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Yorodumi- PDB-6msj: Cryo-EM structures and dynamics of substrate-engaged human 26S pr... -
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-Basic information
Entry | Database: PDB / ID: 6msj | ||||||||||||
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Title | Cryo-EM structures and dynamics of substrate-engaged human 26S proteasome | ||||||||||||
Components |
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Keywords | HYDROLASE / Proteosome | ||||||||||||
Function / homology | Function and homology information positive regulation of inclusion body assembly / Impaired BRCA2 translocation to the nucleus / Impaired BRCA2 binding to SEM1 (DSS1) / thyrotropin-releasing hormone receptor binding / modulation by host of viral transcription / Hydrolases; Acting on peptide bonds (peptidases); Omega peptidases / proteasome accessory complex / integrator complex / purine ribonucleoside triphosphate binding / meiosis I ...positive regulation of inclusion body assembly / Impaired BRCA2 translocation to the nucleus / Impaired BRCA2 binding to SEM1 (DSS1) / thyrotropin-releasing hormone receptor binding / modulation by host of viral transcription / Hydrolases; Acting on peptide bonds (peptidases); Omega peptidases / proteasome accessory complex / integrator complex / purine ribonucleoside triphosphate binding / meiosis I / positive regulation of proteasomal protein catabolic process / proteasome regulatory particle / cytosolic proteasome complex / proteasome regulatory particle, lid subcomplex / proteasome-activating activity / proteasome regulatory particle, base subcomplex / protein K63-linked deubiquitination / metal-dependent deubiquitinase activity / regulation of endopeptidase activity / negative regulation of programmed cell death / 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 / Homologous DNA Pairing and Strand Exchange / Regulation of ornithine decarboxylase (ODC) / Resolution of D-loop Structures through Synthesis-Dependent Strand Annealing (SDSA) / proteasome core complex / Resolution of D-loop Structures through Holliday Junction Intermediates / Cross-presentation of soluble exogenous antigens (endosomes) / Somitogenesis / K63-linked deubiquitinase activity / Impaired BRCA2 binding to RAD51 / immune system process / myofibril / proteasome binding / regulation of protein catabolic process / proteasome storage granule / Presynaptic phase of homologous DNA pairing and strand exchange / transcription factor binding / blastocyst development / general transcription initiation factor binding / NF-kappaB binding / endopeptidase activator activity / polyubiquitin modification-dependent protein binding / proteasome assembly / proteasome endopeptidase complex / positive regulation of RNA polymerase II transcription preinitiation complex assembly / proteasome core complex, beta-subunit complex / proteasome core complex, alpha-subunit complex / threonine-type endopeptidase activity / mRNA export from nucleus / enzyme regulator activity / regulation of proteasomal protein catabolic process / SARS-CoV-1 targets host intracellular signalling and regulatory pathways / ERAD pathway / inclusion body / negative regulation of inflammatory response to antigenic stimulus / : / sarcomere / proteasome complex / Regulation of activated PAK-2p34 by proteasome mediated degradation / ciliary basal body / proteolysis involved in protein catabolic process / N-glycan trimming in the ER and Calnexin/Calreticulin cycle / Autodegradation of Cdh1 by Cdh1:APC/C / APC/C:Cdc20 mediated degradation of Securin / Asymmetric localization of PCP proteins / SCF-beta-TrCP mediated degradation of Emi1 / NIK-->noncanonical NF-kB signaling / Ubiquitin-dependent degradation of Cyclin D / AUF1 (hnRNP D0) binds and destabilizes mRNA / TNFR2 non-canonical NF-kB pathway / Vpu mediated degradation of CD4 / Assembly of the pre-replicative complex / Degradation of DVL / stem cell differentiation / CDK-mediated phosphorylation and removal of Cdc6 / Ubiquitin Mediated Degradation of Phosphorylated Cdc25A / Dectin-1 mediated noncanonical NF-kB signaling / Cdc20:Phospho-APC/C mediated degradation of Cyclin A / Hh mutants are degraded by ERAD / lipopolysaccharide binding / SCF(Skp2)-mediated degradation of p27/p21 / Degradation of AXIN / Degradation of GLI1 by the proteasome / Activation of NF-kappaB in B cells / Hedgehog ligand biogenesis / Defective CFTR causes cystic fibrosis / Negative regulation of NOTCH4 signaling / GSK3B and BTRC:CUL1-mediated-degradation of NFE2L2 / G2/M Checkpoints / Vif-mediated degradation of APOBEC3G / Autodegradation of the E3 ubiquitin ligase COP1 / Hedgehog 'on' state / Regulation of RUNX3 expression and activity / P-body / Degradation of GLI2 by the proteasome / GLI3 is processed to GLI3R by the proteasome / Orc1 removal from chromatin / double-strand break repair via homologous recombination Similarity search - Function | ||||||||||||
Biological species | Homo sapiens (human) Saccharomyces cerevisiae RM11-1a (yeast) | ||||||||||||
Method | ELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.3 Å | ||||||||||||
Authors | Mao, Y.D. | ||||||||||||
Funding support | China, United States, 3items
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Citation | Journal: Nature / Year: 2019 Title: Cryo-EM structures and dynamics of substrate-engaged human 26S proteasome. Authors: Yuanchen Dong / Shuwen Zhang / Zhaolong Wu / Xuemei Li / Wei Li Wang / Yanan Zhu / Svetla Stoilova-McPhie / Ying Lu / Daniel Finley / Youdong Mao / Abstract: The proteasome is an ATP-dependent, 2.5-megadalton molecular machine that is responsible for selective protein degradation in eukaryotic cells. Here we present cryo-electron microscopy structures of ...The proteasome is an ATP-dependent, 2.5-megadalton molecular machine that is responsible for selective protein degradation in eukaryotic cells. Here we present cryo-electron microscopy structures of the substrate-engaged human proteasome in seven conformational states at 2.8-3.6 Å resolution, captured during breakdown of a polyubiquitylated protein. These structures illuminate a spatiotemporal continuum of dynamic substrate-proteasome interactions from ubiquitin recognition to substrate translocation, during which ATP hydrolysis sequentially navigates through all six ATPases. There are three principal modes of coordinated hydrolysis, featuring hydrolytic events in two oppositely positioned ATPases, in two adjacent ATPases and in one ATPase at a time. These hydrolytic modes regulate deubiquitylation, initiation of translocation and processive unfolding of substrates, respectively. Hydrolysis of ATP powers a hinge-like motion in each ATPase that regulates its substrate interaction. Synchronization of ATP binding, ADP release and ATP hydrolysis in three adjacent ATPases drives rigid-body rotations of substrate-bound ATPases that are propagated unidirectionally in the ATPase ring and unfold the substrate. | ||||||||||||
History |
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-Structure visualization
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Structure viewer | Molecule: MolmilJmol/JSmol |
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PDBx/mmCIF format | 6msj.cif.gz | 2.3 MB | Display | PDBx/mmCIF format |
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PDB format | pdb6msj.ent.gz | Display | PDB format | |
PDBx/mmJSON format | 6msj.json.gz | Tree view | PDBx/mmJSON format | |
Others | Other downloads |
-Validation report
Summary document | 6msj_validation.pdf.gz | 1.5 MB | Display | wwPDB validaton report |
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Full document | 6msj_full_validation.pdf.gz | 1.6 MB | Display | |
Data in XML | 6msj_validation.xml.gz | 296.3 KB | Display | |
Data in CIF | 6msj_validation.cif.gz | 477.5 KB | Display | |
Arichive directory | https://data.pdbj.org/pub/pdb/validation_reports/ms/6msj ftp://data.pdbj.org/pub/pdb/validation_reports/ms/6msj | HTTPS FTP |
-Related structure data
Related structure data | 9221MC 9215C 9216C 9217C 9218C 9219C 9220C 9222C 9223C 9224C 9225C 9226C 9227C 9228C 9229C 6msbC 6msdC 6mseC 6msgC 6mshC 6mskC M: map data used to model this data C: citing same article (ref.) |
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Similar structure data | |
EM raw data | EMPIAR-10669 (Title: Cryo-EM dataset of the substrate-engaged human 26S proteasome Data size: 13.9 TB Data #1: Drift-corrected frame-averaged super-counting mode micrographs and extracted particles of substrate-engaged human 26S proteasome [micrographs - single frame]) |
-Links
-Assembly
Deposited unit |
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-Components
-26S proteasome non-ATPase regulatory subunit ... , 11 types, 11 molecules UVWXYZabcdf
#1: Protein | Mass: 105958.234 Da / Num. of mol.: 1 Source method: isolated from a genetically manipulated source Source: (gene. exp.) Homo sapiens (human) / Gene: PSMD1 / Production host: Homo sapiens (human) / References: UniProt: Q99460 |
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#2: Protein | Mass: 60935.297 Da / Num. of mol.: 1 Source method: isolated from a genetically manipulated source Source: (gene. exp.) Homo sapiens (human) / Gene: PSMD3 / Production host: Homo sapiens (human) / References: UniProt: O43242 |
#3: Protein | Mass: 52979.359 Da / Num. of mol.: 1 Source method: isolated from a genetically manipulated source Source: (gene. exp.) Homo sapiens (human) / Gene: PSMD12 / Production host: Homo sapiens (human) / References: UniProt: O00232 |
#4: Protein | Mass: 47526.688 Da / Num. of mol.: 1 Source method: isolated from a genetically manipulated source Source: (gene. exp.) Homo sapiens (human) / Gene: PSMD11 / Production host: Homo sapiens (human) / References: UniProt: O00231 |
#5: Protein | Mass: 45592.285 Da / Num. of mol.: 1 Source method: isolated from a genetically manipulated source Source: (gene. exp.) Homo sapiens (human) / Gene: PSMD6, KIAA0107, PFAAP4 / Production host: Homo sapiens (human) / References: UniProt: Q15008 |
#6: Protein | Mass: 37086.441 Da / Num. of mol.: 1 Source method: isolated from a genetically manipulated source Source: (gene. exp.) Homo sapiens (human) / Gene: PSMD7, MOV34L / Production host: Homo sapiens (human) / References: UniProt: P51665 |
#7: Protein | Mass: 42995.359 Da / Num. of mol.: 1 Source method: isolated from a genetically manipulated source Source: (gene. exp.) Homo sapiens (human) / Gene: PSMD13 / Production host: Homo sapiens (human) / References: UniProt: Q9UNM6 |
#8: Protein | Mass: 40781.590 Da / Num. of mol.: 1 Source method: isolated from a genetically manipulated source Source: (gene. exp.) Homo sapiens (human) / Gene: PSMD4, MCB1 / Production host: Homo sapiens (human) / References: UniProt: P55036 |
#9: Protein | Mass: 34488.824 Da / Num. of mol.: 1 Source method: isolated from a genetically manipulated source Source: (gene. exp.) Homo sapiens (human) / Gene: PSMD14, POH1 / Production host: Homo sapiens (human) References: UniProt: O00487, Hydrolases; Acting on peptide bonds (peptidases); Omega peptidases |
#10: Protein | Mass: 39536.676 Da / Num. of mol.: 1 Source method: isolated from a genetically manipulated source Source: (gene. exp.) Homo sapiens (human) / Gene: PSMD8 / Production host: Homo sapiens (human) / References: UniProt: P48556 |
#12: Protein | Mass: 98425.414 Da / Num. of mol.: 1 Source method: isolated from a genetically manipulated source Source: (gene. exp.) Homo sapiens (human) / Gene: PSMD2, TRAP2 / Production host: Homo sapiens (human) / References: UniProt: Q13200 |
-Protein , 2 types, 2 molecules eB
#11: Protein | Mass: 8284.611 Da / Num. of mol.: 1 Source method: isolated from a genetically manipulated source Source: (gene. exp.) Homo sapiens (human) / Gene: SEM1, C7orf76, DSS1, SHFDG1, SHFM1 / Production host: Homo sapiens (human) / References: UniProt: P60896 |
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#14: Protein | Mass: 49260.504 Da / Num. of mol.: 1 Source method: isolated from a genetically manipulated source Source: (gene. exp.) Homo sapiens (human) / Production host: Homo sapiens (human) / References: UniProt: P62191 |
-26S proteasome regulatory subunit ... , 5 types, 5 molecules ACDEF
#13: Protein | Mass: 48700.805 Da / Num. of mol.: 1 Source method: isolated from a genetically manipulated source Source: (gene. exp.) Homo sapiens (human) / Gene: PSMC2, MSS1 / Production host: Homo sapiens (human) / References: UniProt: P35998 |
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#15: Protein | Mass: 44852.121 Da / Num. of mol.: 1 Source method: isolated from a genetically manipulated source Source: (gene. exp.) Homo sapiens (human) / Gene: PSMC5, SUG1 / Production host: Homo sapiens (human) / References: UniProt: P62195 |
#16: Protein | Mass: 47426.141 Da / Num. of mol.: 1 Source method: isolated from a genetically manipulated source Source: (gene. exp.) Homo sapiens (human) / Gene: PSMC4, MIP224, TBP7 / Production host: Homo sapiens (human) / References: UniProt: P43686 |
#17: Protein | Mass: 45867.027 Da / Num. of mol.: 1 Source method: isolated from a genetically manipulated source Source: (gene. exp.) Homo sapiens (human) / Gene: PSMC6 / Production host: Homo sapiens (human) / References: UniProt: A0A087X2I1, UniProt: P62333*PLUS |
#18: Protein | Mass: 49266.457 Da / Num. of mol.: 1 Source method: isolated from a genetically manipulated source Source: (gene. exp.) Homo sapiens (human) / Gene: PSMC3, TBP1 / Production host: Homo sapiens (human) / References: UniProt: P17980 |
-Protein/peptide , 1 types, 1 molecules v
#19: Protein/peptide | Mass: 3081.790 Da / Num. of mol.: 1 Source method: isolated from a genetically manipulated source Source: (gene. exp.) Saccharomyces cerevisiae RM11-1a (yeast) Production host: Escherichia coli K-12 (bacteria) |
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-Proteasome subunit alpha type- ... , 8 types, 14 molecules GHhIiJjKkLlMmg
#20: Protein | Mass: 27301.262 Da / Num. of mol.: 1 Source method: isolated from a genetically manipulated source Source: (gene. exp.) Homo sapiens (human) / Gene: PSMA6, PROS27 / Production host: Homo sapiens (human) References: UniProt: P60900, proteasome endopeptidase complex | ||||||||||||
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#21: Protein | Mass: 25796.338 Da / Num. of mol.: 2 Source method: isolated from a genetically manipulated source Source: (gene. exp.) Homo sapiens (human) / Gene: PSMA2, HC3, PSC3 / Production host: Homo sapiens (human) References: UniProt: P25787, proteasome endopeptidase complex #22: Protein | Mass: 29394.648 Da / Num. of mol.: 2 Source method: isolated from a genetically manipulated source Source: (gene. exp.) Homo sapiens (human) / Gene: PSMA4, HC9, PSC9 / Production host: Homo sapiens (human) References: UniProt: P25789, proteasome endopeptidase complex #23: Protein | Mass: 27798.695 Da / Num. of mol.: 2 Source method: isolated from a genetically manipulated source Source: (gene. exp.) Homo sapiens (human) / Gene: PSMA7, HSPC / Production host: Homo sapiens (human) References: UniProt: O14818, proteasome endopeptidase complex #24: Protein | Mass: 26304.779 Da / Num. of mol.: 2 Source method: isolated from a genetically manipulated source Source: (gene. exp.) Homo sapiens (human) / Gene: PSMA5 / Production host: Homo sapiens (human) References: UniProt: P28066, proteasome endopeptidase complex #25: Protein | Mass: 30150.277 Da / Num. of mol.: 2 Source method: isolated from a genetically manipulated source Source: (gene. exp.) Homo sapiens (human) / Gene: PSMA1, HC2, NU, PROS30, PSC2 / Production host: Homo sapiens (human) References: UniProt: P25786, proteasome endopeptidase complex #26: Protein | Mass: 28338.057 Da / Num. of mol.: 2 Source method: isolated from a genetically manipulated source Source: (gene. exp.) Homo sapiens (human) / Gene: PSMA3, HC8, PSC8 / Production host: Homo sapiens (human) References: UniProt: P25788, proteasome endopeptidase complex #34: Protein | | Mass: 26727.658 Da / Num. of mol.: 1 Source method: isolated from a genetically manipulated source Source: (gene. exp.) Homo sapiens (human) / Gene: PSMA6, PROS27 / Production host: Homo sapiens (human) References: UniProt: P60900, proteasome endopeptidase complex |
-Proteasome subunit beta type- ... , 7 types, 14 molecules NnOoPpQqRrSsTt
#27: Protein | Mass: 25246.455 Da / Num. of mol.: 2 Source method: isolated from a genetically manipulated source Source: (gene. exp.) Homo sapiens (human) / Gene: PSMB6, LMPY, Y / Production host: Homo sapiens (human) References: UniProt: P28072, proteasome endopeptidase complex #28: Protein | Mass: 29869.223 Da / Num. of mol.: 2 Source method: isolated from a genetically manipulated source Source: (gene. exp.) Homo sapiens (human) / Gene: PSMB7, Z / Production host: Homo sapiens (human) References: UniProt: Q99436, proteasome endopeptidase complex #29: Protein | Mass: 22841.701 Da / Num. of mol.: 2 Source method: isolated from a genetically manipulated source Source: (gene. exp.) Homo sapiens (human) / Gene: PSMB3 / Production host: Homo sapiens (human) References: UniProt: P49720, proteasome endopeptidase complex #30: Protein | Mass: 22864.277 Da / Num. of mol.: 2 Source method: isolated from a genetically manipulated source Source: (gene. exp.) Homo sapiens (human) / Gene: PSMB2 / Production host: Homo sapiens (human) References: UniProt: P49721, proteasome endopeptidase complex #31: Protein | Mass: 28379.053 Da / Num. of mol.: 2 Source method: isolated from a genetically manipulated source Source: (gene. exp.) Homo sapiens (human) / Gene: PSMB5, LMPX, MB1, X / Production host: Homo sapiens (human) References: UniProt: P28074, proteasome endopeptidase complex #32: Protein | Mass: 26391.201 Da / Num. of mol.: 2 Source method: isolated from a genetically manipulated source Source: (gene. exp.) Homo sapiens (human) / Gene: PSMB1, PSC5 / Production host: Homo sapiens (human) References: UniProt: P20618, proteasome endopeptidase complex #33: Protein | Mass: 29099.986 Da / Num. of mol.: 2 Source method: isolated from a genetically manipulated source Source: (gene. exp.) Homo sapiens (human) / Gene: PSMB4, PROS26 / Production host: Homo sapiens (human) References: UniProt: P28070, proteasome endopeptidase complex |
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-Non-polymers , 4 types, 10 molecules
#35: Chemical | ChemComp-ZN / | ||||
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#36: Chemical | ChemComp-ATP / #37: Chemical | ChemComp-MG / #38: Chemical | ChemComp-ADP / | |
-Experimental details
-Experiment
Experiment | Method: ELECTRON MICROSCOPY |
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EM experiment | Aggregation state: PARTICLE / 3D reconstruction method: single particle reconstruction |
-Sample preparation
Component | Name: Proteasome / Type: COMPLEX / Entity ID: #1-#13, #15-#32 / Source: RECOMBINANT |
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Molecular weight | Experimental value: NO |
Source (natural) | Organism: Homo sapiens (human) |
Source (recombinant) | Organism: Homo sapiens (human) |
Buffer solution | pH: 7.5 |
Specimen | Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES |
Specimen support | Details: unspecified |
Vitrification | Cryogen name: ETHANE |
-Electron microscopy imaging
Experimental equipment | Model: Titan Krios / Image courtesy: FEI Company |
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Microscopy | Model: FEI TITAN KRIOS |
Electron gun | Electron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM |
Electron lens | Mode: BRIGHT FIELD |
Image recording | Electron dose: 44 e/Å2 / Film or detector model: GATAN K2 SUMMIT (4k x 4k) |
-Processing
Software | Name: PHENIX / Version: 1.13_2998: / Classification: refinement |
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CTF correction | Type: NONE |
3D reconstruction | Resolution: 3.3 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 288915 / Symmetry type: POINT |