+データを開く
-基本情報
登録情報 | データベース: PDB / ID: 8czo | ||||||
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タイトル | Cryo-EM structure of BCL10 CARD - MALT1 DD filament | ||||||
要素 |
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キーワード | IMMUNE SYSTEM / filament / CBM complex | ||||||
機能・相同性 | 機能・相同性情報 positive regulation of lymphotoxin A production / polkadots / B-1 B cell differentiation / positive regulation of T-helper 17 cell differentiation / CBM complex / regulation of T cell receptor signaling pathway / antifungal innate immune response / protein kinase B binding / response to fungus / T cell apoptotic process ...positive regulation of lymphotoxin A production / polkadots / B-1 B cell differentiation / positive regulation of T-helper 17 cell differentiation / CBM complex / regulation of T cell receptor signaling pathway / antifungal innate immune response / protein kinase B binding / response to fungus / T cell apoptotic process / positive regulation of mast cell cytokine production / CARD domain binding / programmed cell death / negative regulation of mature B cell apoptotic process / B cell apoptotic process / CLEC7A/inflammasome pathway / positive regulation of extrinsic apoptotic signaling pathway / nuclear export / response to food / non-canonical NF-kappaB signal transduction / toll-like receptor signaling pathway / B cell activation / positive regulation of T cell receptor signaling pathway / cytoplasmic microtubule / positive regulation of cysteine-type endopeptidase activity involved in apoptotic process / small molecule binding / positive regulation of phosphorylation / general transcription initiation factor binding / immunological synapse / NF-kappaB binding / immunoglobulin mediated immune response / cellular defense response / T cell proliferation / lipopolysaccharide-mediated signaling pathway / positive regulation of interleukin-2 production / proteolysis involved in protein catabolic process / positive regulation of interleukin-1 beta production / positive regulation of protein ubiquitination / neural tube closure / positive regulation of interleukin-8 production / Activation of NF-kappaB in B cells / cellular response to mechanical stimulus / protein homooligomerization / positive regulation of T cell cytokine production / CLEC7A (Dectin-1) signaling / fibrillar center / defense response / FCERI mediated NF-kB activation / positive regulation of interleukin-6 production / ubiquitin-protein transferase activity / positive regulation of T cell activation / Downstream TCR signaling / E3 ubiquitin ligases ubiquitinate target proteins / positive regulation of NF-kappaB transcription factor activity / peptidase activity / protein-macromolecule adaptor activity / T cell receptor signaling pathway / positive regulation of canonical NF-kappaB signal transduction / endopeptidase activity / protease binding / cellular response to lipopolysaccharide / regulation of apoptotic process / transcription coactivator activity / adaptive immune response / 加水分解酵素; プロテアーゼ; ペプチド結合加水分解酵素; システインプロテアーゼ / lysosome / membrane raft / positive regulation of apoptotic process / cysteine-type endopeptidase activity / innate immune response / ubiquitin protein ligase binding / positive regulation of DNA-templated transcription / negative regulation of apoptotic process / protein-containing complex binding / perinuclear region of cytoplasm / protein-containing complex / proteolysis / identical protein binding / nucleus / 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: 4.3 Å | ||||||
データ登録者 | David, L. / Wu, H. | ||||||
資金援助 | 1件
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引用 | ジャーナル: Cancer Discov / 年: 2022 タイトル: BCL10 Mutations Define Distinct Dependencies Guiding Precision Therapy for DLBCL. 著者: Min Xia / Liron David / Matt Teater / Johana Gutierrez / Xiang Wang / Cem Meydan / Andrew Lytle / Graham W Slack / David W Scott / Ryan D Morin / Ozlem Onder / Kojo S J Elenitoba-Johnson / ...著者: Min Xia / Liron David / Matt Teater / Johana Gutierrez / Xiang Wang / Cem Meydan / Andrew Lytle / Graham W Slack / David W Scott / Ryan D Morin / Ozlem Onder / Kojo S J Elenitoba-Johnson / Nahuel Zamponi / Leandro Cerchietti / Tianbao Lu / Ulrike Philippar / Lorena Fontan / Hao Wu / Ari M Melnick / 要旨: Activated B cell-like diffuse large B-cell lymphomas (ABC-DLBCL) have unfavorable outcomes and chronic activation of CARD11-BCL10-MALT1 (CBM) signal amplification complexes that form due to ...Activated B cell-like diffuse large B-cell lymphomas (ABC-DLBCL) have unfavorable outcomes and chronic activation of CARD11-BCL10-MALT1 (CBM) signal amplification complexes that form due to polymerization of BCL10 subunits, which is affected by recurrent somatic mutations in ABC-DLBCLs. Herein, we show that BCL10 mutants fall into at least two functionally distinct classes: missense mutations of the BCL10 CARD domain and truncation of its C-terminal tail. Truncating mutations abrogated a motif through which MALT1 inhibits BCL10 polymerization, trapping MALT1 in its activated filament-bound state. CARD missense mutations enhanced BCL10 filament formation, forming glutamine network structures that stabilize BCL10 filaments. Mutant forms of BCL10 were less dependent on upstream CARD11 activation and thus manifested resistance to BTK inhibitors, whereas BCL10 truncating but not CARD mutants were hypersensitive to MALT1 inhibitors. Therefore, BCL10 mutations are potential biomarkers for BTK inhibitor resistance in ABC-DLBCL, and further precision can be achieved by selecting therapy based on specific biochemical effects of distinct mutation classes. SIGNIFICANCE: ABC-DLBCLs feature frequent mutations of signaling mediators that converge on the CBM complex. We use structure-function approaches to reveal that BCL10 mutations fall into two distinct ...SIGNIFICANCE: ABC-DLBCLs feature frequent mutations of signaling mediators that converge on the CBM complex. We use structure-function approaches to reveal that BCL10 mutations fall into two distinct biochemical classes. Both classes confer resistance to BTK inhibitors, whereas BCL10 truncations confer hyperresponsiveness to MALT1 inhibitors, providing a road map for precision therapies in ABC-DLBCLs. See related commentary by Phelan and Oellerich, p. 1844. This article is highlighted in the In This Issue feature, p. 1825. | ||||||
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 | 8czo.cif.gz | 716.9 KB | 表示 | PDBx/mmCIF形式 |
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PDB形式 | pdb8czo.ent.gz | 613.8 KB | 表示 | PDB形式 |
PDBx/mmJSON形式 | 8czo.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 | 8czo_validation.pdf.gz | 1.2 MB | 表示 | wwPDB検証レポート |
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文書・詳細版 | 8czo_full_validation.pdf.gz | 1.2 MB | 表示 | |
XML形式データ | 8czo_validation.xml.gz | 81.9 KB | 表示 | |
CIF形式データ | 8czo_validation.cif.gz | 133.5 KB | 表示 | |
アーカイブディレクトリ | https://data.pdbj.org/pub/pdb/validation_reports/cz/8czo ftp://data.pdbj.org/pub/pdb/validation_reports/cz/8czo | HTTPS FTP |
-関連構造データ
関連構造データ | 27100MC 8czdC 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: 10615.389 Da / 分子数: 22 / 由来タイプ: 組換発現 / 由来: (組換発現) Homo sapiens (ヒト) / 遺伝子: MALT1, MLT / 発現宿主: Escherichia phage EcSzw-2 (ファージ) 参照: UniProt: Q9UDY8, 加水分解酵素; プロテアーゼ; ペプチド結合加水分解酵素; システインプロテアーゼ #2: タンパク質 | 分子量: 12614.566 Da / 分子数: 22 / 由来タイプ: 組換発現 / 由来: (組換発現) Homo sapiens (ヒト) / 遺伝子: BCL10, CIPER, CLAP / 発現宿主: Escherichia phage EcSzw-2 (ファージ) / 参照: UniProt: O95999 |
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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: filament / タイプ: COMPLEX / Entity ID: all / 由来: RECOMBINANT | |||||||||||||||
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分子量 | 実験値: NO | |||||||||||||||
由来(天然) | 生物種: Homo sapiens (ヒト) | |||||||||||||||
由来(組換発現) | 生物種: Escherichia phage EcSzw-2 (ファージ) | |||||||||||||||
緩衝液 | pH: 7.5 | |||||||||||||||
緩衝液成分 |
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試料 | 包埋: NO / シャドウイング: NO / 染色: NO / 凍結: YES | |||||||||||||||
急速凍結 | 装置: FEI VITROBOT MARK III / 凍結剤: ETHANE / 湿度: 100 % |
-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 / 倍率(公称値): 47000 X / 最大 デフォーカス(公称値): 2500 nm / 最小 デフォーカス(公称値): 1000 nm / C2レンズ絞り径: 2.7 µm |
試料ホルダ | 凍結剤: NITROGEN |
撮影 | 電子線照射量: 55 e/Å2 フィルム・検出器のモデル: FEI FALCON II (4k x 4k) 撮影したグリッド数: 1 / 実像数: 700 |
-解析
ソフトウェア | 名称: PHENIX / バージョン: 1.18_3845: / 分類: 精密化 | ||||||||||||||||||||||||
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EMソフトウェア | 名称: RELION / バージョン: 3.1 / カテゴリ: 3次元再構成 | ||||||||||||||||||||||||
CTF補正 | タイプ: NONE | ||||||||||||||||||||||||
らせん対称 | 回転角度/サブユニット: -100.8 ° / 軸方向距離/サブユニット: 5 Å / らせん対称軸の対称性: C1 | ||||||||||||||||||||||||
3次元再構成 | 解像度: 4.3 Å / 解像度の算出法: FSC 0.143 CUT-OFF / 粒子像の数: 23000 / 対称性のタイプ: HELICAL | ||||||||||||||||||||||||
拘束条件 |
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