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基本情報
登録情報 | ![]() | ||||||||||||||||||
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タイトル | In vitro grown WT Alpha-Synuclein Fibrils | ||||||||||||||||||
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![]() | Alpha-Synuclein / G14R Mutation / Fibrils / Cryo-EM / Protein Aggregation / Amyloid Structure / PROTEIN FIBRIL | ||||||||||||||||||
機能・相同性 | ![]() negative regulation of mitochondrial electron transport, NADH to ubiquinone / : / neutral lipid metabolic process / regulation of acyl-CoA biosynthetic process / negative regulation of dopamine uptake involved in synaptic transmission / negative regulation of norepinephrine uptake / positive regulation of SNARE complex assembly / positive regulation of hydrogen peroxide catabolic process / supramolecular fiber / mitochondrial membrane organization ...negative regulation of mitochondrial electron transport, NADH to ubiquinone / : / neutral lipid metabolic process / regulation of acyl-CoA biosynthetic process / negative regulation of dopamine uptake involved in synaptic transmission / negative regulation of norepinephrine uptake / positive regulation of SNARE complex assembly / positive regulation of hydrogen peroxide catabolic process / supramolecular fiber / mitochondrial membrane organization / regulation of synaptic vesicle recycling / negative regulation of chaperone-mediated autophagy / regulation of reactive oxygen species biosynthetic process / negative regulation of platelet-derived growth factor receptor signaling pathway / positive regulation of protein localization to cell periphery / negative regulation of exocytosis / regulation of glutamate secretion / response to iron(II) ion / SNARE complex assembly / positive regulation of neurotransmitter secretion / dopamine biosynthetic process / regulation of norepinephrine uptake / transporter regulator activity / regulation of locomotion / mitochondrial ATP synthesis coupled electron transport / regulation of macrophage activation / positive regulation of inositol phosphate biosynthetic process / synaptic vesicle priming / negative regulation of microtubule polymerization / synaptic vesicle transport / positive regulation of receptor recycling / dopamine uptake involved in synaptic transmission / protein kinase inhibitor activity / dynein complex binding / regulation of dopamine secretion / negative regulation of thrombin-activated receptor signaling pathway / cuprous ion binding / positive regulation of exocytosis / response to magnesium ion / synaptic vesicle exocytosis / enzyme inhibitor activity / positive regulation of endocytosis / kinesin binding / synaptic vesicle endocytosis / cysteine-type endopeptidase inhibitor activity / negative regulation of serotonin uptake / regulation of presynapse assembly / response to type II interferon / alpha-tubulin binding / supramolecular fiber organization / inclusion body / phospholipid metabolic process / cellular response to copper ion / axon terminus / cellular response to epinephrine stimulus / Hsp70 protein binding / response to interleukin-1 / regulation of microtubule cytoskeleton organization / SNARE binding / positive regulation of release of sequestered calcium ion into cytosol / adult locomotory behavior / negative regulation of protein kinase activity / excitatory postsynaptic potential / fatty acid metabolic process / phosphoprotein binding / protein tetramerization / microglial cell activation / regulation of long-term neuronal synaptic plasticity / synapse organization / ferrous iron binding / protein destabilization / PKR-mediated signaling / phospholipid binding / receptor internalization / tau protein binding / long-term synaptic potentiation / positive regulation of inflammatory response / synaptic vesicle membrane / actin cytoskeleton / actin binding / growth cone / cell cortex / cellular response to oxidative stress / neuron apoptotic process / chemical synaptic transmission / molecular adaptor activity / negative regulation of neuron apoptotic process / response to lipopolysaccharide / histone binding / amyloid fibril formation / lysosome / oxidoreductase activity / transcription cis-regulatory region binding / postsynapse / positive regulation of apoptotic process / Amyloid fiber formation / copper ion binding / response to xenobiotic stimulus / axon / neuronal cell body 類似検索 - 分子機能 | ||||||||||||||||||
生物種 | ![]() | ||||||||||||||||||
手法 | 単粒子再構成法 / クライオ電子顕微鏡法 / 解像度: 2.7 Å | ||||||||||||||||||
![]() | Sicking K / Al-Azzani M / Outeiro TF / Fernandez-Busnadiego R | ||||||||||||||||||
資金援助 | ![]() ![]()
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![]() | ![]() タイトル: A novel alpha-synuclein G14R missense variant is associated with atypical neuropathological features. 著者: Christof Brücke / Mohammed Al-Azzani / Nagendran Ramalingam / Maria Ramón / Rita L Sousa / Fiamma Buratti / Michael Zech / Kevin Sicking / Leslie Amaral / Ellen Gelpi / Aswathy Chandran / ...著者: Christof Brücke / Mohammed Al-Azzani / Nagendran Ramalingam / Maria Ramón / Rita L Sousa / Fiamma Buratti / Michael Zech / Kevin Sicking / Leslie Amaral / Ellen Gelpi / Aswathy Chandran / Aishwarya Agarwal / Susana R Chaves / Claudio O Fernández / Ulf Dettmer / Janin Lautenschläger / Markus Zweckstetter / Ruben Fernandez Busnadiego / Alexander Zimprich / Tiago Fleming Outeiro / ![]() ![]() ![]() ![]() ![]() ![]() 要旨: BACKGROUND: Parkinson's disease (PD) affects millions of people worldwide, but only 5-10% of patients suffer from a monogenic form of the disease with Mendelian inheritance. , the gene encoding for ...BACKGROUND: Parkinson's disease (PD) affects millions of people worldwide, but only 5-10% of patients suffer from a monogenic form of the disease with Mendelian inheritance. , the gene encoding for the protein alpha-synuclein (aSyn), was the first to be associated with familial forms of PD and, since then, several missense variants and multiplications of the gene have been established as rare causes of autosomal dominant forms of PD. AIM AND METHODS: A patient carrying aSyn missense mutation and his family members were studied. We present the clinical features, genetic testing - whole exome sequencing (WES), and neuropathological ...AIM AND METHODS: A patient carrying aSyn missense mutation and his family members were studied. We present the clinical features, genetic testing - whole exome sequencing (WES), and neuropathological findings. The functional consequences of this aSyn variant were extensively investigated using biochemical, biophysical, and cellular assays. RESULTS: The patient exhibited a complex neurodegenerative disease that included generalized myocloni, bradykinesia, dystonia of the left arm and apraxia. WES identified a novel heterozygous variant ...RESULTS: The patient exhibited a complex neurodegenerative disease that included generalized myocloni, bradykinesia, dystonia of the left arm and apraxia. WES identified a novel heterozygous variant (cDNA 40G>A; protein G14R). Neuropathological examination showed extensive atypical aSyn pathology with frontotemporal lobar degeneration (FTLD) and nigral degeneration pattern with abundant ring-like neuronal inclusions, and few oligodendroglial inclusions. Sanger sequencing confirmed the variant in the healthy, elderly parent of the patient patient suggesting incomplete penetrance. NMR studies suggest that the G14R mutation induces a local structural alteration in aSyn, and lower thioflavin T binding in in vitro fibrillization assays. Interestingly, the G14R aSyn fibers display different fibrillar morphologies as revealed by cryo-electron microscopy. Cellular studies of the G14R variant revealed increased inclusion formation, enhanced membrane association, and impaired dynamic reversibility of serine-129 phosphorylation. SUMMARY: The atypical neuropathological features observed, which are reminiscent of those observed for the G51D aSyn variant, suggest a causal role of the variant with a distinct clinical and ...SUMMARY: The atypical neuropathological features observed, which are reminiscent of those observed for the G51D aSyn variant, suggest a causal role of the variant with a distinct clinical and pathological phenotype, which is further supported by the properties of the mutant aSyn, compatible with the strain hypothesis of proteinopathies. | ||||||||||||||||||
履歴 |
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構造の表示
添付画像 |
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ダウンロードとリンク
-EMDBアーカイブ
マップデータ | ![]() | 202 MB | ![]() | |
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ヘッダ (付随情報) | ![]() ![]() | 17.5 KB 17.5 KB | 表示 表示 | ![]() |
FSC (解像度算出) | ![]() | 13.5 KB | 表示 | ![]() |
画像 | ![]() | 56.3 KB | ||
Filedesc metadata | ![]() | 5.7 KB | ||
その他 | ![]() ![]() | 170 MB 170 MB | ||
アーカイブディレクトリ | ![]() ![]() | HTTPS FTP |
-検証レポート
文書・要旨 | ![]() | 1 MB | 表示 | ![]() |
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文書・詳細版 | ![]() | 1 MB | 表示 | |
XML形式データ | ![]() | 21.2 KB | 表示 | |
CIF形式データ | ![]() | 28.1 KB | 表示 | |
アーカイブディレクトリ | ![]() ![]() | HTTPS FTP |
-関連構造データ
関連構造データ | ![]() 9hgrMC M: このマップから作成された原子モデル C: 同じ文献を引用 ( |
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類似構造データ | 類似検索 - 機能・相同性 ![]() |
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リンク
EMDBのページ | ![]() ![]() |
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マップ
ファイル | ![]() | ||||||||||||||||||||||||||||||||||||
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投影像・断面図 | 画像のコントロール
画像は Spider により作成 | ||||||||||||||||||||||||||||||||||||
ボクセルのサイズ | X=Y=Z: 0.92 Å | ||||||||||||||||||||||||||||||||||||
密度 |
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対称性 | 空間群: 1 | ||||||||||||||||||||||||||||||||||||
詳細 | EMDB XML:
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-添付データ
-ハーフマップ: #1
ファイル | emd_52165_half_map_1.map | ||||||||||||
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投影像・断面図 |
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密度ヒストグラム |
-ハーフマップ: #2
ファイル | emd_52165_half_map_2.map | ||||||||||||
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投影像・断面図 |
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密度ヒストグラム |
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試料の構成要素
-全体 : WT Alpha-Synuclein
全体 | 名称: WT Alpha-Synuclein |
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要素 |
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-超分子 #1: WT Alpha-Synuclein
超分子 | 名称: WT Alpha-Synuclein / タイプ: organelle_or_cellular_component / ID: 1 / 親要素: 0 / 含まれる分子: all |
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由来(天然) | 生物種: ![]() |
分子量 | 理論値: 14.46 kDa/nm |
-分子 #1: Alpha-synuclein
分子 | 名称: Alpha-synuclein / タイプ: protein_or_peptide / ID: 1 / コピー数: 2 / 光学異性体: LEVO |
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由来(天然) | 生物種: ![]() |
分子量 | 理論値: 14.476108 KDa |
組換発現 | 生物種: ![]() ![]() |
配列 | 文字列: MDVFMKGLSK AKEGVVAAAE KTKQGVAEAA GKTKEGVLYV GSKTKEGVVH GVATVAEKTK EQVTNVGGAV VTGVTAVAQK TVEGAGSIA AATGFVKKDQ LGKNEEGAPQ EGILEDMPVD PDNEAYEMPS EEGYQDYEPE A UniProtKB: Alpha-synuclein |
-実験情報
-構造解析
手法 | クライオ電子顕微鏡法 |
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![]() | 単粒子再構成法 |
試料の集合状態 | filament |
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試料調製
緩衝液 | pH: 7 |
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凍結 | 凍結剤: ETHANE-PROPANE |
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電子顕微鏡法
顕微鏡 | TFS KRIOS |
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撮影 | フィルム・検出器のモデル: FEI FALCON IV (4k x 4k) 平均電子線量: 40.0 e/Å2 |
電子線 | 加速電圧: 300 kV / 電子線源: ![]() |
電子光学系 | 照射モード: FLOOD BEAM / 撮影モード: OTHER / 最大 デフォーカス(公称値): 2.4 µm / 最小 デフォーカス(公称値): 1.2 µm |
実験機器 | ![]() モデル: Titan Krios / 画像提供: FEI Company |