EMDB-15770: Type I amyloid-beta 42 filaments from high-spin supernatants of a...

基本情報

登録情報

データベース: EMDB / ID: EMD-15770

• タイトル: Type I amyloid-beta 42 filaments from high-spin supernatants of aqueous extracts from Alzheimer's disease brains | ABeta42

試料

• 組織: Type I amyloid-beta 42 filaments in soluble high-molecular weight aggregate fractions extracted from Alzheimer's disease brain
  • タンパク質・ペプチド: Amyloid-beta precursor protein

• キーワード: amyloid / filaments / Abeta42 / amyloid-beta / cryo-EM / PROTEIN FIBRIL

機能・相同性

分子機能:

amyloid-beta complex / growth cone lamellipodium / cellular response to norepinephrine stimulus / growth cone filopodium / microglia development / collateral sprouting in absence of injury / Formyl peptide receptors bind formyl peptides and many other ligands / axo-dendritic transport / regulation of Wnt signaling pathway / regulation of synapse structure or activity / axon midline choice point recognition / astrocyte activation involved in immune response / NMDA selective glutamate receptor signaling pathway / regulation of spontaneous synaptic transmission / mating behavior / growth factor receptor binding / peptidase activator activity / Golgi-associated vesicle / PTB domain binding / positive regulation of amyloid fibril formation / Insertion of tail-anchored proteins into the endoplasmic reticulum membrane / Lysosome Vesicle Biogenesis / astrocyte projection / neuron remodeling / Deregulated CDK5 triggers multiple neurodegenerative pathways in Alzheimer's disease models / nuclear envelope lumen / dendrite development / positive regulation of protein metabolic process / TRAF6 mediated NF-kB activation / Advanced glycosylation endproduct receptor signaling / signaling receptor activator activity / negative regulation of long-term synaptic potentiation / modulation of excitatory postsynaptic potential / The NLRP3 inflammasome / transition metal ion binding / main axon / regulation of multicellular organism growth / intracellular copper ion homeostasis / regulation of presynapse assembly / ECM proteoglycans / positive regulation of T cell migration / neuronal dense core vesicle / Purinergic signaling in leishmaniasis infection / positive regulation of chemokine production / cellular response to manganese ion / Notch signaling pathway / clathrin-coated pit / extracellular matrix organization / neuron projection maintenance / Mitochondrial protein degradation / astrocyte activation / ionotropic glutamate receptor signaling pathway / positive regulation of calcium-mediated signaling / positive regulation of mitotic cell cycle / response to interleukin-1 / axonogenesis / protein serine/threonine kinase binding / cellular response to copper ion / platelet alpha granule lumen / cellular response to cAMP / positive regulation of glycolytic process / central nervous system development / positive regulation of interleukin-1 beta production / endosome lumen / dendritic shaft / trans-Golgi network membrane / adult locomotory behavior / positive regulation of long-term synaptic potentiation / learning / positive regulation of JNK cascade / Post-translational protein phosphorylation / locomotory behavior / microglial cell activation / serine-type endopeptidase inhibitor activity / positive regulation of non-canonical NF-kappaB signal transduction / TAK1-dependent IKK and NF-kappa-B activation / regulation of long-term neuronal synaptic plasticity / cellular response to nerve growth factor stimulus / synapse organization / recycling endosome / visual learning / positive regulation of interleukin-6 production / response to lead ion / Golgi lumen / cognition / Regulation of Insulin-like Growth Factor (IGF) transport and uptake by Insulin-like Growth Factor Binding Proteins (IGFBPs) / endocytosis / cellular response to amyloid-beta / positive regulation of inflammatory response / neuron projection development / positive regulation of tumor necrosis factor production / Platelet degranulation / heparin binding / regulation of translation / regulation of gene expression / early endosome membrane / perikaryon / G alpha (i) signalling events / G alpha (q) signalling events / dendritic spine

ドメイン・相同性:

Amyloidogenic glycoprotein, copper-binding / Amyloidogenic glycoprotein, copper-binding domain conserved site / Amyloidogenic glycoprotein, copper-binding domain superfamily / Copper-binding of amyloid precursor, CuBD / Amyloid precursor protein (APP) copper-binding (CuBD) domain signature. / Amyloidogenic glycoprotein, amyloid-beta peptide superfamily / Beta-amyloid peptide (beta-APP) / Amyloidogenic glycoprotein, amyloid-beta peptide / Beta-amyloid precursor protein C-terminal / Amyloidogenic glycoprotein, intracellular domain, conserved site / Beta-amyloid precursor protein C-terminus / Amyloid precursor protein (APP) intracellular domain signature. / Amyloidogenic glycoprotein, extracellular / Amyloidogenic glycoprotein, heparin-binding / Amyloidogenic glycoprotein, E2 domain / E2 domain superfamily / Amyloidogenic glycoprotein, heparin-binding domain superfamily / Amyloid A4 N-terminal heparin-binding / E2 domain of amyloid precursor protein / Amyloid precursor protein (APP) E1 domain profile. / Amyloid precursor protein (APP) E2 domain profile. / amyloid A4 / Amyloidogenic glycoprotein / Proteinase inhibitor I2, Kunitz, conserved site / Pancreatic trypsin inhibitor (Kunitz) family signature. / BPTI/Kunitz family of serine protease inhibitors. / Pancreatic trypsin inhibitor Kunitz domain / Kunitz/Bovine pancreatic trypsin inhibitor domain / Pancreatic trypsin inhibitor (Kunitz) family profile. / Pancreatic trypsin inhibitor Kunitz domain superfamily / PH-like domain superfamily

構成要素:

Amyloid-beta precursor protein

• 生物種: Homo sapiens (ヒト)
• 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: 2.9 Å
• データ登録者: Yang Y / Stern MA / Meunier LA / Liu W / Cai YQ / Ericsson M / Liu L / Selkoe JD / Goedert M / Scheres HWS

資金援助

英国, 3件

Organization	Grant number	国
Medical Research Council (MRC, United Kingdom)	MC_UP_1201/25	英国
Medical Research Council (MRC, United Kingdom)	MC_UP_A025_1013	英国
Medical Research Council (MRC, United Kingdom)	MC_U105184291	英国

• 引用: ジャーナル: Neuron / 年: 2023; タイトル: Abundant Aβ fibrils in ultracentrifugal supernatants of aqueous extracts from Alzheimer's disease brains.; 著者: Andrew M Stern / Yang Yang / Shanxue Jin / Keitaro Yamashita / Angela L Meunier / Wen Liu / Yuqi Cai / Maria Ericsson / Lei Liu / Michel Goedert / Sjors H W Scheres / Dennis J Selkoe / ; 要旨: Soluble oligomers of amyloid β-protein (Aβ) have been defined as aggregates in supernatants following ultracentrifugation of aqueous extracts from Alzheimer's disease (AD) brains and are believed to be upstream initiators of synaptic dysfunction, but little is known about their structures. We now report the unexpected presence of Aβ fibrils in synaptotoxic high-speed supernatants from AD brains extracted by soaking in an aqueous buffer. The fibrils did not appear to form during preparation, and their counts by EM correlated with Aβ ELISA quantification. Cryo-EM structures of aqueous Aβ fibrils were identical to those from sarkosyl-insoluble homogenates. The fibrils in aqueous extracts were labeled by lecanemab, an Aβ aggregate-directed antibody reported to improve AD cognitive outcomes. Lecanemab provided protection against aqueous fibril synaptotoxicity. We conclude that fibrils are abundant in aqueous extracts from AD brains and have the same structures as those from plaques. These findings have implications for AD pathogenesis and drug design.

履歴

登録	2022年9月6日	-
ヘッダ(付随情報) 公開	2022年11月2日	-
マップ公開	2022年11月2日	-
更新	2024年7月24日	-
現状	2024年7月24日	処理サイト: PDBe / 状態: 公開

マップ

• ファイル: ダウンロード / ファイル: emd_15770.map.gz / 形式: CCP4 / 大きさ: 64 MB / タイプ: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
• ボクセルのサイズ: X=Y=Z: 0.831 Å

密度

表面レベル	登録者による: 0.0075
最小 - 最大	-0.012463829 - 0.031843863
平均 (標準偏差)	0.00019769648 (±0.0019250719)

• 対称性: 空間群: 1

詳細

EMDB XML:

マップ形状	Axis order X Y Z Origin 0 0 0 サイズ 256 256 256 Spacing 256 256 256
セル	A=B=C: 212.736 Å α=β=γ: 90.0 °

添付データ

マスク #1

• ファイル: emd_15770_msk_1.map

ハーフマップ: #2

• ファイル: emd_15770_half_map_1.map

ハーフマップ: #1

• ファイル: emd_15770_half_map_2.map

試料の構成要素

全体 : Type I amyloid-beta 42 filaments in soluble high-molecular weight...

• 全体: 名称: Type I amyloid-beta 42 filaments in soluble high-molecular weight aggregate fractions extracted from Alzheimer's disease brain

要素

• 組織: Type I amyloid-beta 42 filaments in soluble high-molecular weight aggregate fractions extracted from Alzheimer's disease brain
  • タンパク質・ペプチド: Amyloid-beta precursor protein

超分子 #1: Type I amyloid-beta 42 filaments in soluble high-molecular weight...

• 超分子: 名称: Type I amyloid-beta 42 filaments in soluble high-molecular weight aggregate fractions extracted from Alzheimer's disease brain; タイプ: tissue / ID: 1 / 親要素: 0 / 含まれる分子: all
• 由来(天然): 生物種: Homo sapiens (ヒト)

分子 #1: Amyloid-beta precursor protein

• 分子: 名称: Amyloid-beta precursor protein / タイプ: protein_or_peptide / ID: 1 / コピー数: 1 / 光学異性体: LEVO
• 由来(天然): 生物種: Homo sapiens (ヒト)
• 分子量: 理論値: 4.520087 KDa

配列

文字列:

DAEFRHDSGY EVHHQKLVFF AEDVGSNKGA 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
• 解析: らせん対称体再構成法
• 試料の集合状態: filament

試料調製

• 緩衝液: pH: 7.5
• 凍結: 凍結剤: ETHANE

電子顕微鏡法

• 顕微鏡: FEI TITAN KRIOS
• 撮影: フィルム・検出器のモデル: GATAN K3 (6k x 4k) / 平均電子線量: 40.0 e/Ų
• 電子線: 加速電圧: 300 kV / 電子線源: FIELD EMISSION GUN
• 電子光学系: 照射モード: FLOOD BEAM / 撮影モード: BRIGHT FIELD / 最大 デフォーカス（公称値）: 2.4 µm / 最小 デフォーカス（公称値）: 1.0 µm
• 実験機器: モデル: Titan Krios / 画像提供: FEI Company

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: 2.4 Å; 想定した対称性 - らせんパラメータ - ΔΦ: 178.4 °; 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: 2.9 Å / 解像度の算出法: FSC 0.143 CUT-OFF / ソフトウェア - 名称: RELION / 使用した粒子像数: 37380
• 初期モデル: モデルのタイプ: NONE
• 最終 角度割当: タイプ: NOT APPLICABLE

原子モデル構築 1

初期モデル

PDB ID:

7q4b

Chain - Source name: PDB / Chain - Initial model type: experimental model

得られたモデル

PDB-8azs:
Type I amyloid-beta 42 filaments from high-spin supernatants of aqueous extracts from Alzheimer's disease brains | ABeta42