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基本情報
登録情報 | データベース: PDB / ID: 6r7n | ||||||
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タイトル | Structural basis of Cullin-2 RING E3 ligase regulation by the COP9 signalosome | ||||||
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![]() | LIGASE / Cullin-Ring E3 Ligases (CRLs) COP9 signalosome (CSN) deneddylation VHL tumour suppressor substrate receptor | ||||||
機能・相同性 | ![]() regulation of DNA damage response, signal transduction by p53 class mediator resulting in transcription of p21 class mediator / COP9 signalosome assembly / trophectodermal cell proliferation / deNEDDylase activity / GTPase inhibitor activity / regulation of protein neddylation / protein deneddylation / activation of NF-kappaB-inducing kinase activity / cullin-RING-type E3 NEDD8 transferase / cellular response to chemical stress ...regulation of DNA damage response, signal transduction by p53 class mediator resulting in transcription of p21 class mediator / COP9 signalosome assembly / trophectodermal cell proliferation / deNEDDylase activity / GTPase inhibitor activity / regulation of protein neddylation / protein deneddylation / activation of NF-kappaB-inducing kinase activity / cullin-RING-type E3 NEDD8 transferase / cellular response to chemical stress / NEDD8 transferase activity / cullin-RING ubiquitin ligase complex / COP9 signalosome / Cul7-RING ubiquitin ligase complex / ubiquitin-dependent protein catabolic process via the C-end degron rule pathway / Loss of Function of FBXW7 in Cancer and NOTCH1 Signaling / target-directed miRNA degradation / elongin complex / VCB complex / positive regulation of protein autoubiquitination / protein neddylation / NEDD8 ligase activity / Cul5-RING ubiquitin ligase complex / negative regulation of response to oxidative stress / RHOBTB1 GTPase cycle / ubiquitin-ubiquitin ligase activity / Cul4A-RING E3 ubiquitin ligase complex / SCF ubiquitin ligase complex / inner cell mass cell proliferation / Cul2-RING ubiquitin ligase complex / ubiquitin ligase complex scaffold activity / Cul4B-RING E3 ubiquitin ligase complex / negative regulation of type I interferon production / SCF-dependent proteasomal ubiquitin-dependent protein catabolic process / Cul3-RING ubiquitin ligase complex / Prolactin receptor signaling / skeletal muscle cell differentiation / protein monoubiquitination / cullin family protein binding / Pausing and recovery of Tat-mediated HIV elongation / Tat-mediated HIV elongation arrest and recovery / HIV elongation arrest and recovery / Pausing and recovery of HIV elongation / response to light stimulus / Tat-mediated elongation of the HIV-1 transcript / Formation of HIV-1 elongation complex containing HIV-1 Tat / protein K48-linked ubiquitination / Formation of HIV elongation complex in the absence of HIV Tat / post-translational protein modification / Nuclear events stimulated by ALK signaling in cancer / regulation of cellular response to insulin stimulus / RNA Polymerase II Transcription Elongation / Formation of RNA Pol II elongation complex / JNK cascade / RNA Polymerase II Pre-transcription Events / positive regulation of TORC1 signaling / T cell activation / Regulation of BACH1 activity / intrinsic apoptotic signaling pathway / cellular response to amino acid stimulus / transcription corepressor binding / Degradation of DVL / transcription initiation at RNA polymerase II promoter / TP53 Regulates Transcription of DNA Repair Genes / Recognition of DNA damage by PCNA-containing replication complex / Degradation of GLI1 by the proteasome / transcription elongation by RNA polymerase II / Negative regulation of NOTCH4 signaling / GSK3B and BTRC:CUL1-mediated-degradation of NFE2L2 / Vif-mediated degradation of APOBEC3G / Hedgehog 'on' state / Degradation of GLI2 by the proteasome / GLI3 is processed to GLI3R by the proteasome / Orc1 removal from chromatin / FBXL7 down-regulates AURKA during mitotic entry and in early mitosis / DNA Damage Recognition in GG-NER / RING-type E3 ubiquitin transferase / negative regulation of canonical Wnt signaling pathway / Degradation of beta-catenin by the destruction complex / Oxygen-dependent proline hydroxylation of Hypoxia-inducible Factor Alpha / Inactivation of CSF3 (G-CSF) signaling / Transcription-Coupled Nucleotide Excision Repair (TC-NER) / G1/S transition of mitotic cell cycle / Formation of TC-NER Pre-Incision Complex / Dual Incision in GG-NER / Evasion by RSV of host interferon responses / neuron differentiation / NOTCH1 Intracellular Domain Regulates Transcription / Constitutive Signaling by NOTCH1 PEST Domain Mutants / Constitutive Signaling by NOTCH1 HD+PEST Domain Mutants / Regulation of expression of SLITs and ROBOs / Formation of Incision Complex in GG-NER / Dual incision in TC-NER / Interleukin-1 signaling / Gap-filling DNA repair synthesis and ligation in TC-NER / Regulation of RAS by GAPs / protein polyubiquitination / positive regulation of protein catabolic process / ubiquitin-protein transferase activity / transcription corepressor activity 類似検索 - 分子機能 | ||||||
生物種 | ![]() | ||||||
手法 | 電子顕微鏡法 / 単粒子再構成法 / クライオ電子顕微鏡法 / 解像度: 6.5 Å | ||||||
![]() | Faull, S.V. / Lau, A.M.C. / Martens, C. / Ahdash, Z. / Yebenes, H. / Schmidt, C. / Beuron, F. / Cronin, N.B. / Morris, E.P. / Politis, A. | ||||||
資金援助 | ![]()
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![]() | ![]() タイトル: Structural basis of Cullin 2 RING E3 ligase regulation by the COP9 signalosome. 著者: Sarah V Faull / Andy M C Lau / Chloe Martens / Zainab Ahdash / Kjetil Hansen / Hugo Yebenes / Carla Schmidt / Fabienne Beuron / Nora B Cronin / Edward P Morris / Argyris Politis / ![]() ![]() ![]() 要旨: Cullin-Ring E3 Ligases (CRLs) regulate a multitude of cellular pathways through specific substrate receptors. The COP9 signalosome (CSN) deactivates CRLs by removing NEDD8 from activated Cullins. ...Cullin-Ring E3 Ligases (CRLs) regulate a multitude of cellular pathways through specific substrate receptors. The COP9 signalosome (CSN) deactivates CRLs by removing NEDD8 from activated Cullins. Here we present structures of the neddylated and deneddylated CSN-CRL2 complexes by combining single-particle cryo-electron microscopy (cryo-EM) with chemical cross-linking mass spectrometry (XL-MS). These structures suggest a conserved mechanism of CSN activation, consisting of conformational clamping of the CRL2 substrate by CSN2/CSN4, release of the catalytic CSN5/CSN6 heterodimer and finally activation of the CSN5 deneddylation machinery. Using hydrogen-deuterium exchange (HDX)-MS we show that CRL2 activates CSN5/CSN6 in a neddylation-independent manner. The presence of NEDD8 is required to activate the CSN5 active site. Overall, by synergising cryo-EM with MS, we identify sensory regions of the CSN that mediate its stepwise activation and provide a framework for understanding the regulatory mechanism of other Cullin family members. | ||||||
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構造ビューア | 分子: ![]() ![]() |
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-関連構造データ
関連構造データ | ![]() 4744MC ![]() 4736C ![]() 4739C ![]() 4741C ![]() 4742C ![]() 6r6hC ![]() 6r7fC ![]() 6r7hC ![]() 6r7iC 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 ( |
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リンク
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集合体
登録構造単位 | ![]()
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要素
-COP9 signalosome complex subunit ... , 5種, 5分子 ADHCB
#1: タンパク質 | 分子量: 55606.496 Da / 分子数: 1 / 由来タイプ: 組換発現 / 由来: (組換発現) ![]() 発現宿主: ![]() ![]() 参照: UniProt: Q13098 |
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#2: タンパク質 | 分子量: 46322.688 Da / 分子数: 1 / 由来タイプ: 組換発現 / 由来: (組換発現) ![]() 発現宿主: ![]() ![]() 参照: UniProt: Q9BT78 |
#3: タンパク質 | 分子量: 22258.342 Da / 分子数: 1 / 由来タイプ: 組換発現 / 由来: (組換発現) ![]() 発現宿主: ![]() ![]() 参照: UniProt: Q99627 |
#7: タンパク質 | 分子量: 45606.543 Da / 分子数: 1 / 由来タイプ: 組換発現 / 由来: (組換発現) ![]() 発現宿主: ![]() ![]() 参照: UniProt: Q9UNS2 |
#10: タンパク質 | 分子量: 51664.570 Da / 分子数: 1 / 由来タイプ: 組換発現 / 由来: (組換発現) ![]() 発現宿主: ![]() ![]() 参照: UniProt: P61201 |
-タンパク質 , 5種, 5分子 PQRGO
#4: タンパク質 | 分子量: 11748.406 Da / 分子数: 1 / 由来タイプ: 組換発現 / 由来: (組換発現) ![]() 発現宿主: ![]() ![]() 参照: UniProt: Q15370 |
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#5: タンパク質 | 分子量: 12485.135 Da / 分子数: 1 / 由来タイプ: 組換発現 / 由来: (組換発現) ![]() 発現宿主: ![]() ![]() 参照: UniProt: Q15369 |
#6: タンパク質 | 分子量: 10092.631 Da / 分子数: 1 / 由来タイプ: 組換発現 / 由来: (組換発現) ![]() 発現宿主: ![]() ![]() 参照: UniProt: P62877*PLUS |
#8: タンパク質 | 分子量: 23944.400 Da / 分子数: 1 / 由来タイプ: 組換発現 / 由来: (組換発現) ![]() 発現宿主: ![]() ![]() 参照: UniProt: Q9H9Q2*PLUS |
#9: タンパク質 | 分子量: 87098.930 Da / 分子数: 1 / 由来タイプ: 組換発現 / 由来: (組換発現) ![]() 発現宿主: ![]() ![]() 参照: UniProt: Q13617 |
-非ポリマー , 1種, 3分子 ![](data/chem/img/ZN.gif)
#11: 化合物 |
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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: PARTICLE / 3次元再構成法: 単粒子再構成法 |
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試料調製
構成要素 | 名称: CNS (COP9 Signalosome) with CSN5/CSN6 the catalytic heterodimer complexed with CUL2 (CUL2, ElonginB, ElongingC, Rbx1 and VDL) タイプ: COMPLEX / Entity ID: #1-#10 / 由来: RECOMBINANT |
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分子量 | 実験値: NO |
由来(天然) | 生物種: ![]() |
由来(組換発現) | 生物種: ![]() ![]() |
緩衝液 | pH: 7.5 詳細: 15 mM HEPES pH 7.5 100 mM NaCl 0.5 mM DTT 1% Glycerol |
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 IV / 凍結剤: ETHANE |
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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: ![]() |
電子レンズ | モード: BRIGHT FIELD / 最大 デフォーカス(公称値): 3000 nm / 最小 デフォーカス(公称値): 1800 nm |
試料ホルダ | 試料ホルダーモデル: FEI TITAN KRIOS AUTOGRID HOLDER |
撮影 | 電子線照射量: 45 e/Å2 / 検出モード: COUNTING フィルム・検出器のモデル: GATAN K2 SUMMIT (4k x 4k) |
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解析
CTF補正 | タイプ: PHASE FLIPPING AND AMPLITUDE CORRECTION |
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対称性 | 点対称性: C1 (非対称) |
3次元再構成 | 解像度: 6.5 Å / 解像度の算出法: FSC 0.143 CUT-OFF / 粒子像の数: 22471 / 対称性のタイプ: POINT |
原子モデル構築 | プロトコル: FLEXIBLE FIT |