EMDB-61303: Cryo-EM structure of the class II amyloid-beta 42 fibril containi...

基本情報

登録情報

データベース: EMDB / ID: EMD-61303

• タイトル: Cryo-EM structure of the class II amyloid-beta 42 fibril containing a D-Asp at position 23

試料

• 複合体: Class II amyloid-beta 42 fibril containing a D-Asp at position 23
  • タンパク質・ペプチド: Amyloid-beta precursor protein

• キーワード: aggregation / PROTEIN FIBRIL

機能・相同性

分子機能:

amyloid-beta complex / microglia development / negative regulation of presynapse assembly / collateral sprouting in absence of injury / cytosolic mRNA polyadenylation / synaptic assembly at neuromuscular junction / Formyl peptide receptors bind formyl peptides and many other ligands / regulation of synapse structure or activity / axo-dendritic transport / regulation of Wnt signaling pathway / axon midline choice point recognition / astrocyte activation involved in immune response / smooth endoplasmic reticulum calcium ion homeostasis / NMDA selective glutamate receptor signaling pathway / regulation of spontaneous synaptic transmission / mating behavior / ciliary rootlet / Golgi-associated vesicle / PTB domain binding / Lysosome Vesicle Biogenesis / positive regulation of amyloid fibril formation / Insertion of tail-anchored proteins into the endoplasmic reticulum membrane / neuron remodeling / Deregulated CDK5 triggers multiple neurodegenerative pathways in Alzheimer's disease models / nuclear envelope lumen / suckling behavior / COPII-coated ER to Golgi transport vesicle / positive regulation of protein metabolic process / dendrite development / TRAF6 mediated NF-kB activation / modulation of excitatory postsynaptic potential / presynaptic active zone / Advanced glycosylation endproduct receptor signaling / signaling receptor activator activity / The NLRP3 inflammasome / negative regulation of long-term synaptic potentiation / neuromuscular process controlling balance / transition metal ion binding / regulation of multicellular organism growth / intracellular copper ion homeostasis / regulation of presynapse assembly / negative regulation of neuron differentiation / ECM proteoglycans / spindle midzone / positive regulation of T cell migration / forebrain development / smooth endoplasmic reticulum / Purinergic signaling in leishmaniasis infection / positive regulation of chemokine production / clathrin-coated pit / Notch signaling pathway / positive regulation of G2/M transition of mitotic cell cycle / extracellular matrix organization / neuron projection maintenance / Mitochondrial protein degradation / ionotropic glutamate receptor signaling pathway / axonogenesis / response to interleukin-1 / cholesterol metabolic process / positive regulation of calcium-mediated signaling / positive regulation of mitotic cell cycle / protein serine/threonine kinase binding / platelet alpha granule lumen / positive regulation of glycolytic process / adult locomotory behavior / dendritic shaft / central nervous system development / positive regulation of long-term synaptic potentiation / positive regulation of interleukin-1 beta production / trans-Golgi network membrane / endosome lumen / TAK1-dependent IKK and NF-kappa-B activation / learning / astrocyte activation / positive regulation of JNK cascade / Post-translational protein phosphorylation / locomotory behavior / microglial cell activation / serine-type endopeptidase inhibitor activity / regulation of long-term neuronal synaptic plasticity / positive regulation of non-canonical NF-kappaB signal transduction / synapse organization / visual learning / recycling endosome / neuromuscular junction / positive regulation of interleukin-6 production / Golgi lumen / cognition / neuron cellular homeostasis / endocytosis / Regulation of Insulin-like Growth Factor (IGF) transport and uptake by Insulin-like Growth Factor Binding Proteins (IGFBPs) / positive regulation of inflammatory response / cellular response to amyloid-beta / neuron projection development / G2/M transition of mitotic cell cycle / positive regulation of tumor necrosis factor production / apical part of cell / synaptic vesicle / Platelet degranulation / 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. / 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: Hsiao LC / Lee CH / Hsu MF / Hsu ST

資金援助

台湾, 1件

Organization	Grant number	国
Academia Sinica (Taiwan)	110-2113-M-001-050-MY3	台湾

• 引用: ジャーナル: J Mol Biol / 年: 2025; タイトル: Impacts of D-aspartate on the Aggregation Kinetics and Structural Polymorphism of Amyloid β Peptide 1-42.; 著者: Li-Ching Hsiao / Chih-Hsuan Lee / Karine Mazmanian / Masaya Yoshida / Genta Ito / Takuya Murata / Naoko Utsunomiya-Tate / Takeharu Haino / Shih-Ichi Tate / Shang-Te Danny Hsu / ; 要旨: Isomerization of L-Aspartate (L-Asp) into D-aspartate (D-Asp) occurs naturally in proteins at a rate that is much faster than that of other amino acid types. Accumulation of D-Asp is age-dependent, which could alter protein structures and, therefore, functions. Site-specific introduction of D-Asp can accelerate aggregation kinetics of a variety of proteins associated with misfolding diseases. Here, we showed by thioflavin T fluorescence that the isomerization of L-Asp at different positions of amyloid β peptide 1-42 (Aβ42) generates opposing effects on its aggregation kinetics. We further determined the atomic structures of Aβ42 amyloid fibrils harboring a single D-Asp at position 23 and two D-Asp at positions 7 and 23 by cryo-electron microscopy helical reconstruction - cross-validated by cryo-electron tomography and atomic force microscopy - to reveal how D-Asp contributes to the formation of a unique triple stranded amyloid fibril structure stabilized by two threads of well-ordered water molecules. These findings provide crucial insights into how the conversion from L- to D-Asp influences the aggregation propensity and amyloid polymorphism of Aβ42.

履歴

登録	2024年8月26日	-
ヘッダ(付随情報) 公開	2025年3月26日	-
マップ公開	2025年3月26日	-
更新	2025年4月9日	-
現状	2025年4月9日	処理サイト: PDBj / 状態: 公開

マップ

• ファイル: ダウンロード / ファイル: emd_61303.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: 0.83 Å

密度

表面レベル	登録者による: 0.00685
最小 - 最大	-0.038361743 - 0.057832185
平均 (標準偏差)	0.000006709785 (±0.0010497386)

• 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: 212.48 Å α=β=γ: 90.0 °

添付データ

ハーフマップ: half map2

• ファイル: emd_61303_half_map_1.map
• 注釈: half map2

ハーフマップ: half map1

• ファイル: emd_61303_half_map_2.map
• 注釈: half map1

試料の構成要素

全体 : Class II amyloid-beta 42 fibril containing a D-Asp at position 23

• 全体: 名称: Class II amyloid-beta 42 fibril containing a D-Asp at position 23

要素

• 複合体: Class II amyloid-beta 42 fibril containing a D-Asp at position 23
  • タンパク質・ペプチド: Amyloid-beta precursor protein

超分子 #1: Class II amyloid-beta 42 fibril containing a D-Asp at position 23

• 超分子: 名称: Class II amyloid-beta 42 fibril containing a D-Asp at position 23; タイプ: complex / ID: 1 / 親要素: 0 / 含まれる分子: all
• 由来(天然): 生物種: Homo sapiens (ヒト) / 器官: brain

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: 12 / 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 AE(DAS)VGSNKGA 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: 8
• グリッド: モデル: Quantifoil R1.2/1.3 / 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: GLOW DISCHARGE / 前処理 - 時間: 45 sec.
• 凍結: 凍結剤: ETHANE

電子顕微鏡法

• 顕微鏡: FEI TALOS ARCTICA
• 撮影: フィルム・検出器のモデル: GATAN K3 (6k x 4k) / 平均電子線量: 50.0 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）: 1.7 µm; 最小 デフォーカス（公称値）: 1.4000000000000001 µm; 倍率（公称値）: 105000
• 実験機器: モデル: Talos Arctica / 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: 2.37 Å; 想定した対称性 - らせんパラメータ - ΔΦ: 178.45 °; 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 / 使用した粒子像数: 250544
• 初期モデル: モデルのタイプ: NONE
• 最終 角度割当: タイプ: NOT APPLICABLE