+データを開く
-基本情報
登録情報 | データベース: EMDB / ID: EMD-39126 | |||||||||
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タイトル | Structure of the FADD/Caspase-8/cFLIP death effector domain assembly | |||||||||
マップデータ | sharpened map | |||||||||
試料 |
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キーワード | FADD / caspase-8 / cellular FLICE-like inhibitory protein / Death effector domain / APOPTOSIS | |||||||||
機能・相同性 | 機能・相同性情報 positive regulation of CD8-positive, alpha-beta cytotoxic T cell extravasation / negative regulation of myoblast fusion / negative regulation of activation-induced cell death of T cells / skeletal myofibril assembly / caspase-8 / death effector domain binding / syncytiotrophoblast cell differentiation involved in labyrinthine layer development / FasL/ CD95L signaling / skeletal muscle atrophy / tumor necrosis factor receptor superfamily binding ...positive regulation of CD8-positive, alpha-beta cytotoxic T cell extravasation / negative regulation of myoblast fusion / negative regulation of activation-induced cell death of T cells / skeletal myofibril assembly / caspase-8 / death effector domain binding / syncytiotrophoblast cell differentiation involved in labyrinthine layer development / FasL/ CD95L signaling / skeletal muscle atrophy / tumor necrosis factor receptor superfamily binding / TRAIL signaling / CD95 death-inducing signaling complex / regulation of skeletal muscle satellite cell proliferation / ripoptosome / TRAIL-activated apoptotic signaling pathway / death-inducing signaling complex assembly / Defective RIPK1-mediated regulated necrosis / Apoptotic execution phase / Activation, myristolyation of BID and translocation to mitochondria / TRIF-mediated programmed cell death / TLR3-mediated TICAM1-dependent programmed cell death / Microbial modulation of RIPK1-mediated regulated necrosis / Regulation by c-FLIP / CASP8 activity is inhibited / Dimerization of procaspase-8 / regulation of necroptotic process / positive regulation of adaptive immune response / Caspase activation via Death Receptors in the presence of ligand / positive regulation of extracellular matrix organization / skeletal muscle tissue regeneration / positive regulation of glomerular mesangial cell proliferation / positive regulation of macrophage differentiation / caspase binding / necroptotic signaling pathway / self proteolysis / NF-kB activation through FADD/RIP-1 pathway mediated by caspase-8 and -10 / response to cobalt ion / cysteine-type endopeptidase activity involved in apoptotic signaling pathway / death-inducing signaling complex / negative regulation of hepatocyte apoptotic process / CLEC7A/inflammasome pathway / receptor serine/threonine kinase binding / natural killer cell activation / negative regulation of necroptotic process / activation of cysteine-type endopeptidase activity / cysteine-type endopeptidase activity involved in execution phase of apoptosis / positive regulation of innate immune response / regulation of tumor necrosis factor-mediated signaling pathway / positive regulation of type I interferon-mediated signaling pathway / tumor necrosis factor receptor binding / death receptor binding / positive regulation of extrinsic apoptotic signaling pathway / positive regulation of hepatocyte proliferation / cysteine-type endopeptidase activity involved in apoptotic process / negative regulation of cellular response to transforming growth factor beta stimulus / motor neuron apoptotic process / TNFR1-induced proapoptotic signaling / execution phase of apoptosis / RIPK1-mediated regulated necrosis / negative regulation of cardiac muscle cell apoptotic process / response to testosterone / B cell activation / regulation of innate immune response / positive regulation of activated T cell proliferation / Apoptotic cleavage of cellular proteins / pyroptotic inflammatory response / positive regulation of execution phase of apoptosis / T cell homeostasis / positive regulation of proteolysis / behavioral response to cocaine / macrophage differentiation / protein maturation / cellular response to organic cyclic compound / extrinsic apoptotic signaling pathway via death domain receptors / cellular response to nitric oxide / Caspase-mediated cleavage of cytoskeletal proteins / response to tumor necrosis factor / lymph node development / signaling adaptor activity / negative regulation of reactive oxygen species biosynthetic process / negative regulation of extrinsic apoptotic signaling pathway via death domain receptors / extrinsic apoptotic signaling pathway / negative regulation of canonical NF-kappaB signal transduction / skeletal muscle tissue development / extrinsic apoptotic signaling pathway in absence of ligand / cysteine-type peptidase activity / keratinocyte differentiation / spleen development / enzyme activator activity / cellular response to epidermal growth factor stimulus / regulation of cytokine production / T cell activation / cellular response to dexamethasone stimulus / erythrocyte differentiation / thymus development / proteolysis involved in protein catabolic process / positive regulation of interleukin-1 beta production / kidney development / Regulation of NF-kappa B signaling / positive regulation of interleukin-8 production 類似検索 - 分子機能 | |||||||||
生物種 | Homo sapiens (ヒト) | |||||||||
手法 | 単粒子再構成法 / クライオ電子顕微鏡法 / 解像度: 3.68 Å | |||||||||
データ登録者 | Lin S-C / Yang C-Y | |||||||||
資金援助 | 台湾, 1件
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引用 | ジャーナル: Nat Commun / 年: 2024 タイトル: Deciphering DED assembly mechanisms in FADD-procaspase-8-cFLIP complexes regulating apoptosis. 著者: Chao-Yu Yang / Chia-I Lien / Yi-Chun Tseng / Yi-Fan Tu / Arkadiusz W Kulczyk / Yen-Chen Lu / Yin-Ting Wang / Tsung-Wei Su / Li-Chung Hsu / Yu-Chih Lo / Su-Chang Lin / 要旨: Fas-associated protein with death domain (FADD), procaspase-8, and cellular FLICE-inhibitory proteins (cFLIP) assemble through death-effector domains (DEDs), directing death receptor signaling ...Fas-associated protein with death domain (FADD), procaspase-8, and cellular FLICE-inhibitory proteins (cFLIP) assemble through death-effector domains (DEDs), directing death receptor signaling towards cell survival or apoptosis. Understanding their three-dimensional regulatory mechanism has been limited by the absence of atomic coordinates for their ternary DED complex. By employing X-ray crystallography and cryogenic electron microscopy (cryo-EM), we present the atomic coordinates of human FADD-procaspase-8-cFLIP complexes, revealing structural insights into these critical interactions. These structures illustrate how FADD and cFLIP orchestrate the assembly of caspase-8-containing complexes and offer mechanistic explanations for their role in promoting or inhibiting apoptotic and necroptotic signaling. A helical procaspase-8-cFLIP hetero-double layer in the complex appears to promote limited caspase-8 activation for cell survival. Our structure-guided mutagenesis supports the role of the triple-FADD complex in caspase-8 activation and in regulating receptor-interacting protein kinase 1 (RIPK1). These results propose a unified mechanism for DED assembly and procaspase-8 activation in the regulation of apoptotic and necroptotic signaling across various cellular pathways involved in development, innate immunity, and disease. | |||||||||
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 | emd_39126.map.gz | 70.2 MB | EMDBマップデータ形式 | |
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ヘッダ (付随情報) | emd-39126-v30.xml emd-39126.xml | 18.8 KB 18.8 KB | 表示 表示 | EMDBヘッダ |
FSC (解像度算出) | emd_39126_fsc.xml | 11 KB | 表示 | FSCデータファイル |
画像 | emd_39126.png | 37.3 KB | ||
Filedesc metadata | emd-39126.cif.gz | 6.4 KB | ||
その他 | emd_39126_half_map_1.map.gz emd_39126_half_map_2.map.gz | 127.1 MB 127.1 MB | ||
アーカイブディレクトリ | http://ftp.pdbj.org/pub/emdb/structures/EMD-39126 ftp://ftp.pdbj.org/pub/emdb/structures/EMD-39126 | HTTPS FTP |
-検証レポート
文書・要旨 | emd_39126_validation.pdf.gz | 1.1 MB | 表示 | EMDB検証レポート |
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文書・詳細版 | emd_39126_full_validation.pdf.gz | 1.1 MB | 表示 | |
XML形式データ | emd_39126_validation.xml.gz | 19.6 KB | 表示 | |
CIF形式データ | emd_39126_validation.cif.gz | 25.1 KB | 表示 | |
アーカイブディレクトリ | https://ftp.pdbj.org/pub/emdb/validation_reports/EMD-39126 ftp://ftp.pdbj.org/pub/emdb/validation_reports/EMD-39126 | HTTPS FTP |
-関連構造データ
-リンク
EMDBのページ | EMDB (EBI/PDBe) / EMDataResource |
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「今月の分子」の関連する項目 |
-マップ
ファイル | ダウンロード / ファイル: emd_39126.map.gz / 形式: CCP4 / 大きさ: 137.1 MB / タイプ: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES) | ||||||||||||||||||||
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注釈 | sharpened map | ||||||||||||||||||||
ボクセルのサイズ | X=Y=Z: 0.84 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: #2
ファイル | emd_39126_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: #1
ファイル | emd_39126_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 |
-試料の構成要素
-全体 : FADD/Caspase-8/cFLIP death effector domain assembly
全体 | 名称: FADD/Caspase-8/cFLIP death effector domain assembly |
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要素 |
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-超分子 #1: FADD/Caspase-8/cFLIP death effector domain assembly
超分子 | 名称: FADD/Caspase-8/cFLIP death effector domain assembly / タイプ: complex / ID: 1 / 親要素: 0 / 含まれる分子: all |
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由来(天然) | 生物種: Homo sapiens (ヒト) |
-分子 #1: Caspase-8 subunit p10
分子 | 名称: Caspase-8 subunit p10 / タイプ: protein_or_peptide / ID: 1 / コピー数: 3 / 光学異性体: LEVO |
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由来(天然) | 生物種: Homo sapiens (ヒト) |
分子量 | 理論値: 55.191648 KDa |
組換発現 | 生物種: Escherichia coli BL21 (大腸菌) |
配列 | 文字列: MDFSRNLYDI GEQLDSEDLA SLKFLSLDYI PQRKQEPIKD ALMLFQRLQE KRMLEESNLS FLKELLFRIN RLDLLITYLN TRKEEMERE LQTPGRAQIS AYRVMLYQIS EEVSRSELRS FKGGLQEEIS KCKLDDDMNL LDIFIEMEKR VILGEGKLDI L KRVCAQIN ...文字列: MDFSRNLYDI GEQLDSEDLA SLKFLSLDYI PQRKQEPIKD ALMLFQRLQE KRMLEESNLS FLKELLFRIN RLDLLITYLN TRKEEMERE LQTPGRAQIS AYRVMLYQIS EEVSRSELRS FKGGLQEEIS KCKLDDDMNL LDIFIEMEKR VILGEGKLDI L KRVCAQIN KSLLKIINDY EEFSKERSSS LEGSPDEFSN GEELCGVMTI SDSPREQDSE SQTLDKVYQM KSKPRGYCLI IN NHNFAKA REKVPKLHSI RDRNGTHLDA GALTTTFEEL HFEIKPHDDC TVEQIYEILK IYQLMDHSNM DCFICCILSH GDK GIIYGT DGQEAPIYEL TSQFTGLKCP SLAGKPKVFF IQAAQGDNYQ KGIPVETASE EQPYLEMALS SPQTRYIPDE ADFL LGMAT VNNCVSYRNP AEGTWYIQSL CQSLRERCPR GDDILTILTE VNYEVSNKDD KKNMGKQMPQ PTFTLRKKLV FPSD UniProtKB: Caspase-8 |
-分子 #2: CASP8 and FADD-like apoptosis regulator subunit p43
分子 | 名称: CASP8 and FADD-like apoptosis regulator subunit p43 / タイプ: protein_or_peptide / ID: 2 / コピー数: 4 / 光学異性体: LEVO |
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由来(天然) | 生物種: Homo sapiens (ヒト) |
分子量 | 理論値: 20.878479 KDa |
組換発現 | 生物種: Escherichia coli BL21 (大腸菌) |
配列 | 文字列: MSAEVIHQVE EALDTDEKEM LLFLCRDVAI DVVPPNVRDL LDILRERGKL SVGDLAELLY RVRRFDLLKR ILKMDRKAVE THLLRNPHL VSDYRVLMAE IGEDLDKSDV SSLIFLMKDY MGRGKISKEK SFLDLVVELE KLNLVAPDQL DLLEKCLKNI H RIDLKTKI QKYKQSVQGA GTS UniProtKB: CASP8 and FADD-like apoptosis regulator |
-分子 #3: FAS-associated death domain protein
分子 | 名称: FAS-associated death domain protein / タイプ: protein_or_peptide / ID: 3 / コピー数: 3 / 光学異性体: LEVO |
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由来(天然) | 生物種: Homo sapiens (ヒト) |
分子量 | 理論値: 24.381533 KDa |
組換発現 | 生物種: Escherichia coli BL21 (大腸菌) |
配列 | 文字列: MDPFLVLLHS VSSSLSSSEL TELKFLCLGR VGKRKLERVQ SGLDLFSMLL EQNDLEPGHT ELLRELLASL RRHDLLRRVD DFEAGAAAG AAPGEEDLCA AFNVICDNVG KDWRRLARQL KVSDTKIDSI EDRYPRNLTE RVRESLRIWK NTEKENATVA H LVGALRSC ...文字列: MDPFLVLLHS VSSSLSSSEL TELKFLCLGR VGKRKLERVQ SGLDLFSMLL EQNDLEPGHT ELLRELLASL RRHDLLRRVD DFEAGAAAG AAPGEEDLCA AFNVICDNVG KDWRRLARQL KVSDTKIDSI EDRYPRNLTE RVRESLRIWK NTEKENATVA H LVGALRSC QMNLVADLVQ EVQQARDLQN RSGAMSPMSW NSDASTSEAS LEHHHHHH UniProtKB: FAS-associated death domain protein |
-実験情報
-構造解析
手法 | クライオ電子顕微鏡法 |
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解析 | 単粒子再構成法 |
試料の集合状態 | particle |
-試料調製
濃度 | 0.2 mg/mL | |||||||||
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緩衝液 | pH: 8 構成要素:
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グリッド | モデル: Quantifoil R1.2/1.3 / 材質: COPPER / メッシュ: 300 / 支持フィルム - 材質: CARBON / 支持フィルム - トポロジー: HOLEY / 前処理 - タイプ: GLOW DISCHARGE / 前処理 - 時間: 60 sec. / 前処理 - 雰囲気: AIR | |||||||||
凍結 | 凍結剤: ETHANE / チャンバー内湿度: 95 % / チャンバー内温度: 279 K / 装置: FEI VITROBOT MARK IV |
-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: GATAN K2 SUMMIT (4k x 4k) 検出モード: COUNTING / 平均電子線量: 72.0 e/Å2 |
電子線 | 加速電圧: 300 kV / 電子線源: FIELD EMISSION GUN |
電子光学系 | 照射モード: FLOOD BEAM / 撮影モード: BRIGHT FIELD / Cs: 2.7 mm / 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): 0.5 µm / 倍率(公称値): 165000 |
試料ステージ | 試料ホルダーモデル: FEI TITAN KRIOS AUTOGRID HOLDER ホルダー冷却材: NITROGEN |
実験機器 | モデル: Titan Krios / 画像提供: FEI Company |