- EMDB-39126: Structure of the FADD/Caspase-8/cFLIP death effector domain assembly -
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基本情報
登録情報
データベース: EMDB / ID: EMD-39126
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
複合体: FADD/Caspase-8/cFLIP death effector domain assembly
タンパク質・ペプチド: Caspase-8 subunit p10
タンパク質・ペプチド: CASP8 and FADD-like apoptosis regulator subunit p43
タンパク質・ペプチド: FAS-associated death domain protein
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 / necroptotic signaling pathway / caspase binding / 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 / natural killer cell activation / receptor serine/threonine kinase binding / 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 / extrinsic apoptotic signaling pathway / negative regulation of extrinsic apoptotic signaling pathway via death domain receptors / negative regulation of canonical NF-kappaB signal transduction / skeletal muscle tissue development / cysteine-type peptidase activity / keratinocyte differentiation / extrinsic apoptotic signaling pathway in absence of ligand / 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 / cellular response to estradiol stimulus 類似検索 - 分子機能
: / FADD / Caspase-8 / Death effector domain / Death effector domain / Death effector domain (DED) profile. / Death effector domain / Death domain profile. / DEATH domain, found in proteins involved in cell death (apoptosis). / Death domain ...: / FADD / Caspase-8 / Death effector domain / Death effector domain / Death effector domain (DED) profile. / Death effector domain / Death domain profile. / DEATH domain, found in proteins involved in cell death (apoptosis). / Death domain / Death domain / Peptidase family C14A, His active site / Caspase family histidine active site. / Peptidase C14, caspase non-catalytic subunit p10 / Peptidase family C14A, cysteine active site / Caspase family cysteine active site. / Caspase family p10 domain profile. / Peptidase C14A, caspase catalytic domain / Caspase, interleukin-1 beta converting enzyme (ICE) homologues / Peptidase C14, p20 domain / Caspase family p20 domain profile. / : / Caspase domain / Caspase-like domain superfamily / Death-like domain superfamily 類似検索 - ドメイン・相同性
CASP8 and FADD-like apoptosis regulator / FAS-associated death domain protein / Caspase-8 類似検索 - 構成要素
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.