EMDB-61946: Cryo-EM structure of Amyloid-beta42-4b polymorph 3

基本情報

登録情報

データベース: EMDB / ID: EMD-61946

• タイトル: Cryo-EM structure of Amyloid-beta42-4b polymorph 3

試料

• 細胞器官・細胞要素: Cryo-EM structure of Amyloid-beta42-4b polymorph 3
  • タンパク質・ペプチド: Amyloid-beta A4 protein
  • タンパク質・ペプチド: Amyloid-beta protein 40
• リガンド: water

• キーワード: helical fibril / amyloid-beta / PROTEIN FIBRIL / MEMBRANE PROTEIN

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 / Advanced glycosylation endproduct receptor signaling / signaling receptor activator activity / 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 / growth cone / early endosome membrane / G alpha (i) signalling events / perikaryon / G alpha (q) signalling events

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 / 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: 2.8 Å
• データ登録者: Xia WC / Sun YP / Liu C

資金援助

1件

Organization	Grant number	国
Not funded

• 引用: ジャーナル: Nat Commun / 年: 2025; タイトル: An O-glycopeptide participates in the formation of distinct Aβ fibril structures and attenuates Aβ neurotoxicity.; 著者: Qijia Wei / Dangliang Liu / Wencheng Xia / Fengzhang Wang / Lu Huang / Jun Zhang / Xiaoya Wang / Zhongxin Xu / Changdong He / Wenzhe Li / Xiaomeng Shi / Chu Wang / Yuan Liu / Cong Liu / Suwei Dong / ; 要旨: The self-assembly of biomolecules through noncovalent interactions is critical in both physiological and pathological processes, as exemplified by the assembly of amyloid β peptide (Aβ) into oligomers or fibrils in Alzheimer's disease (AD). Developing molecules that can modulate this assembly process holds significant mechanistic and therapeutic potential. In this study, we identified glycopeptides as a class of protein aggregation modulators, showing that β-N-acetylgalactosamine (β-GalNAc)-modified Aβ promotes Aβ fibrillation while reducing its toxic oligomers. Using biochemical assays, cryo-EM, and molecular dynamics simulations, we demonstrated that β-GalNAc-modified Aβ coassembles with Aβ, forming unique fibril structures stabilized by both hydrophobic interactions and an organized hydrogen bond network facilitated by the glycopeptide. Importantly, β-GalNAc-modified Aβ can alleviate the neurotoxicity of Aβ in neuronal cells and an AD male mouse model. These findings underscore the potential of glycopeptides in regulating amyloid aggregation and provide structural insights for designing molecules targeting amyloid-related pathologies.

履歴

登録	2024年10月15日	-
ヘッダ(付随情報) 公開	2025年8月6日	-
マップ公開	2025年8月6日	-
更新	2025年8月6日	-
現状	2025年8月6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_61946.map.gz / 形式: CCP4 / 大きさ: 178 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: 0.00883
最小 - 最大	-0.027972184 - 0.06328577
平均 (標準偏差)	0.00028990375 (±0.0024723285)

• 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 360 360 360 Spacing 360 360 360
セル	A=B=C: 298.8 Å α=β=γ: 90.0 °

添付データ

マスク #1

• ファイル: emd_61946_msk_1.map

ハーフマップ: #2

• ファイル: emd_61946_half_map_1.map

ハーフマップ: #1

• ファイル: emd_61946_half_map_2.map

試料の構成要素

全体 : Cryo-EM structure of Amyloid-beta42-4b polymorph 3

• 全体: 名称: Cryo-EM structure of Amyloid-beta42-4b polymorph 3

要素

• 細胞器官・細胞要素: Cryo-EM structure of Amyloid-beta42-4b polymorph 3
  • タンパク質・ペプチド: Amyloid-beta A4 protein
  • タンパク質・ペプチド: Amyloid-beta protein 40
• リガンド: water

超分子 #1: Cryo-EM structure of Amyloid-beta42-4b polymorph 3

• 超分子: 名称: Cryo-EM structure of Amyloid-beta42-4b polymorph 3 / タイプ: organelle_or_cellular_component / ID: 1 / 親要素: 0 / 含まれる分子: #1-#2
• 由来(天然): 生物種: Homo sapiens (ヒト)

分子 #1: Amyloid-beta A4 protein

• 分子: 名称: Amyloid-beta A4 protein / タイプ: protein_or_peptide / ID: 1 / コピー数: 9 / 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

分子 #2: Amyloid-beta protein 40

• 分子: 名称: Amyloid-beta protein 40 / タイプ: protein_or_peptide / ID: 2 / コピー数: 3 / 光学異性体: LEVO
• 由来(天然): 生物種: Homo sapiens (ヒト)
• 分子量: 理論値: 1.577802 KDa

配列

文字列:

GYEVHHQKLV FFA

UniProtKB: Amyloid-beta precursor protein

分子 #3: water

• 分子: 名称: water / タイプ: ligand / ID: 3 / コピー数: 6 / 式: HOH
• 分子量: 理論値: 18.015 Da

Chemical component information

ChemComp-HOH:
WATER

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: 7.4
• 凍結: 凍結剤: ETHANE

電子顕微鏡法

• 顕微鏡: TFS KRIOS
• 撮影: フィルム・検出器のモデル: GATAN K3 BIOCONTINUUM (6k x 4k); 平均電子線量: 55.0 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）: 2.0 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: 4.82 Å; 想定した対称性 - らせんパラメータ - ΔΦ: -0.76 °; 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: 2.8 Å / 解像度の算出法: FSC 0.143 CUT-OFF / 使用した粒子像数: 24373
• CTF補正: タイプ: NONE
• 初期モデル: モデルのタイプ: NONE
• 最終 角度割当: タイプ: NOT APPLICABLE