EMDB-60603: J-shaped conformer of amyloid beta (1-40)

基本情報

登録情報

データベース: EMDB / ID: EMD-60603

• タイトル: J-shaped conformer of amyloid beta (1-40)
• マップデータ: Helical symmetry imposed map of wild-type ground-grown amyloid

試料

• 複合体: J-type amyloid beta (1-40)
  • タンパク質・ペプチド: Amyloid-beta protein 40

• キーワード: Amyloid / 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 / 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 / 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 / Lysosome Vesicle Biogenesis / positive regulation of amyloid fibril formation / Insertion of tail-anchored proteins into the endoplasmic reticulum membrane / astrocyte projection / neuron remodeling / Deregulated CDK5 triggers multiple neurodegenerative pathways in Alzheimer's disease models / nuclear envelope lumen / positive regulation of protein metabolic process / dendrite development / TRAF6 mediated NF-kB activation / modulation of excitatory postsynaptic potential / signaling receptor activator activity / Advanced glycosylation endproduct receptor signaling / The NLRP3 inflammasome / negative regulation of long-term synaptic potentiation / main axon / transition metal ion binding / 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 / clathrin-coated pit / Notch signaling pathway / extracellular matrix organization / neuron projection maintenance / Mitochondrial protein degradation / astrocyte activation / ionotropic glutamate receptor signaling pathway / axonogenesis / response to interleukin-1 / positive regulation of mitotic cell cycle / positive regulation of calcium-mediated signaling / protein serine/threonine kinase binding / cellular response to copper ion / platelet alpha granule lumen / cellular response to cAMP / positive regulation of glycolytic process / adult locomotory behavior / central nervous system development / positive regulation of long-term synaptic potentiation / positive regulation of interleukin-1 beta production / trans-Golgi network membrane / endosome lumen / dendritic shaft / TAK1-dependent IKK and NF-kappa-B activation / learning / 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 / cellular response to nerve growth factor stimulus / visual learning / recycling endosome / response to lead ion / positive regulation of interleukin-6 production / Golgi lumen / cognition / 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 / positive regulation of tumor necrosis factor production / Platelet degranulation / heparin binding / regulation of gene expression / regulation of translation / early endosome membrane / G alpha (i) signalling events / perikaryon / 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: 3.3 Å
• データ登録者: Burton-Smith RN / Murata K

資金援助

日本, 1件

Organization	Grant number	国
Ministry of Education, Culture, Sports, Science and Technology (Japan)		日本

• 引用: ジャーナル: Int J Mol Sci / 年: 2025; タイトル: Elucidating the Unique J-Shaped Protomer Structure of Amyloid-β(1-40) Fibril with Cryo-Electron Microscopy.; 著者: Raymond N Burton-Smith / Maho Yagi-Utsumi / Saeko Yanaka / Chihong Song / Kazuyoshi Murata / Koichi Kato / ; 要旨: Although the structural diversity of amyloid-β (Aβ) fibrils plays a critical role in the pathology of Alzheimer's disease (AD), the mechanisms underlying this diversity remain poorly understood. In this study, we report the discovery of a novel J-shaped protomer structure of Aβ40 fibrils, resolved at 3.3 Å resolution using cryo-electron microscopy. Under controlled conditions (20 mM sodium phosphate buffer, pH 8.0) designed to emphasize intra-protomer interactions and slow fibril elongation, the J-shaped structure revealed distinct salt bridges (e.g., D1-K28, R5-E22) that stabilize the fibril core. These findings expand our understanding of the free energy landscape of fibril formation, shedding light on how specific environmental factors, such as pH and ionic strength, may influence fibril polymorphism. Importantly, the unique features of the J-shaped protomer provide insights into the structural basis of amyloid plaque diversity in AD and suggest potential therapeutic strategies targeting intra-protomer interactions. This study underscores the importance of fibril polymorphism in AD pathology and offers a foundation for future research into fibril-targeted therapies.

履歴

登録	2024年6月21日	-
ヘッダ(付随情報) 公開	2025年2月26日	-
マップ公開	2025年2月26日	-
更新	2025年2月26日	-
現状	2025年2月26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_60603.map.gz / 形式: CCP4 / 大きさ: 325 MB / タイプ: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
• 注釈: Helical symmetry imposed map of wild-type ground-grown amyloid
• ボクセルのサイズ: X=Y=Z: 1.14 Å

密度

表面レベル	登録者による: 0.01
最小 - 最大	-0.03029707 - 0.06140099
平均 (標準偏差)	0.00010549026 (±0.0016536529)

• 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 440 440 440 Spacing 440 440 440
セル	A=B=C: 501.6 Å α=β=γ: 90.0 °

添付データ

追加マップ: Post-processed map of wild-type ground-grown amyloid

• ファイル: emd_60603_additional_1.map
• 注釈: Post-processed map of wild-type ground-grown amyloid

ハーフマップ: Half-map 1 of wild-type ground-grown amyloid

• ファイル: emd_60603_half_map_1.map
• 注釈: Half-map 1 of wild-type ground-grown amyloid

ハーフマップ: Half-map 2 of wild-type ground-grown amyloid

• ファイル: emd_60603_half_map_2.map
• 注釈: Half-map 2 of wild-type ground-grown amyloid

試料の構成要素

全体 : J-type amyloid beta (1-40)

• 全体: 名称: J-type amyloid beta (1-40)

要素

• 複合体: J-type amyloid beta (1-40)
  • タンパク質・ペプチド: Amyloid-beta protein 40

超分子 #1: J-type amyloid beta (1-40)

• 超分子: 名称: J-type amyloid beta (1-40) / 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)

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: 40 / 光学異性体: LEVO
• 由来(天然): 生物種: Homo sapiens (ヒト)
• 分子量: 理論値: 4.335852 KDa

配列

文字列:

DAEFRHDSGY EVHHQKLVFF AEDVGSNKGA IIGLMVGGVV

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: helical array

試料調製

• 緩衝液: pH: 8
• 凍結: 凍結剤: ETHANE / チャンバー内湿度: 100 % / 装置: FEI VITROBOT MARK IV

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 BIOQUANTUM (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）: 1.4000000000000001 µm; 最小 デフォーカス（公称値）: 0.8 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: 2.454 Å; 想定した対称性 - らせんパラメータ - ΔΦ: 179.2 °; 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: 3.3 Å / 解像度の算出法: FSC 0.143 CUT-OFF / 使用した粒子像数: 577094
• 初期モデル: モデルのタイプ: OTHER
• 最終 角度割当: タイプ: NOT APPLICABLE