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基本情報
登録情報 | データベース: PDB / ID: 5v5b | |||||||||||||||
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タイトル | KVQIINKKLD, Structure of the amyloid spine from microtubule associated protein tau Repeat 2 | |||||||||||||||
![]() | Microtubule-associated protein tau | |||||||||||||||
![]() | STRUCTURAL PROTEIN / Amyloid / tau / Alzheimer's Disease / tauopathy / MAPT | |||||||||||||||
機能・相同性 | ![]() plus-end-directed organelle transport along microtubule / histone-dependent DNA binding / neurofibrillary tangle assembly / positive regulation of diacylglycerol kinase activity / axonal transport / negative regulation of establishment of protein localization to mitochondrion / neurofibrillary tangle / positive regulation of protein localization to synapse / microtubule lateral binding / tubulin complex ...plus-end-directed organelle transport along microtubule / histone-dependent DNA binding / neurofibrillary tangle assembly / positive regulation of diacylglycerol kinase activity / axonal transport / negative regulation of establishment of protein localization to mitochondrion / neurofibrillary tangle / positive regulation of protein localization to synapse / microtubule lateral binding / tubulin complex / phosphatidylinositol bisphosphate binding / main axon / regulation of long-term synaptic depression / negative regulation of kinase activity / negative regulation of tubulin deacetylation / generation of neurons / positive regulation of protein localization / rRNA metabolic process / internal protein amino acid acetylation / regulation of chromosome organization / regulation of mitochondrial fission / axonal transport of mitochondrion / intracellular distribution of mitochondria / axon development / central nervous system neuron development / regulation of microtubule polymerization / microtubule polymerization / minor groove of adenine-thymine-rich DNA binding / lipoprotein particle binding / dynactin binding / glial cell projection / apolipoprotein binding / negative regulation of mitochondrial membrane potential / protein polymerization / axolemma / negative regulation of mitochondrial fission / Caspase-mediated cleavage of cytoskeletal proteins / regulation of microtubule polymerization or depolymerization / positive regulation of axon extension / regulation of microtubule cytoskeleton organization / Activation of AMPK downstream of NMDARs / supramolecular fiber organization / cytoplasmic microtubule organization / regulation of cellular response to heat / stress granule assembly / regulation of calcium-mediated signaling / axon cytoplasm / positive regulation of microtubule polymerization / somatodendritic compartment / synapse assembly / cellular response to brain-derived neurotrophic factor stimulus / phosphatidylinositol binding / nuclear periphery / cellular response to nerve growth factor stimulus / positive regulation of superoxide anion generation / protein phosphatase 2A binding / regulation of autophagy / astrocyte activation / response to lead ion / synapse organization / microglial cell activation / Hsp90 protein binding / regulation of synaptic plasticity / PKR-mediated signaling / protein homooligomerization / memory / microtubule cytoskeleton organization / SH3 domain binding / cellular response to reactive oxygen species / cytoplasmic ribonucleoprotein granule / activation of cysteine-type endopeptidase activity involved in apoptotic process / microtubule cytoskeleton / neuron projection development / cell-cell signaling / protein-macromolecule adaptor activity / actin binding / single-stranded DNA binding / protein-folding chaperone binding / cellular response to heat / cell body / growth cone / microtubule binding / double-stranded DNA binding / microtubule / amyloid fibril formation / sequence-specific DNA binding / dendritic spine / learning or memory / nuclear speck / neuron projection / membrane raft / axon / negative regulation of gene expression / neuronal cell body / dendrite / DNA damage response / protein kinase binding / enzyme binding / mitochondrion / DNA binding 類似検索 - 分子機能 | |||||||||||||||
生物種 | ![]() | |||||||||||||||
手法 | 電子線結晶学 / ![]() | |||||||||||||||
![]() | Seidler, P.M. / Sawaya, M.R. / Rodriguez, J.A. / Eisenberg, D.S. / Cascio, D. / Boyer, D.R. | |||||||||||||||
資金援助 | ![]()
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![]() | ![]() タイトル: Structure-based inhibitors of tau aggregation. 著者: P M Seidler / D R Boyer / J A Rodriguez / M R Sawaya / D Cascio / K Murray / T Gonen / D S Eisenberg / ![]() 要旨: Aggregated tau protein is associated with over 20 neurological disorders, which include Alzheimer's disease. Previous work has shown that tau's sequence segments VQIINK and VQIVYK drive its ...Aggregated tau protein is associated with over 20 neurological disorders, which include Alzheimer's disease. Previous work has shown that tau's sequence segments VQIINK and VQIVYK drive its aggregation, but inhibitors based on the structure of the VQIVYK segment only partially inhibit full-length tau aggregation and are ineffective at inhibiting seeding by full-length fibrils. Here we show that the VQIINK segment is the more powerful driver of tau aggregation. Two structures of this segment determined by the cryo-electron microscopy method micro-electron diffraction explain its dominant influence on tau aggregation. Of practical significance, the structures lead to the design of inhibitors that not only inhibit tau aggregation but also inhibit the ability of exogenous full-length tau fibrils to seed intracellular tau in HEK293 biosensor cells into amyloid. We also raise the possibility that the two VQIINK structures represent amyloid polymorphs of tau that may account for a subset of prion-like strains of tau. | |||||||||||||||
履歴 |
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構造の表示
ムービー |
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構造ビューア | 分子: ![]() ![]() |
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PDBx/mmCIF形式 | ![]() | 17 KB | 表示 | ![]() |
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PDB形式 | ![]() | 8.1 KB | 表示 | ![]() |
PDBx/mmJSON形式 | ![]() | ツリー表示 | ![]() | |
その他 | ![]() |
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アーカイブディレクトリ | ![]() ![]() | HTTPS FTP |
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-関連構造データ
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リンク
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集合体
登録構造単位 | ![]()
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2 | ![]()
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単位格子 |
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要素
#1: タンパク質・ペプチド | 分子量: 1201.478 Da / 分子数: 1 / 断片: Repeat 2 peptide (UNP residues 591-600) / 由来タイプ: 合成 / 由来: (合成) ![]() |
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#2: 水 | ChemComp-HOH / |
-実験情報
-実験
実験 | 手法: 電子線結晶学 |
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EM実験 | 試料の集合状態: 3D ARRAY / 3次元再構成法: 電子線結晶学 |
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試料調製
構成要素 | 名称: KVQIINKKLD Tau peptide / タイプ: ORGANELLE OR CELLULAR COMPONENT / Entity ID: #1 / 由来: NATURAL |
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分子量 | 実験値: NO |
由来(天然) | 生物種: ![]() |
緩衝液 | pH: 4.2 |
試料 | 包埋: NO / シャドウイング: NO / 染色: NO / 凍結: YES |
急速凍結 | 凍結剤: ETHANE |
結晶 | マシュー密度: 1.74 Å3/Da / 溶媒含有率: 29.23 % |
結晶化 | 温度: 310 K / 手法: 蒸気拡散法, ハンギングドロップ法 / pH: 4.2 / 詳細: 0.1 M phosphate citrate, 32% PEG10000 |
-データ収集
顕微鏡 | モデル: FEI TECNAI 20 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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電子銃 | 電子線源: ![]() | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
電子レンズ | モード: DIFFRACTION | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
撮影 | 電子線照射量: 0.1 e/Å2 フィルム・検出器のモデル: TVIPS TEMCAM-F416 (4k x 4k) | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
EM回折 | カメラ長: 1850 mm | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
EM回折 シェル | 解像度: 1.5→1.68 Å / フーリエ空間範囲: 82.4 % / 多重度: 6.2 / 構造因子数: 370 / 位相残差: 0.1 ° | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
EM回折 統計 | 詳細: This is a crystallography experiment. / フーリエ空間範囲: 84.8 % / 再高解像度: 1.5 Å / 測定した強度の数: 20047 / 構造因子数: 2203 / 位相誤差: 0 ° / 位相残差: 0.1 ° / 位相誤差の除外基準: 0 / Rmerge: 25 / Rsym: 25 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
回折 | 平均測定温度: 100 K | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
放射光源 | 由来: ELECTRON MICROSCOPE / タイプ: TECNAI F20 TEM / 波長: 0.0251 Å | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
検出器 | タイプ: TVIPS TEMCAM-F416 / 検出器: CMOS / 日付: 2016年8月25日 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
放射波長 | 波長: 0.0251 Å / 相対比: 1 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
反射 | 解像度: 1.5→18.83 Å / Num. obs: 2203 / % possible obs: 84.8 % / Observed criterion σ(I): -3 / 冗長度: 9.133 % / Biso Wilson estimate: 8.37 Å2 / CC1/2: 0.984 / Rmerge(I) obs: 0.255 / Rrim(I) all: 0.268 / Χ2: 0.851 / Net I/σ(I): 5.24 / Num. measured all: 20119 / Scaling rejects: 12 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
反射 シェル | Diffraction-ID: 1
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-位相決定
位相決定 | 手法: ![]() |
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解析
ソフトウェア |
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EMソフトウェア |
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EM 3D crystal entity | ∠α: 90 ° / ∠β: 105.53 ° / ∠γ: 90 ° / A: 27.12 Å / B: 4.83 Å / C: 32.43 Å / 空間群名: P21 / 空間群番号: 4 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
CTF補正 | タイプ: NONE | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
3次元再構成 | 解像度の算出法: DIFFRACTION PATTERN/LAYERLINES / 対称性のタイプ: 3D CRYSTAL | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
精密化 | 構造決定の手法: ![]()
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原子変位パラメータ | Biso max: 66.55 Å2 / Biso mean: 16.92 Å2 / Biso min: 3 Å2
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Refine analyze | Luzzati coordinate error obs: 0.214 Å | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
精密化ステップ | サイクル: final / 解像度: 1.5→18.83 Å
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拘束条件 |
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LS精密化 シェル | 解像度: 1.5→1.68 Å / Rfactor Rfree error: 0 / Total num. of bins used: 5
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