EMDB-16023: Amyloid-beta tetrameric filaments with the Arctic mutation (E22G)...

基本情報

登録情報

データベース: EMDB / ID: EMD-16023

• タイトル: Amyloid-beta tetrameric filaments with the Arctic mutation (E22G) from Alzheimer's disease brains | ABeta40

試料

• 組織: Amyloid-beta filaments extracted from the human brain with Arctic mutation (E693G) of Alzheimer's disease
  • タンパク質・ペプチド: Amyloid-beta precursor proteinアミロイド前駆体タンパク質
• リガンド: water水

機能・相同性

分子機能:

regulation of epidermal growth factor-activated receptor activity / signaling receptor activator activity / collateral sprouting in absence of injury / cytosolic mRNA polyadenylation / microglia development / regulation of synapse structure or activity / Formyl peptide receptors bind formyl peptides and many other ligands / regulation of Wnt signaling pathway / axo-dendritic transport / synaptic assembly at neuromuscular junction / smooth endoplasmic reticulum calcium ion homeostasis / axon midline choice point recognition / astrocyte activation involved in immune response / regulation of spontaneous synaptic transmission / mating behavior / NMDA selective glutamate receptor signaling pathway / 繊毛 / Lysosome Vesicle Biogenesis / PTB domain binding / Golgi-associated vesicle / positive regulation of amyloid fibril formation / neuron remodeling / Insertion of tail-anchored proteins into the endoplasmic reticulum membrane / protein serine/threonine kinase binding / Deregulated CDK5 triggers multiple neurodegenerative pathways in Alzheimer's disease models / : / nuclear envelope lumen / suckling behavior / presynaptic active zone / dendrite development / COPII-coated ER to Golgi transport vesicle / modulation of excitatory postsynaptic potential / 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 / regulation of multicellular organism growth / intracellular copper ion homeostasis / negative regulation of long-term synaptic potentiation / negative regulation of neuron differentiation / ECM proteoglycans / 小胞体 / Mitochondrial protein degradation / positive regulation of T cell migration / spindle midzone / Purinergic signaling in leishmaniasis infection / positive regulation of calcium-mediated signaling / forebrain development / クラスリン / regulation of peptidyl-tyrosine phosphorylation / positive regulation of chemokine production / Notchシグナリング / positive regulation of G2/M transition of mitotic cell cycle / neuron projection maintenance / positive regulation of protein metabolic process / ionotropic glutamate receptor signaling pathway / positive regulation of glycolytic process / cholesterol metabolic process / response to interleukin-1 / positive regulation of mitotic cell cycle / extracellular matrix organization / 軸索誘導 / adult locomotory behavior / trans-Golgi network membrane / dendritic shaft / platelet alpha granule lumen / locomotory behavior / positive regulation of peptidyl-threonine phosphorylation / 学習 / positive regulation of interleukin-1 beta production / central nervous system development / positive regulation of long-term synaptic potentiation / endosome lumen / astrocyte activation / Post-translational protein phosphorylation / positive regulation of JNK cascade / synapse organization / regulation of long-term neuronal synaptic plasticity / microglial cell activation / TAK1-dependent IKK and NF-kappa-B activation / visual learning / serine-type endopeptidase inhibitor activity / neuromuscular junction / recycling endosome / 認識 / positive regulation of inflammatory response / Golgi lumen / neuron cellular homeostasis / エンドサイトーシス / positive regulation of non-canonical NF-kappaB signal transduction / cellular response to amyloid-beta / positive regulation of interleukin-6 production / Regulation of Insulin-like Growth Factor (IGF) transport and uptake by Insulin-like Growth Factor Binding Proteins (IGFBPs) / neuron projection development / G2/M transition of mitotic cell cycle / positive regulation of tumor necrosis factor production / cell-cell junction / シナプス小胞

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. / Amyloid precursor protein (APP) E1 domain profile. / Amyloid precursor protein (APP) E2 domain profile. / 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 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:

アミロイド前駆体タンパク質

• 生物種: Homo sapiens (ヒト) / human (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: 1.99 Å
• データ登録者: Yang Y / Zhang WJ / Murzin AG / Schweighauser M / Huang M / Lovestam SKA / Peak-Chew SY / Macdonald J / Lavenir I / Ghetti B / Graff C / Kumar A / Nordber A / Goedert M / Scheres SHW

資金援助

英国, 2件

Organization	Grant number	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: Acta Neuropathol / 年: 2023; タイトル: Cryo-EM structures of amyloid-β filaments with the Arctic mutation (E22G) from human and mouse brains.; 著者: Yang Yang / Wenjuan Zhang / Alexey G Murzin / Manuel Schweighauser / Melissa Huang / Sofia Lövestam / Sew Y Peak-Chew / Takashi Saito / Takaomi C Saido / Jennifer Macdonald / Isabelle Lavenir / Bernardino Ghetti / Caroline Graff / Amit Kumar / Agneta Nordberg / Michel Goedert / Sjors H W Scheres / ; 要旨: 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 App. Most filaments are made of two identical mutant protofilaments that extend from D1 to G37 (App murine Arctic fold). In a minority of filaments, two dimeric folds pack against each other in an anti-parallel fashion. The App murine Arctic fold differs from the human Arctic folds, but shares some substructure.

履歴

登録	2022年10月27日	-
ヘッダ(付随情報) 公開	2023年1月18日	-
マップ公開	2023年1月18日	-
更新	2023年2月22日	-
現状	2023年2月22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_16023.map.gz / 形式: CCP4 / 大きさ: 103 MB / タイプ: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
• ボクセルのサイズ: X=Y=Z: 0.653 Å

密度

表面レベル	登録者による: 0.0085
最小 - 最大	-0.013728813 - 0.028257012
平均 (標準偏差)	0.00010991787 (±0.001825292)

• 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 300 300 300 Spacing 300 300 300
セル	A=B=C: 195.9 Å α=β=γ: 90.0 °

添付データ

ハーフマップ: #1

• ファイル: emd_16023_half_map_1.map

ハーフマップ: #2

• ファイル: emd_16023_half_map_2.map

試料の構成要素

全体 : Amyloid-beta filaments extracted from the human brain with Arctic...

• 全体: 名称: Amyloid-beta filaments extracted from the human brain with Arctic mutation (E693G) of Alzheimer's disease

要素

• 組織: Amyloid-beta filaments extracted from the human brain with Arctic mutation (E693G) of Alzheimer's disease
  • タンパク質・ペプチド: Amyloid-beta precursor proteinアミロイド前駆体タンパク質
• リガンド: water水

超分子 #1: Amyloid-beta filaments extracted from the human brain with Arctic...

• 超分子: 名称: Amyloid-beta filaments extracted from the human brain with Arctic mutation (E693G) of Alzheimer's disease; タイプ: tissue / ID: 1 / 親要素: 0 / 含まれる分子: #1
• 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: 4 / 光学異性体: LEVO
• 由来(天然): 生物種: human (ヒト)
• 分子量: 理論値: 4.335852 KDa

配列

文字列:

DAEFRHDSGY EVHHQKLVFF AEDVGSNKGA IIGLMVGGVV

分子 #2: water

• 分子: 名称: water / タイプ: ligand / ID: 2 / コピー数: 12 / 式: HOH
• 分子量: 理論値: 18.015 Da

Chemical component information

ChemComp-HOH:
WATER / 水

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
• 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 FIELDBright-field microscopy / 最大 デフォーカス（公称値）: 2.2 µm / 最小 デフォーカス（公称値）: 0.8 µm
• 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
• 実験機器: モデル: Titan Krios / 画像提供: FEI Company

画像解析

• 最終 角度割当: タイプ: NOT APPLICABLE / ソフトウェア - 名称: RELION
• 最終 再構成: 想定した対称性 - らせんパラメータ - Δz: 4.74 Å; 想定した対称性 - らせんパラメータ - ΔΦ: -2.93 °; 想定した対称性 - らせんパラメータ - 軸対称性: C₂ (2回回転対称); 解像度のタイプ: BY AUTHOR / 解像度: 1.99 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: 115228