+データを開く
-基本情報
登録情報 | データベース: PDB / ID: 9for | ||||||
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タイトル | Structure of heteromeric amyloid filament of TDP-43 and AXNA11 from FTLD-TDP Type C (variant 1) | ||||||
要素 |
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キーワード | PROTEIN FIBRIL / TDP-43 / ANXA11 / amyloid / heteromeric amyloid / FTLD-TDP / FTLD-TDP Type C / neurodegeneration / neurodegenerative disease / dementia / brain / filament | ||||||
機能・相同性 | 機能・相同性情報 cytokinetic process / nuclear inner membrane organization / interchromatin granule / perichromatin fibrils / 3'-UTR-mediated mRNA destabilization / specific granule / phosphatidylethanolamine binding / calcium-dependent phospholipid binding / S100 protein binding / azurophil granule ...cytokinetic process / nuclear inner membrane organization / interchromatin granule / perichromatin fibrils / 3'-UTR-mediated mRNA destabilization / specific granule / phosphatidylethanolamine binding / calcium-dependent phospholipid binding / S100 protein binding / azurophil granule / 3'-UTR-mediated mRNA stabilization / intracellular non-membrane-bounded organelle / phosphatidylserine binding / negative regulation by host of viral transcription / phagocytosis / pre-mRNA intronic binding / phagocytic vesicle / response to endoplasmic reticulum stress / RNA splicing / negative regulation of protein phosphorylation / molecular condensate scaffold activity / mRNA 3'-UTR binding / regulation of protein stability / regulation of circadian rhythm / positive regulation of insulin secretion / mRNA processing / positive regulation of protein import into nucleus / response to calcium ion / cytoplasmic stress granule / spindle / calcium-dependent protein binding / rhythmic process / melanosome / MHC class II protein complex binding / nuclear envelope / midbody / regulation of gene expression / double-stranded DNA binding / regulation of apoptotic process / collagen-containing extracellular matrix / amyloid fibril formation / regulation of cell cycle / nuclear speck / RNA polymerase II cis-regulatory region sequence-specific DNA binding / negative regulation of gene expression / lipid binding / calcium ion binding / mitochondrion / DNA binding / RNA binding / extracellular exosome / nucleoplasm / identical protein binding / membrane / nucleus / plasma membrane / cytoplasm / cytosol 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: 2.75 Å | ||||||
データ登録者 | Arseni, D. / Ryskeldi-Falcon, B. | ||||||
資金援助 | 英国, 1件
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引用 | ジャーナル: bioRxiv / 年: 2024 タイトル: Heteromeric amyloid filaments of ANXA11 and TDP-43 in FTLD-TDP Type C. 著者: Diana Arseni / Takashi Nonaka / Max H Jacobsen / Alexey G Murzin / Laura Cracco / Sew Y Peak-Chew / Holly J Garringer / Ito Kawakami / Hisaomi Suzuki / Misumoto Onaya / Yuko Saito / Shigeo ...著者: Diana Arseni / Takashi Nonaka / Max H Jacobsen / Alexey G Murzin / Laura Cracco / Sew Y Peak-Chew / Holly J Garringer / Ito Kawakami / Hisaomi Suzuki / Misumoto Onaya / Yuko Saito / Shigeo Murayama / Changiz Geula / Ruben Vidal / Kathy L Newell / Marsel Mesulam / Bernardino Ghetti / Masato Hasegawa / Benjamin Ryskeldi-Falcon 要旨: Neurodegenerative diseases are characterised by the abnormal filamentous assembly of specific proteins in the central nervous system . Human genetic studies established a causal role for protein ...Neurodegenerative diseases are characterised by the abnormal filamentous assembly of specific proteins in the central nervous system . Human genetic studies established a causal role for protein assembly in neurodegeneration . However, the underlying molecular mechanisms remain largely unknown, which is limiting progress in developing clinical tools for these diseases. Recent advances in electron cryo-microscopy (cryo-EM) have enabled the structures of the protein filaments to be determined from patient brains . All diseases studied to date have been characterised by the self-assembly of a single intracellular protein in homomeric amyloid filaments, including that of TAR DNA-binding protein 43 (TDP-43) in amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration with TDP-43 inclusions (FTLD-TDP) Types A and B . Here, we used cryo-EM to determine filament structures from the brains of individuals with FTLD-TDP Type C, one of the most common forms of sporadic FTLD-TDP. Unexpectedly, the structures revealed that a second protein, annexin A11 (ANXA11), co-assembles with TDP-43 in heteromeric amyloid filaments. The ordered filament fold is formed by TDP-43 residues G282/284-N345 and ANXA11 residues L39-L74 from their respective low-complexity domains (LCDs). Regions of TDP-43 and ANXA11 previously implicated in protein-protein interactions form an extensive hydrophobic interface at the centre of the filament fold. Immunoblots of the filaments revealed that the majority of ANXA11 exists as a ∼22 kDa N-terminal fragment (NTF) lacking the annexin core domain. Immunohistochemistry of brain sections confirmed the co-localisation of ANXA11 and TDP-43 in inclusions, redefining the histopathology of FTLD-TDP Type C. This work establishes a central role for ANXA11 in FTLD-TDP Type C. The unprecedented formation of heteromeric amyloid filaments in human brain revises our understanding of amyloid assembly and may be of significance for the pathogenesis of neurodegenerative diseases. | ||||||
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 | 9for.cif.gz | 93.5 KB | 表示 | PDBx/mmCIF形式 |
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PDB形式 | pdb9for.ent.gz | 71.2 KB | 表示 | PDB形式 |
PDBx/mmJSON形式 | 9for.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 | 9for_validation.pdf.gz | 1.4 MB | 表示 | wwPDB検証レポート |
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文書・詳細版 | 9for_full_validation.pdf.gz | 1.4 MB | 表示 | |
XML形式データ | 9for_validation.xml.gz | 22.8 KB | 表示 | |
CIF形式データ | 9for_validation.cif.gz | 32.3 KB | 表示 | |
アーカイブディレクトリ | https://data.pdbj.org/pub/pdb/validation_reports/fo/9for ftp://data.pdbj.org/pub/pdb/validation_reports/fo/9for | HTTPS FTP |
-関連構造データ
関連構造データ | 50628MC 9fofC M: このデータのモデリングに利用したマップデータ C: 同じ文献を引用 (文献) |
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類似構造データ | 類似検索 - 機能・相同性F&H 検索 |
-リンク
-集合体
登録構造単位 |
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1 |
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-要素
#1: タンパク質 | 分子量: 6027.645 Da / 分子数: 5 / 由来タイプ: 天然 / 由来: (天然) Homo sapiens (ヒト) / 組織: Brain / 参照: UniProt: Q13148 #2: タンパク質・ペプチド | 分子量: 3805.148 Da / 分子数: 5 / 由来タイプ: 天然 / 由来: (天然) Homo sapiens (ヒト) / 組織: Brain / 参照: UniProt: P50995 |
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-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: Heteromeric amyloid filament of TDP-43 and AXNA11 from FTLD-TDP Type C (variant 1) タイプ: TISSUE / Entity ID: all / 由来: NATURAL |
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分子量 | 値: 9.8 kDa/nm / 実験値: NO |
由来(天然) | 生物種: Homo sapiens (ヒト) / 組織: Brain |
緩衝液 | pH: 7.4 |
試料 | 包埋: NO / シャドウイング: NO / 染色: NO / 凍結: YES 詳細: Heteromeric amyloid filament of TDP-43 and AXNA11 from FTLD-TDP Type C (variant 1) |
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: TFS 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): 2200 nm / 最小 デフォーカス(公称値): 1000 nm |
撮影 | 電子線照射量: 38 e/Å2 フィルム・検出器のモデル: GATAN K3 BIOQUANTUM (6k x 4k) |
-解析
EMソフトウェア | 名称: RELION / バージョン: 5 / カテゴリ: 3次元再構成 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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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: -1.83 ° / 軸方向距離/サブユニット: 4.98 Å / らせん対称軸の対称性: C1 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
3次元再構成 | 解像度: 2.75 Å / 解像度の算出法: FSC 0.143 CUT-OFF / 粒子像の数: 18020 / 対称性のタイプ: HELICAL | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
精密化 | 解像度: 2.75→96.32 Å / Cor.coef. Fo:Fc: 0.819 / SU B: 6.419 / SU ML: 0.128 / ESU R: 0.119 立体化学のターゲット値: MAXIMUM LIKELIHOOD WITH PHASES 詳細: HYDROGENS HAVE BEEN USED IF PRESENT IN THE INPUT
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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: 55.771 Å2 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
精密化ステップ | サイクル: 1 / 合計: 689 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
拘束条件 |
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