+データを開く
-基本情報
登録情報 | データベース: PDB / ID: 8bqv | |||||||||||||||
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タイトル | Cryo-EM structure of alpha-synuclein singlet filament from Juvenile-onset synucleinopathy | |||||||||||||||
要素 |
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キーワード | PROTEIN FIBRIL / alpha-synuclein / amyloid / fibril / insertion / juvenile-onset synucleinopathy (JOS) / synucleinopathy | |||||||||||||||
機能・相同性 | 機能・相同性情報 regulation of phospholipase activity / negative regulation of monooxygenase activity / negative regulation of mitochondrial electron transport, NADH to ubiquinone / positive regulation of glutathione peroxidase activity / 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 ...regulation of phospholipase activity / negative regulation of monooxygenase activity / negative regulation of mitochondrial electron transport, NADH to ubiquinone / positive regulation of glutathione peroxidase activity / 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 / negative regulation of transporter activity / mitochondrial membrane organization / negative regulation of chaperone-mediated autophagy / regulation of reactive oxygen species biosynthetic process / regulation of synaptic vesicle recycling / 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 / regulation of norepinephrine uptake / SNARE complex assembly / positive regulation of neurotransmitter secretion / dopamine biosynthetic process / regulation of locomotion / positive regulation of inositol phosphate biosynthetic process / synaptic vesicle priming / regulation of macrophage activation / negative regulation of microtubule polymerization / synaptic vesicle transport / dopamine uptake involved in synaptic transmission / regulation of dopamine secretion / dynein complex binding / positive regulation of receptor recycling / protein kinase inhibitor activity / negative regulation of thrombin-activated receptor signaling pathway / response to type II interferon / cuprous ion binding / response to magnesium ion / positive regulation of exocytosis / synaptic vesicle exocytosis / positive regulation of endocytosis / kinesin binding / cysteine-type endopeptidase inhibitor activity involved in apoptotic process / mitochondrial ATP synthesis coupled electron transport / synaptic vesicle endocytosis / regulation of presynapse assembly / negative regulation of serotonin uptake / alpha-tubulin binding / phospholipid metabolic process / supramolecular fiber organization / axon terminus / inclusion body / cellular response to copper ion / cellular response to epinephrine stimulus / Hsp70 protein binding / response to interleukin-1 / : / adult locomotory behavior / positive regulation of release of sequestered calcium ion into cytosol / excitatory postsynaptic potential / SNARE binding / fatty acid metabolic process / long-term synaptic potentiation / phosphoprotein binding / protein tetramerization / regulation of transmembrane transporter activity / protein destabilization / negative regulation of protein kinase activity / microglial cell activation / regulation of long-term neuronal synaptic plasticity / synapse organization / ferrous iron binding / positive regulation of protein serine/threonine kinase activity / tau protein binding / PKR-mediated signaling / receptor internalization / phospholipid binding / : / synaptic vesicle membrane / positive regulation of inflammatory response / actin cytoskeleton / positive regulation of peptidyl-serine phosphorylation / actin binding / cell cortex / cellular response to oxidative stress / histone binding / growth cone / chemical synaptic transmission / neuron apoptotic process / negative regulation of neuron apoptotic process / postsynapse / response to lipopolysaccharide / amyloid fibril formation / molecular adaptor activity / lysosome / oxidoreductase activity / transcription cis-regulatory region binding / positive regulation of apoptotic process 類似検索 - 分子機能 | |||||||||||||||
生物種 | Homo sapiens (ヒト) | |||||||||||||||
手法 | 電子顕微鏡法 / らせん対称体再構成法 / クライオ電子顕微鏡法 / 解像度: 2 Å | |||||||||||||||
データ登録者 | Yang, Y. / Garringer, J.H. / Shi, Y. / Lovestam, S. / Peak-Chew, S.Y. / Zhang, X.J. / Kotecha, A. / Bacioglu, M. / Koto, A. / Takao, M. ...Yang, Y. / Garringer, J.H. / Shi, Y. / Lovestam, S. / Peak-Chew, S.Y. / Zhang, X.J. / Kotecha, A. / Bacioglu, M. / Koto, A. / Takao, M. / Spillantini, G.M. / Ghetti, B. / Vidal, R. / Murzin, G.A. / Scheres, H.W.S. / Goedert, M. | |||||||||||||||
資金援助 | 英国, 米国, 4件
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引用 | ジャーナル: Acta Neuropathol / 年: 2023 タイトル: New SNCA mutation and structures of α-synuclein filaments from juvenile-onset synucleinopathy. 著者: Yang Yang / Holly J Garringer / Yang Shi / Sofia Lövestam / Sew Peak-Chew / Xianjun Zhang / Abhay Kotecha / Mehtap Bacioglu / Atsuo Koto / Masaki Takao / Maria Grazia Spillantini / ...著者: Yang Yang / Holly J Garringer / Yang Shi / Sofia Lövestam / Sew Peak-Chew / Xianjun Zhang / Abhay Kotecha / Mehtap Bacioglu / Atsuo Koto / Masaki Takao / Maria Grazia Spillantini / Bernardino Ghetti / Ruben Vidal / Alexey G Murzin / Sjors H W Scheres / Michel Goedert / 要旨: A 21-nucleotide duplication in one allele of SNCA was identified in a previously described disease with abundant α-synuclein inclusions that we now call juvenile-onset synucleinopathy (JOS). This ...A 21-nucleotide duplication in one allele of SNCA was identified in a previously described disease with abundant α-synuclein inclusions that we now call juvenile-onset synucleinopathy (JOS). This mutation translates into the insertion of MAAAEKT after residue 22 of α-synuclein, resulting in a protein of 147 amino acids. Both wild-type and mutant proteins were present in sarkosyl-insoluble material that was extracted from frontal cortex of the individual with JOS and examined by electron cryo-microscopy. The structures of JOS filaments, comprising either a single protofilament, or a pair of protofilaments, revealed a new α-synuclein fold that differs from the folds of Lewy body diseases and multiple system atrophy (MSA). The JOS fold consists of a compact core, the sequence of which (residues 36-100 of wild-type α-synuclein) is unaffected by the mutation, and two disconnected density islands (A and B) of mixed sequences. There is a non-proteinaceous cofactor bound between the core and island A. The JOS fold resembles the common substructure of MSA Type I and Type II dimeric filaments, with its core segment approximating the C-terminal body of MSA protofilaments B and its islands mimicking the N-terminal arm of MSA protofilaments A. The partial similarity of JOS and MSA folds extends to the locations of their cofactor-binding sites. In vitro assembly of recombinant wild-type α-synuclein, its insertion mutant and their mixture yielded structures that were distinct from those of JOS filaments. Our findings provide insight into a possible mechanism of JOS fibrillation in which mutant α-synuclein of 147 amino acids forms a nucleus with the JOS fold, around which wild-type and mutant proteins assemble during elongation. | |||||||||||||||
履歴 |
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-構造の表示
構造ビューア | 分子: MolmilJmol/JSmol |
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-ダウンロードとリンク
-ダウンロード
PDBx/mmCIF形式 | 8bqv.cif.gz | 28.4 KB | 表示 | PDBx/mmCIF形式 |
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PDB形式 | pdb8bqv.ent.gz | 14.9 KB | 表示 | PDB形式 |
PDBx/mmJSON形式 | 8bqv.json.gz | ツリー表示 | PDBx/mmJSON形式 | |
その他 | その他のダウンロード |
-検証レポート
文書・要旨 | 8bqv_validation.pdf.gz | 1.1 MB | 表示 | wwPDB検証レポート |
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文書・詳細版 | 8bqv_full_validation.pdf.gz | 1.1 MB | 表示 | |
XML形式データ | 8bqv_validation.xml.gz | 20.2 KB | 表示 | |
CIF形式データ | 8bqv_validation.cif.gz | 27.4 KB | 表示 | |
アーカイブディレクトリ | https://data.pdbj.org/pub/pdb/validation_reports/bq/8bqv ftp://data.pdbj.org/pub/pdb/validation_reports/bq/8bqv | HTTPS FTP |
-関連構造データ
-リンク
-集合体
登録構造単位 |
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非結晶学的対称性 (NCS) | NCS oper:
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-要素
#1: タンパク質 | 分子量: 14476.108 Da / 分子数: 1 / 由来タイプ: 天然 / 由来: (天然) Homo sapiens (ヒト) / 参照: UniProt: P37840 |
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#2: タンパク質・ペプチド | 分子量: 613.749 Da / 分子数: 1 / 由来タイプ: 天然 / 由来: (天然) Homo sapiens (ヒト) |
#3: 水 | ChemComp-HOH / |
-実験情報
-実験
実験 | 手法: 電子顕微鏡法 |
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EM実験 | 試料の集合状態: FILAMENT / 3次元再構成法: らせん対称体再構成法 |
-試料調製
構成要素 | 名称: Alpha-synuclein singlet filament extracted from the human brain with JOS タイプ: TISSUE / Entity ID: #1-#2 / 由来: NATURAL |
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由来(天然) | 生物種: Homo sapiens (ヒト) |
緩衝液 | pH: 7.5 |
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 |
-電子顕微鏡撮影
実験機器 | モデル: Titan Krios / 画像提供: FEI Company |
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顕微鏡 | モデル: FEI TITAN KRIOS |
電子銃 | 電子線源: FIELD EMISSION GUN / 加速電圧: 300 kV / 照射モード: FLOOD BEAM |
電子レンズ | モード: BRIGHT FIELD / 最大 デフォーカス(公称値): 1400 nm / 最小 デフォーカス(公称値): 600 nm |
撮影 | 電子線照射量: 40 e/Å2 フィルム・検出器のモデル: FEI FALCON IV (4k x 4k) |
-解析
ソフトウェア | 名称: REFMAC / バージョン: 5.8.0350 / 分類: 精密化 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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EMソフトウェア |
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CTF補正 | タイプ: PHASE FLIPPING AND AMPLITUDE CORRECTION | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
らせん対称 | 回転角度/サブユニット: -1.33 ° / 軸方向距離/サブユニット: 4.77 Å / らせん対称軸の対称性: C1 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
3次元再構成 | 解像度: 2 Å / 解像度の算出法: FSC 0.143 CUT-OFF / 粒子像の数: 214769 / 対称性のタイプ: HELICAL | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
原子モデル構築 | 詳細: servalcat | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
精密化 | 解像度: 2→85.79 Å / Cor.coef. Fo:Fc: 0.769 / SU B: 2.933 / SU ML: 0.077 / ESU R: 0.077 立体化学のターゲット値: MAXIMUM LIKELIHOOD WITH PHASES 詳細: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
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溶媒の処理 | 溶媒モデル: PARAMETERS FOR MASK CACLULATION | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
原子変位パラメータ | Biso mean: 44.528 Å2 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
精密化ステップ | サイクル: 1 / 合計: 573 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
拘束条件 |
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