EMDB-16027: Murine amyloid-beta filaments with the Arctic mutation (E22G) fro...

基本情報

登録情報

データベース: EMDB / ID: EMD-16027

• タイトル: Murine amyloid-beta filaments with the Arctic mutation (E22G) from APP(NL-G-F) mouse brains | ABeta

試料

• 組織: Amyloid-beta filaments extracted from the mouse brains with APP NL-G-F mutations
  • タンパク質・ペプチド: Amyloid-beta protein 40

• キーワード: Amyloid / amyloid-beta / Arctic mutation / APP / NL-G-F / mouse brains / filaments / E22G / E693G / PROTEIN FIBRIL

機能・相同性

分子機能:

regulation of response to calcium ion / Formyl peptide receptors bind formyl peptides and many other ligands / growth cone lamellipodium / cellular response to norepinephrine stimulus / Advanced glycosylation endproduct receptor signaling / growth cone filopodium / ECM proteoglycans / Insertion of tail-anchored proteins into the endoplasmic reticulum membrane / TRAF6 mediated NF-kB activation / Lysosome Vesicle Biogenesis / Regulation of Insulin-like Growth Factor (IGF) transport and uptake by Insulin-like Growth Factor Binding Proteins (IGFBPs) / Post-translational protein phosphorylation / G alpha (q) signalling events / TAK1-dependent IKK and NF-kappa-B activation / G alpha (i) signalling events / response to yeast / peptidase activator activity / Platelet degranulation / growth factor receptor binding / antifungal humoral response / Mitochondrial protein degradation / astrocyte projection / cytosolic mRNA polyadenylation / collateral sprouting in absence of injury / microglia development / regulation of synapse structure or activity / 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 / ciliary rootlet / PTB domain binding / Golgi-associated vesicle / main axon / positive regulation of amyloid fibril formation / neuron remodeling / nuclear envelope lumen / COPII-coated ER to Golgi transport vesicle / suckling behavior / neuronal dense core vesicle / dendrite development / presynaptic active zone / modulation of excitatory postsynaptic potential / neuromuscular process controlling balance / transition metal ion binding / regulation of presynapse assembly / negative regulation of long-term synaptic potentiation / regulation of multicellular organism growth / negative regulation of neuron differentiation / intracellular copper ion homeostasis / positive regulation of T cell migration / smooth endoplasmic reticulum / spindle midzone / clathrin-coated pit / positive regulation of chemokine production / regulation of peptidyl-tyrosine phosphorylation / forebrain development / Notch signaling pathway / neuron projection maintenance / positive regulation of G2/M transition of mitotic cell cycle / positive regulation of protein metabolic process / positive regulation of calcium-mediated signaling / 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 / axonogenesis / adult locomotory behavior / positive regulation of peptidyl-threonine phosphorylation / positive regulation of interleukin-1 beta production / dendritic shaft / cognition / positive regulation of long-term synaptic potentiation / central nervous system development / locomotory behavior / long-term synaptic potentiation / positive regulation of JNK cascade / microglial cell activation / serine-type endopeptidase inhibitor activity / regulation of long-term neuronal synaptic plasticity / visual learning / neuromuscular junction / recycling endosome / neuron differentiation / memory / positive regulation of interleukin-6 production / neuron cellular homeostasis / positive regulation of inflammatory response / positive regulation of non-canonical NF-kappaB signal transduction / endocytosis / cellular response to amyloid-beta / positive regulation of tumor necrosis factor production / G2/M transition of mitotic cell cycle / cell-cell junction

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. / 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:

Amyloid-beta precursor protein

• 生物種: Mus musculus (ハツカネズミ)
• 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: 3.5 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	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_16027.map.gz / 形式: CCP4 / 大きさ: 30.5 MB / タイプ: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
• ボクセルのサイズ: X=Y=Z: 1.204 Å

密度

表面レベル	登録者による: 0.03
最小 - 最大	-0.05223707 - 0.084781475
平均 (標準偏差)	0.00048409565 (±0.005094125)

• 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 200 200 200 Spacing 200 200 200
セル	A=B=C: 240.8 Å α=β=γ: 90.0 °

添付データ

マスク #1

• ファイル: emd_16027_msk_1.map

ハーフマップ: #1

• ファイル: emd_16027_half_map_1.map

ハーフマップ: #2

• ファイル: emd_16027_half_map_2.map

試料の構成要素

全体 : Amyloid-beta filaments extracted from the mouse brains with APP N...

• 全体: 名称: Amyloid-beta filaments extracted from the mouse brains with APP NL-G-F mutations

要素

• 組織: Amyloid-beta filaments extracted from the mouse brains with APP NL-G-F mutations
  • タンパク質・ペプチド: Amyloid-beta protein 40

超分子 #1: Amyloid-beta filaments extracted from the mouse brains with APP N...

• 超分子: 名称: Amyloid-beta filaments extracted from the mouse brains with APP NL-G-F mutations; タイプ: tissue / ID: 1 / 親要素: 0 / 含まれる分子: all
• 由来(天然): 生物種: Mus musculus (ハツカネズミ)

分子 #1: Amyloid-beta protein 40

• 分子: 名称: Amyloid-beta protein 40 / タイプ: protein_or_peptide / ID: 1 / コピー数: 2 / 光学異性体: LEVO
• 由来(天然): 生物種: Mus musculus (ハツカネズミ)
• 分子量: 理論値: 4.080538 KDa

配列

文字列:

DAEFRHDSGY EVHHQKLVFF AEDVGSNKGA IIGLMVG

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）: 2.6 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: 2.46009 Å; 想定した対称性 - らせんパラメータ - ΔΦ: 179.347 °; 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: 3.5 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: 39823
• 初期モデル: モデルのタイプ: NONE
• 最終 角度割当: タイプ: NOT APPLICABLE / ソフトウェア - 名称: RELION