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- EMDB-0780: cryo-EM structure of human PA200 -

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Basic information

Entry
Database: EMDB / ID: EMD-0780
Titlecryo-EM structure of human PA200
Map data
Sample
  • Cell: human PA200
    • Protein or peptide: Proteasome activator complex subunit 4
  • Ligand: [(1~{S},2~{R},3~{R},4~{S},5~{S},6~{R})-2-[oxidanyl(phosphonooxy)phosphoryl]oxy-3,4,5,6-tetraphosphonooxy-cyclohexyl] phosphono hydrogen phosphate
  • Ligand: INOSITOL HEXAKISPHOSPHATE
KeywordsProteasome activator / HYDROLASE
Function / homology
Function and homology information


spermatoproteasome complex / sperm DNA condensation / peptidase activator activity / Regulation of ornithine decarboxylase (ODC) / Cross-presentation of soluble exogenous antigens (endosomes) / proteasomal ubiquitin-independent protein catabolic process / proteasome binding / Regulation of activated PAK-2p34 by proteasome mediated degradation / APC/C:Cdc20 mediated degradation of Securin / Asymmetric localization of PCP proteins ...spermatoproteasome complex / sperm DNA condensation / peptidase activator activity / Regulation of ornithine decarboxylase (ODC) / Cross-presentation of soluble exogenous antigens (endosomes) / proteasomal ubiquitin-independent protein catabolic process / proteasome binding / Regulation of activated PAK-2p34 by proteasome mediated degradation / 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 / Degradation of DVL / Ubiquitin Mediated Degradation of Phosphorylated Cdc25A / Cdc20:Phospho-APC/C mediated degradation of Cyclin A / Dectin-1 mediated noncanonical NF-kB signaling / Hh mutants are degraded by ERAD / Degradation of AXIN / Activation of NF-kappaB in B cells / Degradation of GLI1 by the proteasome / lysine-acetylated histone binding / Hedgehog ligand biogenesis / G2/M Checkpoints / Defective CFTR causes cystic fibrosis / Autodegradation of the E3 ubiquitin ligase COP1 / Vif-mediated degradation of APOBEC3G / Hedgehog 'on' state / Degradation of GLI2 by the proteasome / GLI3 is processed to GLI3R by the proteasome / FBXL7 down-regulates AURKA during mitotic entry and in early mitosis / MAPK6/MAPK4 signaling / APC/C:Cdh1 mediated degradation of Cdc20 and other APC/C:Cdh1 targeted proteins in late mitosis/early G1 / Degradation of beta-catenin by the destruction complex / Oxygen-dependent proline hydroxylation of Hypoxia-inducible Factor Alpha / ABC-family proteins mediated transport / CDK-mediated phosphorylation and removal of Cdc6 / CLEC7A (Dectin-1) signaling / Regulation of expression of SLITs and ROBOs / FCERI mediated NF-kB activation / Regulation of PTEN stability and activity / Interleukin-1 signaling / Orc1 removal from chromatin / Regulation of RAS by GAPs / Separation of Sister Chromatids / Regulation of RUNX2 expression and activity / The role of GTSE1 in G2/M progression after G2 checkpoint / UCH proteinases / KEAP1-NFE2L2 pathway / Antigen processing: Ubiquitination & Proteasome degradation / Downstream TCR signaling / RUNX1 regulates transcription of genes involved in differentiation of HSCs / Neddylation / ER-Phagosome pathway / Ub-specific processing proteases / nuclear speck / DNA repair / DNA damage response / nucleoplasm / nucleus / cytosol
Similarity search - Function
Proteasome activator complex subunit 4 C-terminal domain / Proteasome activator Blm10, mid region / Proteasome activator complex subunit 4 / Domain of unknown function (DUF3437) / Proteasome-substrate-size regulator, mid region / Armadillo-like helical / Armadillo-type fold
Similarity search - Domain/homology
Proteasome activator complex subunit 4
Similarity search - Component
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.75 Å
AuthorsOuyang S / Hongxin G
Funding support China, 1 items
OrganizationGrant numberCountry
National Science Foundation (NSF, China)31770948 China
CitationJournal: PLoS Biol / Year: 2020
Title: Cryo-EM structures of the human PA200 and PA200-20S complex reveal regulation of proteasome gate opening and two PA200 apertures.
Authors: Hongxin Guan / Youwang Wang / Ting Yu / Yini Huang / Mianhuan Li / Abdullah F U H Saeed / Vanja Perčulija / Daliang Li / Jia Xiao / Dongmei Wang / Ping Zhu / Songying Ouyang /
Abstract: Proteasomes are highly abundant and conserved protease complexes that eliminate unwanted proteins in the cells. As a single-chain ATP-independent nuclear proteasome activator, proteasome activator ...Proteasomes are highly abundant and conserved protease complexes that eliminate unwanted proteins in the cells. As a single-chain ATP-independent nuclear proteasome activator, proteasome activator 200 (PA200) associates with 20S core particle to form proteasome complex that catalyzes polyubiquitin-independent degradation of acetylated histones, thus playing a pivotal role in DNA repair and spermatogenesis. Here, we present cryo-electron microscopy (cryo-EM) structures of the human PA200-20S complex and PA200 at 2.72 Å and 3.75 Å, respectively. PA200 exhibits a dome-like architecture that caps 20S and uses its C-terminal YYA (Tyr-Tyr-Ala) to induce the α-ring rearrangements and partial opening of the 20S gate. Our structural data also indicate that PA200 has two openings formed by numerous positively charged residues that respectively bind (5,6)-bisdiphosphoinositol tetrakisphosphate (5,6[PP]2-InsP4) and inositol hexakisphosphate (InsP6) and are likely to be the gates that lead unfolded proteins through PA200 and into the 20S. Besides, our structural analysis of PA200 found that the bromodomain (BRD)-like (BRDL) domain of PA200 shows considerable sequence variation in comparison to other human BRDs, as it contains only 82 residues because of a short ZA loop, and cannot be classified into any of the eight typical human BRD families. Taken together, the results obtained from this study provide important insights into human PA200-induced 20S gate opening for substrate degradation and the opportunities to explore the mechanism for its recognition of H4 histone in acetylation-mediated proteasomal degradation.
History
DepositionSep 9, 2019-
Header (metadata) releaseApr 1, 2020-
Map releaseApr 1, 2020-
UpdateMar 27, 2024-
Current statusMar 27, 2024Processing site: PDBj / Status: Released

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Structure visualization

Movie
  • Surface view with section colored by density value
  • Surface level: 4
  • Imaged by UCSF Chimera
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  • Surface view colored by radius
  • Surface level: 4
  • Imaged by UCSF Chimera
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  • Surface view with fitted model
  • Atomic models: PDB-6kwx
  • Surface level: 4
  • Imaged by UCSF Chimera
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Movie viewer
Structure viewerEM map:
SurfViewMolmilJmol/JSmol
Supplemental images

emd_0780.png

Downloads & links

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Map

FileDownload / File: emd_0780.map.gz / Format: CCP4 / Size: 30.5 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
1.04 Å/pix.
x 200 pix.
= 208. Å		1.04 Å/pix.
x 200 pix.
= 208. Å		1.04 Å/pix.
x 200 pix.
= 208. Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 1.04 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 4.0 / Movie #1: 4
Minimum - Maximum-11.800967999999999 - 18.900901999999999
Average (Standard dev.)-0.009729608 (±1.0053567)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions200200200
Spacing200200200
CellA=B=C: 208.0 Å
α=β=γ: 90.0 °

CCP4 map header:

modeImage stored as Reals
Å/pix. X/Y/Z1.041.041.04
M x/y/z200200200
origin x/y/z0.0000.0000.000
length x/y/z208.000208.000208.000
α/β/γ90.00090.00090.000
MAP C/R/S123
start NC/NR/NS000
NC/NR/NS200200200
D min/max/mean-11.80118.901-0.010

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Supplemental data

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Sample components

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Entire : human PA200

EntireName: human PA200
Components
  • Cell: human PA200
    • Protein or peptide: Proteasome activator complex subunit 4
  • Ligand: [(1~{S},2~{R},3~{R},4~{S},5~{S},6~{R})-2-[oxidanyl(phosphonooxy)phosphoryl]oxy-3,4,5,6-tetraphosphonooxy-cyclohexyl] phosphono hydrogen phosphate
  • Ligand: INOSITOL HEXAKISPHOSPHATE

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Supramolecule #1: human PA200

SupramoleculeName: human PA200 / type: cell / ID: 1 / Parent: 0 / Macromolecule list: #1
Source (natural)Organism: Homo sapiens (human)

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Macromolecule #1: Proteasome activator complex subunit 4

MacromoleculeName: Proteasome activator complex subunit 4 / type: protein_or_peptide / ID: 1 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 215.774875 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: MGTTRSTMSY YHHHHHHDYD IPTTENLYFQ GAMDPMEPAE RAGVGEPPEP GGRPEPGPRG FVPQKEIVYN KLLPYAERLD AESDLQLAQ IKCNLGRAVQ LQELWPGGLF WTRKLSTYIR LYGRKFSKED HVLFIKLLYE LVSIPKLEIS MMQGFARLLI N LLKKKELL ...String:
MGTTRSTMSY YHHHHHHDYD IPTTENLYFQ GAMDPMEPAE RAGVGEPPEP GGRPEPGPRG FVPQKEIVYN KLLPYAERLD AESDLQLAQ IKCNLGRAVQ LQELWPGGLF WTRKLSTYIR LYGRKFSKED HVLFIKLLYE LVSIPKLEIS MMQGFARLLI N LLKKKELL SRADLELPWR PLYDMVERIL YSKTEHLGLN WFPNSVENIL KTLVKSCRPY FPADATAEML EEWRPLMCPF DV TMQKAIT YFEIFLPTSL PPELHHKGFK LWFDELIGLW VSVQNLPQWE GQLVNLFARL ATDNIGYIDW DPYVPKIFTR ILR SLNLPV GSSQVLVPRF LTNAYDIGHA VIWITAMMGG PSKLVQKHLA GLFNSITSFY HPSNNGRWLN KLMKLLQRLP NSVV RRLHR ERYKKPSWLT PVPDSHKLTD QDVTDFVQCI IQPVLLAMFS KTGSLEAAQA LQNLALMRPE LVIPPVLERT YPALE TLTE PHQLTATLSC VIGVARSLVS GGRWFPEGPT HMLPLLMRAL PGVDPNDFSK CMITFQFIAT FSTLVPLVDC SSVLQE RND LTEVERELCS ATAEFEDFVL QFMDRCFGLI ESSTLEQTRE ETETEKMTHL ESLVELGLSS TFSTILTQCS KEIFMVA LQ KVFNFSTSHI FETRVAGRMV ADMCRAAVKC CPEESLKLFV PHCCSVITQL TMNDDVLNDE ELDKELLWNL QLLSEITR V DGRKLLLYRE QLVKILQRTL HLTCKQGYTL SCNLLHHLLR STTLIYPTEY CSVPGGFDKP PSEYFPIKDW GKPGDLWNL GIQWHVPSSE EVSFAFYLLD SFLQPELVKL QHCGDGKLEM SRDDILQSLT IVHNCILGSG NLLPPLKGEP VTNLVPSMVS LEETKLYTG LEYDLSRENH REVIATVIRK LLNHILDNSE DDTKSLFLII KIIGDLLQFQ GSHKHEFDSR WKSFNLVKKS M ENRLHGKK QHIRALLIDR VMLQHELRTL TVEGCEYKKI HQDMIRDLLR LSTSSYSQVR NKAQQTFFAA LGAYNFCCRD II PLVLEFL RPDRQGVTQQ QFKGALYCLL GNHSGVCLAN LHDWDCIVQT WPAIVSSGLS QAMSLEKPSI VRLFDDLAEK IHR QYETIG LDFTIPKSCV EIAELLQQSK NPSINQILLS PEKIKEGIKR QQEKNADALR NYENLVDTLL DGVEQRNLPW KFEH IGIGL LSLLLRDDRV LPLRAIRFFV ENLNHDAIVV RKMAISAVAG ILKQLKRTHK KLTINPCEIS GCPKPTQIIA GDRPD NHWL HYDSKTIPRT KKEWESSCFV EKTHWGYYTW PKNMVVYAGV EEQPKLGRSR EDMTEAEQII FDHFSDPKFV EQLITF LSL EDRKGKDKFN PRRFCLFKGI FRNFDDAFLP VLKPHLEHLV ADSHESTQRC VAEIIAGLIR GSKHWTFEKV EKLWELL CP LLRTALSNIT VETYNDWGAC IATSCESRDP RKLHWLFELL LESPLSGEGG SFVDACRLYV LQGGLAQQEW RVPELLHR L LKYLEPKLTQ VYKNVRERIG SVLTYIFMID VSLPNTTPTI SPHVPEFTAR ILEKLKPLMD VDEEIQNHVM EENGIGEED ERTQGIKLLK TILKWLMASA GRSFSTAVTE QLQLLPLFFK IAPVENDNSY DELKRDAKLC LSLMSQGLLY PHQVPLVLQV LKQTARSSS WHARYTVLTY LQTMVFYNLF IFLNNEDAVK DIRWLVISLL EDEQLEVREM AATTLSGLLQ CNFLTMDSPM Q IHFEQLCK TKLPKKRKRD PGSVGDTIPS AELVKRHAGV LGLGACVLSS PYDVPTWMPQ LLMNLSAHLN DPQPIEMTVK KT LSNFRRT HHDNWQEHKQ QFTDDQLLVL TDLLVSPCYY A

UniProtKB: Proteasome activator complex subunit 4

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Macromolecule #2: [(1~{S},2~{R},3~{R},4~{S},5~{S},6~{R})-2-[oxidanyl(phosphonooxy)p...

MacromoleculeName: [(1~{S},2~{R},3~{R},4~{S},5~{S},6~{R})-2-[oxidanyl(phosphonooxy)phosphoryl]oxy-3,4,5,6-tetraphosphonooxy-cyclohexyl] phosphono hydrogen phosphate
type: ligand / ID: 2 / Number of copies: 1 / Formula: K0W
Molecular weightTheoretical: 819.995 Da
Chemical component information

ChemComp-K0W:
[(1~{S},2~{R},3~{R},4~{S},5~{S},6~{R})-2-[oxidanyl(phosphonooxy)phosphoryl]oxy-3,4,5,6-tetraphosphonooxy-cyclohexyl] phosphono hydrogen phosphate

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Macromolecule #3: INOSITOL HEXAKISPHOSPHATE

MacromoleculeName: INOSITOL HEXAKISPHOSPHATE / type: ligand / ID: 3 / Number of copies: 1 / Formula: IHP
Molecular weightTheoretical: 660.035 Da
Chemical component information

ChemComp-IHP:
INOSITOL HEXAKISPHOSPHATE

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Experimental details

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Structure determination

Methodcryo EM
Processingsingle particle reconstruction
Aggregation stateparticle

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Sample preparation

BufferpH: 7.5
VitrificationCryogen name: ETHANE

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Image recordingFilm or detector model: GATAN K2 SUMMIT (4k x 4k) / Average electron dose: 60.0 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: OTHER / Imaging mode: BRIGHT FIELD
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Startup modelType of model: NONE
Final reconstructionResolution.type: BY AUTHOR / Resolution: 3.75 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 103000
Initial angle assignmentType: RANDOM ASSIGNMENT
Final angle assignmentType: MAXIMUM LIKELIHOOD
FSC plot (resolution estimation)

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