリッド数: 1 / 実像数: 4165 / 平均露光時間: 6.0 sec. / 平均電子線量: 41.0 e/Å2 詳細: 1442 raw EER frames were collected per image and combined into 40 fractions for processing |
電子線 | 加速電圧: 300 kV / 電子線源: ![]() |
電子光学系 | C2レンズ絞り径: 50.0 µm / 照射モード: FLOOD BEAM / 撮影モード: BRIGHT FIELD / Cs: 2.7 mm / 最大 デフォーカス(公称値): 2.9 µm 最小 デフォーカス(公称値): 1.4000000000000001 µm 倍率(公称値): 130000 |
試料ステージ | 試料ホルダーモデル: FEI TITAN KRIOS AUTOGRID HOLDER |
実験機器 | ![]() モデル: Titan Krios / 画像提供: FEI Company |
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画像解析
最終 再構成 | 想定した対称性 - らせんパラメータ - Δz: 2.414 Å 想定した対称性 - らせんパラメータ - ΔΦ: 179.355 ° 想定した対称性 - らせんパラメータ - 軸対称性: C1 (非対称) 解像度のタイプ: BY AUTHOR / 解像度: 3.2 Å / 解像度の算出法: FSC 0.143 CUT-OFF / ソフトウェア - 名称: RELION (ver. 4.0) / 使用した粒子像数: 3640 |
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Segment selection | 選択した数: 136214 / ソフトウェア - 名称: crYOLO 詳細: Manually picked a subset of images to train a model for automatic fibril segment picking in crYOLO |
初期モデル | モデルのタイプ: INSILICO MODEL 詳細: Model generated from 2D class averages using relion_helix_inimodel2d |
最終 角度割当 | タイプ: NOT APPLICABLE / ソフトウェア - 名称: RELION (ver. 4.0) |
-原子モデル構築 1
精密化 | 空間: REAL / プロトコル: AB INITIO MODEL / 温度因子: 52 / 当てはまり具合の基準: Correlation coefficient |
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得られたモデル | ![]() PDB-8bfb: |