EMDB-29037: Amyloid-beta (1-40) fibrils derived from familial Dutch-type CAA ...

基本情報

登録情報

データベース: EMDB / ID: EMD-29037

• タイトル: Amyloid-beta (1-40) fibrils derived from familial Dutch-type CAA patient (population B)
• マップデータ: Final sharpened map.

試料

• 複合体: Fibrillar assembly of human Amyloid-beta 1-40 from a familial Dutch-type cerebral amyloid angiopathy patient
  • タンパク質・ペプチド: Amyloid-beta precursor protein

• キーワード: amyloid / vascular / fibril / human / 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 / axo-dendritic transport / regulation of Wnt signaling pathway / regulation of synapse structure or activity / 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 / positive regulation of amyloid fibril formation / Lysosome Vesicle Biogenesis / 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 / dendrite development / positive regulation of protein metabolic process / TRAF6 mediated NF-kB activation / signaling receptor activator activity / Advanced glycosylation endproduct receptor signaling / negative regulation of long-term synaptic potentiation / modulation of excitatory postsynaptic potential / The NLRP3 inflammasome / transition metal ion binding / main axon / regulation of multicellular organism growth / intracellular copper ion homeostasis / ECM proteoglycans / regulation of presynapse assembly / 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 / Notch signaling pathway / clathrin-coated pit / extracellular matrix organization / neuron projection maintenance / Mitochondrial protein degradation / astrocyte activation / ionotropic glutamate receptor signaling pathway / positive regulation of mitotic cell cycle / axonogenesis / positive regulation of calcium-mediated signaling / response to interleukin-1 / protein serine/threonine kinase binding / cellular response to copper ion / platelet alpha granule lumen / cellular response to cAMP / positive regulation of glycolytic process / central nervous system development / positive regulation of interleukin-1 beta production / adult locomotory behavior / endosome lumen / dendritic shaft / positive regulation of long-term synaptic potentiation / trans-Golgi network membrane / 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 / positive regulation of non-canonical NF-kappaB signal transduction / regulation of long-term neuronal synaptic plasticity / synapse organization / cellular response to nerve growth factor stimulus / recycling endosome / visual learning / positive regulation of interleukin-6 production / response to lead ion / 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 translation / regulation of gene expression / 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: 3.09 Å
• データ登録者: Crooks EJ / Fu Z / Chowdury S / Smith SO

資金援助

米国, 2件

Organization	Grant number	国
National Institutes of Health/National Institute on Aging (NIH/NIA)	AG061775	米国
National Institutes of Health/National Institute on Aging (NIH/NIA)	AG027317	米国

• 引用: ジャーナル: J Struct Biol / 年: 2024; タイトル: An electrostatic cluster guides Aβ40 fibril formation in sporadic and Dutch-type cerebral amyloid angiopathy.; 著者: Ziao Fu / Elliot J Crooks / Brandon A Irizarry / Xiaoyue Zhu / Saikat Chowdhury / William E Van Nostrand / Steven O Smith / ; 要旨: Cerebral amyloid angiopathy (CAA) is associated with the accumulation of fibrillar Aβ peptides upon and within the cerebral vasculature, which leads to loss of vascular integrity and contributes to disease progression in Alzheimer's disease (AD). We investigate the structure of human-derived Aβ40 fibrils obtained from patients diagnosed with sporadic or familial Dutch-type (E22Q) CAA. Using cryo-EM, two primary structures are identified containing elements that have not been observed in in vitro Aβ40 fibril structures. One population has an ordered N-terminal fold comprised of two β-strands stabilized by electrostatic interactions involving D1, E22, D23 and K28. This charged cluster is disrupted in the second population, which exhibits a disordered N-terminus and is favored in fibrils derived from the familial Dutch-type CAA patient. These results illustrate differences between human-derived CAA and AD fibrils, and how familial CAA mutations can guide fibril formation.

履歴

登録	2022年12月7日	-
ヘッダ(付随情報) 公開	2023年12月6日	-
マップ公開	2023年12月6日	-
更新	2024年5月1日	-
現状	2024年5月1日	処理サイト: RCSB / 状態: 公開

マップ

• ファイル: ダウンロード / ファイル: emd_29037.map.gz / 形式: CCP4 / 大きさ: 56.8 MB / タイプ: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
• 注釈: Final sharpened map.
• ボクセルのサイズ: X=Y=Z: 1.12 Å

密度

表面レベル	登録者による: 0.03
最小 - 最大	-0.0024120803 - 1.8017218
平均 (標準偏差)	0.0031962765 (±0.04078554)

• 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 246 246 246 Spacing 246 246 246
セル	A=B=C: 275.52 Å α=β=γ: 90.0 °

添付データ

マスク #1

• ファイル: emd_29037_msk_1.map

ハーフマップ: Half-map 2.

• ファイル: emd_29037_half_map_1.map
• 注釈: Half-map 2.

ハーフマップ: Half-map 1.

• ファイル: emd_29037_half_map_2.map
• 注釈: Half-map 1.

試料の構成要素

全体 : Fibrillar assembly of human Amyloid-beta 1-40 from a familial Dut...

• 全体: 名称: Fibrillar assembly of human Amyloid-beta 1-40 from a familial Dutch-type cerebral amyloid angiopathy patient

要素

• 複合体: Fibrillar assembly of human Amyloid-beta 1-40 from a familial Dutch-type cerebral amyloid angiopathy patient
  • タンパク質・ペプチド: Amyloid-beta precursor protein

超分子 #1: Fibrillar assembly of human Amyloid-beta 1-40 from a familial Dut...

• 超分子: 名称: Fibrillar assembly of human Amyloid-beta 1-40 from a familial Dutch-type cerebral amyloid angiopathy patient; 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 / 組織: Vasculature
• 分子量: 理論値: 4.3299 MDa

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: 6 / 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: filament

試料調製

• 緩衝液: pH: 7.4
• 凍結: 凍結剤: ETHANE / チャンバー内湿度: 100 % / チャンバー内温度: 295 K / 装置: FEI VITROBOT MARK IV
• 詳細: Templated growth from human-derived vascular amyloid deposits

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: FEI FALCON III (4k x 4k); 検出モード: COUNTING / デジタル化 - サイズ - 横: 4096 pixel / デジタル化 - サイズ - 縦: 4096 pixel / デジタル化 - 画像ごとのフレーム数: 1-99 / 撮影したグリッド数: 1 / 実像数: 2140 / 平均露光時間: 86.11 sec. / 平均電子線量: 56.92 e/Ų
• 電子線: 加速電圧: 200 kV / 電子線源: FIELD EMISSION GUN
• 電子光学系: C2レンズ絞り径: 70.0 µm / 照射モード: FLOOD BEAM / 撮影モード: BRIGHT FIELD / Cs: 2.7 mm; 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）: 0.6 µm / 倍率（公称値）: 92000
• 試料ステージ: ホルダー冷却材: NITROGEN
• 実験機器: モデル: Talos Arctica / 画像提供: FEI Company

画像解析

• 最終 再構成: 使用したクラス数: 1 ; 想定した対称性 - らせんパラメータ - Δz: 2.44 Å; 想定した対称性 - らせんパラメータ - ΔΦ: 179.75 °; 想定した対称性 - らせんパラメータ - 軸対称性: C₁ (非対称); アルゴリズム: FOURIER SPACE / 解像度のタイプ: BY AUTHOR / 解像度: 3.09 Å / 解像度の算出法: FSC 0.143 CUT-OFF / ソフトウェア - 名称: RELION (ver. 3.1.1) / 使用した粒子像数: 73287
• Segment selection: 選択した数: 6946 / 詳細: Manual helical picking
• 初期モデル: モデルのタイプ: OTHER / 詳細: Feature-less cylinder
• 最終 角度割当: タイプ: NOT APPLICABLE / ソフトウェア - 名称: RELION (ver. 3.1.1)

原子モデル構築 1

初期モデル

PDB ID:

6w0o

Chain - Chain ID: A / Chain - Residue range: 10-40 / Chain - Source name: PDB / Chain - Initial model type: experimental model

• 精密化: 空間: REAL / プロトコル: AB INITIO MODEL / 温度因子: 71.7

得られたモデル

PDB-8ff3:
Amyloid-beta (1-40) fibrils derived from familial Dutch-type CAA patient (population B)