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基本情報
登録情報 | ![]() | |||||||||
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タイトル | Cryo-EM structure of BCL10 CARD - MALT1 DD filament | |||||||||
![]() | CryoEM structure BCL10 CARD-MALT1 | |||||||||
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機能・相同性 | ![]() 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 / negative regulation of mature B cell apoptotic process / B cell apoptotic process / activation of NF-kappaB-inducing kinase activity / CLEC7A/inflammasome pathway / programmed cell death / kinase activator activity / positive regulation of extrinsic apoptotic signaling pathway / nuclear export / response to food / toll-like receptor signaling pathway / B cell activation / positive regulation of T cell receptor signaling pathway / non-canonical NF-kappaB signal transduction / cytoplasmic microtubule / positive regulation of cysteine-type endopeptidase activity involved in apoptotic process / general transcription initiation factor binding / immunological synapse / NF-kappaB binding / immunoglobulin mediated immune response / small molecule binding / canonical NF-kappaB signal transduction / cellular defense response / T cell proliferation / positive regulation of phosphorylation / 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 / protein homooligomerization / positive regulation of T cell cytokine production / CLEC7A (Dectin-1) signaling / fibrillar center / defense response / FCERI mediated NF-kB activation / cellular response to mechanical stimulus / ubiquitin-protein transferase activity / : / positive regulation of interleukin-6 production / Downstream TCR signaling / positive regulation of T cell activation / E3 ubiquitin ligases ubiquitinate target proteins / peptidase activity / positive regulation of NF-kappaB transcription factor activity / T cell receptor signaling pathway / cellular response to lipopolysaccharide / regulation of apoptotic process / positive regulation of canonical NF-kappaB signal transduction / adaptive immune response / endopeptidase activity / protease binding / 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 / transcription coactivator activity / lysosome / positive regulation of apoptotic process / membrane raft / cysteine-type endopeptidase activity / innate immune response / ubiquitin protein ligase binding / protein-containing complex binding / negative regulation of apoptotic process / positive regulation of DNA-templated transcription / 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 | ![]() | |||||||||
手法 | 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 | |||||||||
![]() | David L / Wu H | |||||||||
資金援助 | 1件
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![]() | ![]() 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. | |||||||||
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構造の表示
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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 | ![]() | 118.9 MB | ![]() | |
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ヘッダ (付随情報) | ![]() ![]() | 16.5 KB 16.5 KB | 表示 表示 | ![]() |
画像 | ![]() | 173.3 KB | ||
その他 | ![]() ![]() | 108.1 MB 108.1 MB | ||
アーカイブディレクトリ | ![]() ![]() | HTTPS FTP |
-検証レポート
文書・要旨 | ![]() | 724.3 KB | 表示 | ![]() |
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文書・詳細版 | ![]() | 723.8 KB | 表示 | |
XML形式データ | ![]() | 14.2 KB | 表示 | |
CIF形式データ | ![]() | 16.8 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 | ![]() 8czoMC ![]() 8czdC 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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「今月の分子」の関連する項目 |
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マップ
ファイル | ![]() | ||||||||||||||||||||
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注釈 | CryoEM structure BCL10 CARD-MALT1 | ||||||||||||||||||||
ボクセルのサイズ | X=Y=Z: 1.1019 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: half2 map
ファイル | emd_27100_half_map_1.map | ||||||||||||
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注釈 | half2 map | ||||||||||||
投影像・断面図 |
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密度ヒストグラム |
-ハーフマップ: half1 map
ファイル | emd_27100_half_map_2.map | ||||||||||||
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注釈 | half1 map | ||||||||||||
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 : filament
全体 | 名称: filament |
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要素 |
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-超分子 #1: filament
超分子 | 名称: filament / タイプ: complex / キメラ: Yes / ID: 1 / 親要素: 0 / 含まれる分子: all |
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由来(天然) | 生物種: ![]() |
組換発現 | 生物種: ![]() |
-分子 #1: Mucosa-associated lymphoid tissue lymphoma translocation protein 1
分子 | 名称: Mucosa-associated lymphoid tissue lymphoma translocation protein 1 タイプ: protein_or_peptide / ID: 1 / コピー数: 22 / 光学異性体: LEVO EC番号: 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 |
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由来(天然) | 生物種: ![]() |
分子量 | 理論値: 10.615389 KDa |
組換発現 | 生物種: ![]() |
配列 | 文字列: TLNRLREPLL RRLSELLDQA PEGRGWRRLA ELAGSRGRLR LSCLDLEQCS LKVLEPEGSP SLCLLKLMGE KGCTVTELSD FLQAMEHTE VLQLL |
-分子 #2: B-cell lymphoma/leukemia 10
分子 | 名称: B-cell lymphoma/leukemia 10 / タイプ: protein_or_peptide / ID: 2 / コピー数: 22 / 光学異性体: LEVO |
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由来(天然) | 生物種: ![]() |
分子量 | 理論値: 12.614566 KDa |
組換発現 | 生物種: ![]() |
配列 | 文字列: EEDLTEVKKD ALENLRVYLC EKIIAERHFD HLRAKKILSR EDTEEISCRT SSRKRAGKLL DYLQENPKGL DTLVESIRRE KTQNFLIQK ITDEVLKLRN IKLEHLK |
-実験情報
-構造解析
手法 | クライオ電子顕微鏡法 |
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![]() | らせん対称体再構成法 |
試料の集合状態 | filament |
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試料調製
緩衝液 | pH: 7.5 構成要素:
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凍結 | 凍結剤: ETHANE / チャンバー内湿度: 100 % / 装置: FEI VITROBOT MARK III |
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電子顕微鏡法
顕微鏡 | FEI TITAN KRIOS |
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撮影 | 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 / 平均電子線量: 55.0 e/Å2 |
電子線 | 加速電圧: 300 kV / 電子線源: ![]() |
電子光学系 | C2レンズ絞り径: 2.7 µm / 照射モード: FLOOD BEAM / 撮影モード: BRIGHT FIELD / 最大 デフォーカス(公称値): 2.5 µm / 最小 デフォーカス(公称値): 1.0 µm / 倍率(公称値): 47000 |
試料ステージ | ホルダー冷却材: NITROGEN |
実験機器 | ![]() モデル: Titan Krios / 画像提供: FEI Company |
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画像解析
最終 再構成 | 想定した対称性 - らせんパラメータ - Δz: 5.0 Å 想定した対称性 - らせんパラメータ - ΔΦ: -100.8 ° 想定した対称性 - らせんパラメータ - 軸対称性: C1 (非対称) 解像度のタイプ: BY AUTHOR / 解像度: 4.3 Å / 解像度の算出法: FSC 0.143 CUT-OFF / ソフトウェア - 名称: RELION (ver. 3.1) / 使用した粒子像数: 23000 |
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初期モデル | モデルのタイプ: EMDB MAP EMDB ID: |
最終 角度割当 | タイプ: NOT APPLICABLE |