- EMDB-36764: Cryo-EM structure of human 26S RP (Ed state) bound to K11/K48-bra... -
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基本情報
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データベース: EMDB / ID: EMD-36764
タイトル
Cryo-EM structure of human 26S RP (Ed state) bound to K11/K48-branched ubiquitin (Ub) chain composed of four Ub.
マップデータ
Composite sharpened cryo-EM map of human 26S RP (Ed state) bound to K11/K48-branched ubiquitin (Ub) chain composed of four Ub.
試料
複合体: Human 26S proteasome
複合体: 19S regulatory particle (RP) of human 26S proteasome
複合体: AAA+-ATPase of 19S regulatory particle (RP) of human 26S proteasome
タンパク質・ペプチド: x 6種
タンパク質・ペプチド: x 12種
複合体: alpha subunits of the 20S core particle (CP) of human 26S proteasome
タンパク質・ペプチド: x 7種
複合体: Ubiquitinated substrate
複合体: K11/K48-branched ubiquitin (Ub) chain composed of four Ub.
タンパク質・ペプチド: x 1種
複合体: Sic1_PY substrate polypeptide
タンパク質・ペプチド: x 1種
リガンド: x 3種
キーワード
protein degradation / macromolecular complex / ubiquitin-proteasome system / CYTOSOLIC PROTEIN
機能・相同性
機能・相同性情報
SCF ubiquitin ligase complex binding / Impaired BRCA2 translocation to the nucleus / Impaired BRCA2 binding to SEM1 (DSS1) / thyrotropin-releasing hormone receptor binding / nuclear proteasome complex / host-mediated perturbation of viral transcription / positive regulation of inclusion body assembly / 加水分解酵素; プロテアーゼ; ペプチド結合加水分解酵素; オメガペプチターゼ / integrator complex / proteasome accessory complex ...SCF ubiquitin ligase complex binding / Impaired BRCA2 translocation to the nucleus / Impaired BRCA2 binding to SEM1 (DSS1) / thyrotropin-releasing hormone receptor binding / nuclear proteasome complex / host-mediated perturbation of viral transcription / positive regulation of inclusion body assembly / 加水分解酵素; プロテアーゼ; ペプチド結合加水分解酵素; オメガペプチターゼ / integrator complex / proteasome accessory complex / meiosis I / cyclin-dependent protein serine/threonine kinase inhibitor activity / purine ribonucleoside triphosphate binding / proteasome regulatory particle / cytosolic proteasome complex / positive regulation of proteasomal protein catabolic process / proteasome-activating activity / proteasome regulatory particle, lid subcomplex / proteasome regulatory particle, base subcomplex / hypothalamus gonadotrophin-releasing hormone neuron development / metal-dependent deubiquitinase activity / protein K63-linked deubiquitination / female meiosis I / negative regulation of programmed cell death / positive regulation of protein monoubiquitination / Regulation of ornithine decarboxylase (ODC) / Proteasome assembly / Cross-presentation of soluble exogenous antigens (endosomes) / fat pad development / mitochondrion transport along microtubule / Homologous DNA Pairing and Strand Exchange / Defective homologous recombination repair (HRR) due to BRCA1 loss of function / Defective HDR through Homologous Recombination Repair (HRR) due to PALB2 loss of BRCA1 binding function / Defective HDR through Homologous Recombination Repair (HRR) due to PALB2 loss of BRCA2/RAD51/RAD51C binding function / Resolution of D-loop Structures through Synthesis-Dependent Strand Annealing (SDSA) / proteasome core complex / Resolution of D-loop Structures through Holliday Junction Intermediates / Somitogenesis / K63-linked deubiquitinase activity / negative regulation of macroautophagy / female gonad development / Impaired BRCA2 binding to RAD51 / seminiferous tubule development / proteasome binding / transcription factor binding / regulation of protein catabolic process / myofibril / male meiosis I / proteasome storage granule / Presynaptic phase of homologous DNA pairing and strand exchange / positive regulation of intrinsic apoptotic signaling pathway by p53 class mediator / general transcription initiation factor binding / blastocyst development / polyubiquitin modification-dependent protein binding / positive regulation of RNA polymerase II transcription preinitiation complex assembly / protein deubiquitination / immune system process / NF-kappaB binding / endopeptidase activator activity / mRNA export from nucleus / proteasome assembly / proteasome core complex, alpha-subunit complex / energy homeostasis / SARS-CoV-1 targets host intracellular signalling and regulatory pathways / regulation of neuron apoptotic process / neuron projection morphogenesis / enzyme regulator activity / regulation of proteasomal protein catabolic process / ERAD pathway / Maturation of protein E / Maturation of protein E / ER Quality Control Compartment (ERQC) / Myoclonic epilepsy of Lafora / FLT3 signaling by CBL mutants / inclusion body / Prevention of phagosomal-lysosomal fusion / IRAK2 mediated activation of TAK1 complex / Alpha-protein kinase 1 signaling pathway / Glycogen synthesis / IRAK1 recruits IKK complex / IRAK1 recruits IKK complex upon TLR7/8 or 9 stimulation / Endosomal Sorting Complex Required For Transport (ESCRT) / Membrane binding and targetting of GAG proteins / Negative regulation of FLT3 / Regulation of TBK1, IKKε (IKBKE)-mediated activation of IRF3, IRF7 / PTK6 Regulates RTKs and Their Effectors AKT1 and DOK1 / Regulation of TBK1, IKKε-mediated activation of IRF3, IRF7 upon TLR3 ligation / Constitutive Signaling by NOTCH1 HD Domain Mutants / IRAK2 mediated activation of TAK1 complex upon TLR7/8 or 9 stimulation / NOTCH2 Activation and Transmission of Signal to the Nucleus / TICAM1,TRAF6-dependent induction of TAK1 complex / TICAM1-dependent activation of IRF3/IRF7 / APC/C:Cdc20 mediated degradation of Cyclin B / Downregulation of ERBB4 signaling / Regulation of FZD by ubiquitination / APC-Cdc20 mediated degradation of Nek2A / p75NTR recruits signalling complexes / InlA-mediated entry of Listeria monocytogenes into host cells / TRAF6 mediated IRF7 activation in TLR7/8 or 9 signaling / TRAF6-mediated induction of TAK1 complex within TLR4 complex 類似検索 - 分子機能
ジャーナル: Nat Commun / 年: 2025 タイトル: Structural basis of K11/K48-branched ubiquitin chain recognition by the human 26S proteasome. 著者: Piotr Draczkowski / Szu-Ni Chen / Ting Chen / Yong-Sheng Wang / Hsin-An Shih / Jessica Y C Huang / Ming-Chieh Tsai / Shu-Yu Lin / Steven Lin / Rosa Viner / Yuan-Chih Chang / Kuen-Phon Wu / Shang-Te Danny Hsu / 要旨: Beyond the canonical K48-linked homotypic polyubiquitination for proteasome-targeted proteolysis, K11/K48-branched ubiquitin (Ub) chains are involved in fast-tracking protein turnover during cell ...Beyond the canonical K48-linked homotypic polyubiquitination for proteasome-targeted proteolysis, K11/K48-branched ubiquitin (Ub) chains are involved in fast-tracking protein turnover during cell cycle progression and proteotoxic stress. Here, we report cryo-EM structures of human 26S proteasome in a complex with a K11/K48-branched Ub chain. The structures revealed a multivalent substrate recognition mechanism involving a hitherto unknown K11-linked Ub binding site at the groove formed by RPN2 and RPN10 in addition to the canonical K48-linkage binding site formed by RPN10 and RPT4/5 coiled-coil. Additionally, RPN2 recognizes an alternating K11-K48-linkage through a conserved motif similar to the K48-specific T1 binding site of RPN1. The insights gleaned from these structures explain the molecular mechanism underlying the recognition of the K11/K48-branched Ub as a priority signal in the ubiquitin-mediated proteasomal degradation.
複合体: alpha subunits of the 20S core particle (CP) of human 26S proteasome
タンパク質・ペプチド: Proteasome subunit alpha type-6
タンパク質・ペプチド: Proteasome subunit alpha type-2
タンパク質・ペプチド: Proteasome subunit alpha type-4
タンパク質・ペプチド: Proteasome subunit alpha type-7
タンパク質・ペプチド: Proteasome subunit alpha type-5
タンパク質・ペプチド: Proteasome subunit alpha type-1
タンパク質・ペプチド: Proteasome subunit alpha type-3
複合体: Ubiquitinated substrate
複合体: K11/K48-branched ubiquitin (Ub) chain composed of four Ub.
タンパク質・ペプチド: Polyubiquitin-B
複合体: Sic1_PY substrate polypeptide
タンパク質・ペプチド: Protein SIC1
リガンド: ADENOSINE-5'-TRIPHOSPHATE
リガンド: MAGNESIUM ION
リガンド: ADENOSINE-5'-DIPHOSPHATE
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超分子 #1: Human 26S proteasome
超分子
名称: Human 26S proteasome / タイプ: complex / ID: 1 / 親要素: 0 / 含まれる分子: #1-#27 詳細: Images of double-capped (RP-CP-RP) 26S proteasome particles were split in half. After combining with subset of single-capped (RP-CP) complexes the signal in particle images was partially ...詳細: Images of double-capped (RP-CP-RP) 26S proteasome particles were split in half. After combining with subset of single-capped (RP-CP) complexes the signal in particle images was partially subtracted leaving only the signal of 19S RP together with alpha subunits of the 20S CP proteasomal subcomplex.
由来(天然)
生物種: Homo sapiens (ヒト)
分子量
理論値: 2.5 MDa
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超分子 #2: 19S regulatory particle (RP) of human 26S proteasome
モデルのタイプ: INSILICO MODEL In silico モデル: Generated by cryoSPARC using Ab-initio Reconstruction job type.
最終 再構成
使用したクラス数: 2 / 想定した対称性 - 点群: C1 (非対称) / アルゴリズム: FOURIER SPACE / 解像度のタイプ: BY AUTHOR / 解像度: 3.8 Å / 解像度の算出法: FSC 0.143 CUT-OFF / ソフトウェア - 名称: cryoSPARC (ver. 3.1) 詳細: Performed in cryoSPARC using Non-uniform Refinement job type. Some parts of the map were then improved by using focused local refinement. 使用した粒子像数: 84476
初期 角度割当
タイプ: MAXIMUM LIKELIHOOD / ソフトウェア - 名称: RELION (ver. 3.1) / 詳細: Performed in Relion.
最終 角度割当
タイプ: MAXIMUM LIKELIHOOD / ソフトウェア - 名称: cryoSPARC (ver. 3.1) 詳細: Performed in cryoSPARC using Non-uniform Refinement and Local Refinement job type.
最終 3次元分類
クラス数: 6 / ソフトウェア - 名称: RELION (ver. 3.1) 詳細: 3D classification without angular search with mask focused on the AAA+-ATPase of 19S regulatory particle.