- EMDB-46686: Structure of human UBR4-KCMF1-CaM E3 ligase complex (Silencing Fa... -
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基本情報
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データベース: EMDB / ID: EMD-46686
タイトル
Structure of human UBR4-KCMF1-CaM E3 ligase complex (Silencing Factor of the Integrated stress response, SiFI)
マップデータ
試料
複合体: Endogenous UBR4-KCMF1-CaM E3 Ligase complex (Silencing Factor of the Integrated stress response)
タンパク質・ペプチド: UBR4 (endogenously FLAG-tagged at the N-terminus),E3 ubiquitin-protein ligase UBR4,E3 ubiquitin-protein ligase UBR4,E3 ubiquitin-protein ligase UBR4
タンパク質・ペプチド: Calmodulin-1
タンパク質・ペプチド: E3 ubiquitin-protein ligase KCMF1
リガンド: ZINC ION
リガンド: CALCIUM ION
キーワード
E3 liase / UBR4 / SIFI / LIGASE
機能・相同性
機能・相同性情報
negative regulation of HRI-mediated signaling / synaptic signaling / ubiquitin-dependent protein catabolic process via the N-end rule pathway / protein K27-linked ubiquitination / cytoplasm protein quality control by the ubiquitin-proteasome system / protein branched polyubiquitination / negative regulation of fatty acid biosynthetic process / endosome organization / cytoplasm protein quality control / protein K11-linked ubiquitination ...negative regulation of HRI-mediated signaling / synaptic signaling / ubiquitin-dependent protein catabolic process via the N-end rule pathway / protein K27-linked ubiquitination / cytoplasm protein quality control by the ubiquitin-proteasome system / protein branched polyubiquitination / negative regulation of fatty acid biosynthetic process / endosome organization / cytoplasm protein quality control / protein K11-linked ubiquitination / CaM pathway / Cam-PDE 1 activation / Sodium/Calcium exchangers / Calmodulin induced events / Reduction of cytosolic Ca++ levels / Activation of Ca-permeable Kainate Receptor / CREB1 phosphorylation through the activation of CaMKII/CaMKK/CaMKIV cascasde / Loss of phosphorylation of MECP2 at T308 / CREB1 phosphorylation through the activation of Adenylate Cyclase / CaMK IV-mediated phosphorylation of CREB / PKA activation / negative regulation of high voltage-gated calcium channel activity / Glycogen breakdown (glycogenolysis) / CLEC7A (Dectin-1) induces NFAT activation / Activation of RAC1 downstream of NMDARs / negative regulation of ryanodine-sensitive calcium-release channel activity / organelle localization by membrane tethering / mitochondrion-endoplasmic reticulum membrane tethering / autophagosome membrane docking / negative regulation of calcium ion export across plasma membrane / regulation of cardiac muscle cell action potential / presynaptic endocytosis / Synthesis of IP3 and IP4 in the cytosol / regulation of cell communication by electrical coupling involved in cardiac conduction / Phase 0 - rapid depolarisation / calcineurin-mediated signaling / Negative regulation of NMDA receptor-mediated neuronal transmission / Unblocking of NMDA receptors, glutamate binding and activation / RHO GTPases activate PAKs / Ion transport by P-type ATPases / Uptake and function of anthrax toxins / regulation of ryanodine-sensitive calcium-release channel activity / tertiary granule membrane / Long-term potentiation / protein phosphatase activator activity / ficolin-1-rich granule membrane / Calcineurin activates NFAT / Regulation of MECP2 expression and activity / DARPP-32 events / catalytic complex / protein K63-linked ubiquitination / Smooth Muscle Contraction / detection of calcium ion / regulation of cardiac muscle contraction / RHO GTPases activate IQGAPs / regulation of cardiac muscle contraction by regulation of the release of sequestered calcium ion / protein K48-linked ubiquitination / cellular response to interferon-beta / specific granule membrane / Protein methylation / calcium channel inhibitor activity / presynaptic cytosol / Activation of AMPK downstream of NMDARs / Ion homeostasis / regulation of release of sequestered calcium ion into cytosol by sarcoplasmic reticulum / eNOS activation / titin binding / Tetrahydrobiopterin (BH4) synthesis, recycling, salvage and regulation / sperm midpiece / regulation of calcium-mediated signaling / voltage-gated potassium channel complex / calcium channel complex / positive regulation of autophagy / substantia nigra development / FCERI mediated Ca+2 mobilization / Ras activation upon Ca2+ influx through NMDA receptor / regulation of heart rate / FCGR3A-mediated IL10 synthesis / calyx of Held / Antigen activates B Cell Receptor (BCR) leading to generation of second messengers / adenylate cyclase activator activity / sarcomere / VEGFR2 mediated cell proliferation / regulation of cytokinesis / protein serine/threonine kinase activator activity / VEGFR2 mediated vascular permeability / spindle microtubule / calcium channel regulator activity / Translocation of SLC2A4 (GLUT4) to the plasma membrane / positive regulation of receptor signaling pathway via JAK-STAT / Stimuli-sensing channels / RAF activation / Transcriptional activation of mitochondrial biogenesis / response to calcium ion / RING-type E3 ubiquitin transferase / RAS processing / cellular response to type II interferon / G2/M transition of mitotic cell cycle / long-term synaptic potentiation / spindle pole 類似検索 - 分子機能
ジャーナル: Nature / 年: 2025 タイトル: Molecular basis of SIFI activity in the integrated stress response. 著者: Zhi Yang / Diane L Haakonsen / Michael Heider / Samuel R Witus / Alex Zelter / Tobias Beschauner / Michael J MacCoss / Michael Rapé / 要旨: Chronic stress response activation impairs cell survival and causes devastating degenerative diseases. Organisms accordingly deploy silencing factors, such as the E3 ubiquitin ligase silencing factor ...Chronic stress response activation impairs cell survival and causes devastating degenerative diseases. Organisms accordingly deploy silencing factors, such as the E3 ubiquitin ligase silencing factor of the integrated stress response (SIFI), to terminate stress response signalling and ensure cellular homeostasis. How a silencing factor can sense stress across cellular scales to elicit timely stress response inactivation is poorly understood. Here we combine cryo-electron microscopy analysis of endogenous SIFI with AlphaFold modelling and biochemical studies to report the structural and mechanistic basis of the silencing of the integrated stress response. SIFI detects both stress indicators and stress response components through flexible domains within an easily accessible scaffold, before building linkage-specific ubiquitin chains at separate, sterically restricted elongation modules. Ubiquitin handover by a ubiquitin-like domain couples versatile substrate modification to linkage-specific ubiquitin polymer formation. Stress response silencing therefore exploits a catalytic mechanism that is geared towards processing many diverse proteins and therefore allows a single enzyme to monitor and, if needed, modulate a complex cellular state.