Affinage

PSME4

Proteasome activator complex subunit 4 · UniProt Q14997

Length
1843 aa
Mass
211.3 kDa
Annotated
2026-06-10
28 papers in source corpus 24 papers cited in narrative 25 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 8/8 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

PSME4/PA200 is a large nuclear proteasome activator that caps the 20S core particle and stimulates ubiquitin- and ATP-independent peptide hydrolysis, coupling proteasomal proteolysis to chromatin biology, the DNA damage response, and male germ cell development (PMID:12093752, PMID:18845680, PMID:30104204). Structurally it binds as a monomer to one or both ends of the 20S cylinder, forming an asymmetric dome of HEAT-like repeats that contacts the alpha-ring and allosterically opens the axial gate; near-atomic cryo-EM resolves its C-terminal YYA motif driving alpha-ring rearrangement and partial gate opening, inositol-phosphate binding pockets, and an unusually short bromodomain-like (BRDL) module distinct from canonical bromodomains (PMID:15713476, PMID:31473102, PMID:32134919). PA200 enhances cleavage after glutamate (postglutamyl activity), and this activity sustains glutamine homeostasis and proper mTOR/S6K growth restriction after irradiation (PMID:22550082). Upon ionizing radiation and replication stress, PA200 and core proteasomes co-accumulate on chromatin and form hybrid 19S-20S-PA200 proteasomes through a DNA-PK-dependent, ATM/p53-independent pathway, with loss of PA200 causing genomic instability and reduced survival (PMID:18845680, PMID:22550082). A central function is the targeted, ubiquitylation-independent degradation of acetylated core histones (H3.3, H4) during replication stress and transcription, which shapes deposition of active histone marks; its acetyl-lysine-binding region is required for this activity, and its loss perturbs transcription and accelerates cellular and organismal aging (PMID:30104204, PMID:33391545). Beyond histones, nuclear PA200 degrades acetylated YAP1 to enable cardiac commitment of mesenchymal stem cells (PMID:36015285, PMID:37386838) and clears aggregation-prone substrates including N-terminal Huntingtin and alpha-synuclein (PMID:33233776, PMID:42206954). PA200 is essential for male fertility, with germ cell maturation defects in knockouts and functional redundancy with PA28gamma (PSME3) and ECPAS in maintaining sperm proteasome activity and oxidative-damage protection (PMID:16581775, PMID:27003159, PMID:37189334). In disease contexts it plays divergent roles: upregulated PA200 in NSCLC reshapes the proteasome degradome to narrow antigenic peptide diversity and associates with immunotherapy resistance and tumor cell migration (PMID:37217651, PMID:41784105), whereas its upregulation is maladaptive in CMT1B neuropathy (PMID:38320810).

Mechanistic history

Synthesis pass · year-by-year structured walk · 20 steps
  1. 2002 High

    Established that PA200 is a nuclear proteasome activator and linked it to the DNA damage response, answering whether this 200 kDa protein had a defined biochemical activity.

    Evidence Purification from bovine testis, in vitro peptide hydrolysis assay, immunofluorescence after gamma-irradiation in HeLa cells

    PMID:12093752

    Open questions at the time
    • Did not resolve how PA200 engages the 20S core
    • Did not identify physiological substrates
    • Activity shown only on peptides, not intact proteins
  2. 2005 High

    Defined the structural basis of activation, showing PA200 forms a HEAT-repeat dome on the 20S alpha-ring and allosterically opens the axial gate.

    Evidence Cryo-EM 3D reconstruction at 23 A resolution; in vitro peptide hydrolysis with tissue-purified PA200

    PMID:15713476 PMID:16275339

    Open questions at the time
    • Low resolution left atomic contacts unresolved
    • Gate-opening element on PA200 not identified
    • Functional consequences in cells not addressed
  3. 2006 High

    Genetic knockout assigned PA200 an essential, tissue-specific role in spermatogenesis rather than a general DNA-damage survival function.

    Evidence Cre-loxP Psme4 knockout mice with fertility, histological, immunological, and IR/bleomycin sensitivity assays

    PMID:16581775

    Open questions at the time
    • Molecular substrates in germ cells not defined
    • Why ES cells tolerated IR despite the DDR localization phenotype unexplained
    • Possible redundancy not tested
  4. 2008 High

    Showed PA200 forms hybrid proteasomes that accumulate on chromatin via DNA-PK after irradiation, placing postglutamyl proteasome activity in a defined genome-stability pathway.

    Evidence siRNA knockdown, chromatin fractionation, proteasome activity assays, genetic epistasis with DNA-PK/ATM/p53, colony survival

    PMID:17523843 PMID:18845680

    Open questions at the time
    • Chromatin substrates degraded after IR not identified
    • Recruitment mechanism to damaged chromatin unresolved
    • Direct DNA-PK-PA200 relationship not biochemically defined
  5. 2012 Medium

    Connected PA200's postglutamyl activity to metabolic control, showing it is required for glutamine homeostasis and mTOR/S6K growth restriction after irradiation, while also restraining oxidized-protein degradation.

    Evidence siRNA knockdown with glutamine rescue, postglutamyl inhibitor, S6K phosphorylation blots; in vitro degradation of oxidized substrates

    PMID:22550082 PMID:22564544

    Open questions at the time
    • Direct substrates linking PA200 to glutamine pools not identified
    • In vivo relevance of oxidized-protein suppression untested
    • Single-lab in vitro oxidation assay
  6. 2016 High

    Revealed functional redundancy between PA200 and PA28gamma in sperm, resolving why single PA200 knockouts retained partial fertility-related proteasome function.

    Evidence Psme3/Psme4 double knockout mice with sperm motility, proteasome activity, ubiquitin and 8-OHdG immunostaining, proteomics

    PMID:27003159

    Open questions at the time
    • Shared substrates of the two activators not pinpointed
    • Mechanism of oxidative damage protection in sperm unresolved
    • Redundancy in non-germline tissues untested
  7. 2018 High

    Identified acetylated histones as bona fide PA200-dependent, ubiquitin-independent substrates degraded during replication stress, defining the activator's chromatin function.

    Evidence Quantitative MS of acetylated histone peptides with PA200 genetic ablation and differential parallel proteolysis

    PMID:30104204

    Open questions at the time
    • Acetyl-lysine recognition element on PA200 not yet mapped
    • Selectivity for specific acetyl marks unresolved
    • Coupling to replication-stress signaling not detailed
  8. 2019 High

    Delivered a near-atomic recombinant 20S-PA200 structure, resolving alpha-ring contacts, allosteric active-site modulation, and inositol-phosphate binding.

    Evidence Recombinant reconstitution and 3.0 A cryo-EM with biochemical characterization

    PMID:31473102

    Open questions at the time
    • Functional role of bound inositol phosphates not established
    • Substrate channeling into the activated pore not visualized
  9. 2019 Medium

    Extended PA200 function beyond germline and DDR to a species-specific negative regulator of myofibroblast differentiation in human fibrosis.

    Evidence siRNA silencing and overexpression in primary human lung myofibroblasts, in vivo fibrosis models, complex-formation assay

    PMID:31645612

    Open questions at the time
    • Substrates mediating the anti-fibrotic effect unknown
    • Basis of human-vs-mouse difference unexplained
    • Single-lab study
  10. 2020 High

    Pinpointed the YYA motif as the gate-opening element and characterized PA200's unusual short BRDL domain and inositol-phosphate pockets at 2.72 A.

    Evidence Cryo-EM at 2.72 and 3.75 A with structural analysis and YYA motif identification

    PMID:32134919

    Open questions at the time
    • Whether BRDL directly reads acetyl-lysine not demonstrated structurally
    • Allosteric path from YYA to catalytic sites not fully traced
  11. 2020 Low

    Implicated PA200 in transcriptional regulation and metabolic adaptation, with genomic occupancy near transcription start sites and a glycolytic shift upon depletion.

    Evidence ChIP-seq in SH-SY5Y cells; shRNA knockdown with Seahorse flux, RNA-seq, Opa1/OMA1 blots

    PMID:32368861 PMID:33562813

    Open questions at the time
    • Single ChIP-seq with functional consequences not directly demonstrated
    • Indirect link between PA200 and Opa1 processing
    • Direct chromatin-binding mechanism unresolved
  12. 2020 Medium

    Identified N-terminal Huntingtin as a PA200/Blm10-proteasome substrate, expanding PA200's role to clearance of aggregation-prone proteins.

    Evidence Co-IP of PA200 with N-Htt, cell-based aggregate and toxicity assays, in vitro Blm10 degradation assay

    PMID:33233776

    Open questions at the time
    • Reciprocal validation of PA200-N-Htt binding limited
    • In vivo relevance to Huntington pathology untested
    • Acetylation dependence not examined
  13. 2021 High

    Showed PA200 drives transcription-coupled, acetylation-dependent core histone degradation and that its loss perturbs transcription and accelerates aging, requiring its acetyl-lysine-binding region.

    Evidence Pulse-chase histone degradation sequencing, RNA-seq, ChIP-seq, acetyl-lysine-binding domain mutants, KO mouse phenotyping

    PMID:33391545

    Open questions at the time
    • Direct acetyl-lysine readout by PA200 not structurally proven
    • Mechanism linking histone turnover to lifespan not fully resolved
  14. 2022 Medium

    Demonstrated that nuclear PA200 degrades acetylated YAP1 via a ubiquitin-independent route downstream of HDAC6, controlling stem cell fate and cardiac function.

    Evidence Fractionation, co-IP, PSME4 KO MSCs, acetylation-dead YAP1 mutant, HDAC inhibitor, in vivo myocardial injection

    PMID:36015285 PMID:37386838

    Open questions at the time
    • Direct PA200-YAP1 binding interface not defined
    • Whether the BRDL domain recognizes acetyl-YAP1 untested
    • Single-lab system
  15. 2023 Medium

    Refined the germline role by mapping PA200 to the sperm midpiece, establishing redundancy with ECPAS, and identifying LPIN1 as a target.

    Evidence PA200/ECPAS double KO mice, immunostaining, proteasome activity assay, MS and immunoblotting

    PMID:37189334

    Open questions at the time
    • Whether LPIN1 is directly degraded by PA200-proteasomes not shown
    • Mechanism of mitochondrial sheath organization unresolved
  16. 2023 Medium

    Linked PA200 upregulation in NSCLC to a reshaped proteasome degradome that narrows antigen diversity and associates with immunotherapy resistance.

    Evidence Proteasome degradome profiling and antigen presentation analysis of patient-derived NSCLC samples

    PMID:37217651

    Open questions at the time
    • Causal contribution to immune evasion vs correlation not fully separated
    • Specific peptides lost from presentation not catalogued
  17. 2024 Medium

    Showed PA200 upregulation can be maladaptive, as its deletion in a CMT1B model restored proteasome activity and myelination.

    Evidence PA200 KO in S63del mice, proteasome activity and UPR markers, nerve conduction, myelin EM

    PMID:38320810

    Open questions at the time
    • Why PA200 upregulation suppresses 26S assembly unclear
    • Substrates relevant to myelin maintenance unidentified
  18. 2026 Medium

    Established a cell-context-dependent role for PA200 in tumor cell migration via integrin ITGB3 and adhesion/ECM gene regulation, with a variable interactome.

    Evidence CRISPR deletion in two NSCLC lines, migration/invasion assays, transcriptome and co-IP/MS interactome

    PMID:41784105

    Open questions at the time
    • Direct substrates driving ITGB3 downregulation unknown
    • Mechanism of transcriptional dysregulation by a proteasome activator unresolved
  19. 2026 Medium

    Identified alpha-synuclein as a PA200/Blm10-proteasome substrate, showing PA200-capped proteasomes degrade monomeric and oligomeric species and resist alpha-synuclein inhibition.

    Evidence In vitro degradation assays, yeast/mammalian overexpression, aggregate quantification, autophagy and S129 phosphorylation experiments

    PMID:42206954

    Open questions at the time
    • In vivo therapeutic relevance untested
    • Basis of inhibition resistance not structurally defined
    • Single-lab study
  20. 2025 Medium

    Revealed differential allosteric coupling of PA200 to the immunoproteasome versus standard proteasome, with greater activation and occupancy on i20S.

    Evidence Cryo-EM of i20S-PA200 complexes, mass photometry, co-expression analysis (preprint)

    Open questions at the time
    • Preprint not yet peer-reviewed
    • Functional consequence of i20S-PA200 bending in cells untested
    • Relevance to antigen presentation not directly linked

Open questions

Synthesis pass · forward-looking unresolved questions
  • How PA200 achieves substrate selectivity for acetylated proteins at the molecular level and how its diverse context-dependent roles are coordinated remains unresolved.
  • Direct acetyl-lysine binding by PA200 not structurally proven
  • Mechanism of chromatin and gene-specific recruitment unknown
  • How a single activator produces opposing tissue-specific phenotypes unexplained

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0098772 molecular function regulator activity 5 GO:0140096 catalytic activity, acting on a protein 4 GO:0042393 histone binding 2
Localization
GO:0005654 nucleoplasm 3 GO:0000228 nuclear chromosome 2 GO:0005634 nucleus 2
Pathway
R-HSA-392499 Metabolism of proteins 4 R-HSA-4839726 Chromatin organization 2 R-HSA-73894 DNA Repair 2 R-HSA-1474244 Extracellular matrix organization 1
Partners
ECPASHTTPSMA1PSME3SNCAYAP1
Complex memberships
20S proteasome (PA200-capped)hybrid 19S-20S-PA200 proteasomeimmunoproteasome-PA200

Evidence

Reading pass · 25 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2002 PA200 (PSME4) is a ~200 kDa nuclear protein that activates proteasomal hydrolysis of peptides but not intact proteins when purified to homogeneity from bovine testis. Following gamma-irradiation of HeLa cells, PA200 redistributes from a uniform nuclear pattern to a punctate pattern characteristic of DNA repair proteins. Protein purification, in vitro peptide hydrolysis assay, immunofluorescence after gamma-irradiation The EMBO journal High 12093752
2005 PA200 binds as a monomer to one or both ends of the cylindrical 20S proteasome core, forming an asymmetric dome-like structure composed of HEAT-like repeats. PA200 contacts all alpha-subunits except alpha7 and induces opening of the axial channel through the alpha-ring, revealing an allosteric activation mechanism. Cryo-electron microscopy and 3D reconstruction at 23 Å resolution Journal of molecular biology High 15713476
2005 PA200 purified from bovine testis activates peptide hydrolysis by the 20S proteasome in vitro; two forms (160 kDa and 200 kDa) exist in mammalian tissues, with the 200 kDa form highest in testis. Protein purification from bovine testis, in vitro peptide hydrolysis assay, Western blot organ survey Methods in enzymology Medium 16275339
2006 Genetic deletion of PA200 (Psme4) in mice causes male infertility due to defects in meiotic spermatocytes and postmeiotic haploid spermatid maturation, without affecting lymphocyte development, immunoglobulin class switching, or sensitivity to ionizing radiation or bleomycin in embryonic stem cells. Cre-loxP knockout mouse generation, fertility assays, histological analysis, immunological assays, IR/bleomycin sensitivity in ES cells Molecular and cellular biology High 16581775
2007 Three isoforms of PA200 exist (PA200i, PA200ii, PA200iii); only PA200i associates with proteasomes. Ionizing radiation causes equivalent co-accumulation of PA200i and core proteasomes on chromatin, independent of cell cycle stage, indicating PA200 and proteasomes function together in the radiation response. Chromatin fractionation, co-immunoprecipitation, RT-PCR/Western blot for isoforms, radiation treatment Radiation research Medium 17523843
2008 In response to ionizing radiation, PA200 forms hybrid proteasomes with 19S caps and 20S cores that accumulate on chromatin, increasing proteolytic activity. This response is independent of ATM and p53 but dependent on DNA-dependent protein kinase (DNA-PK). PA200 knockdown causes genomic instability and reduced survival after IR, phenocopied by specific inhibition of postglutamyl proteasome activity; combined PA200 siRNA plus postglutamyl inhibitor showed no additive effect, placing PA200 in the same pathway. siRNA knockdown, chromatin fractionation, proteasome activity assays, genetic epistasis with DNA-PK/ATM/p53, colony survival assay Proceedings of the National Academy of Sciences of the United States of America High 18845680
2012 Purified PA200 decreases the ability of purified 20S proteasome and immunoproteasome to degrade oxidized proteins, in contrast to Pa28αβ and Pa28γ which enhance it. PA200 and poly-ADP ribose polymerase may cooperate in enabling initiation of DNA repair. In vitro degradation assay with purified proteasome components and oxidized protein substrates Archives of biochemistry and biophysics Medium 22564544
2012 PA200 enhances proteasome-mediated cleavage after glutamate (postglutamyl activity), and this activity is required for maintaining intracellular glutamine homeostasis and for appropriate mTOR/S6K-mediated growth restriction in response to nutrient depletion after ionizing radiation. PA200-deficient cells fail to slow growth under glutamine deprivation. PA200 siRNA knockdown, cell survival assay, glutamine supplementation rescue, postglutamyl activity inhibitor, S6K phosphorylation western blot Molecular cancer research : MCR Medium 22550082
2016 Double knockout of Psme3 (PA28γ) and Psme4 (PA200) in male mice causes complete infertility with severely defective sperm motility, markedly reduced proteasome activity, ubiquitin accumulation in sperm, and increased 8-OHdG staining in sperm heads indicating defective oxidative damage response; single knockouts are individually fertile. Double knockout mouse generation, fertility assay, sperm motility analysis, proteasome activity assay, ubiquitin immunostaining, 8-OHdG staining, quantitative proteomics Scientific reports High 27003159
2018 DNA damage-induced replication stress causes proteasome-dependent degradation of acetylated histones in a ubiquitylation-independent manner, specifically requiring the PA200 proteasome activator. This was established by quantitative mass spectrometry of acetylated histone peptides with genetic ablation of PA200. Quantitative mass spectrometry of acetylated histone peptides, PA200 genetic ablation, differential parallel proteolysis EMBO reports High 30104204
2019 The human 20S-PA200 complex was reconstituted recombinantly, and its 3.0 Å cryo-EM structure reveals the detailed architecture of PA200, its intricate contacts with the proteasome alpha ring, allosteric modulation of proteasome active sites, and binding of inositol phosphates (5,6[PP]2-InsP4 and InsP6) to PA200. Recombinant protein reconstitution, cryo-EM at 3.0 Å resolution, biochemical characterization Molecular cell High 31473102
2019 PA200 functions as a negative regulator of myofibroblast differentiation in human (but not mouse) cells. PA200 expression is upregulated in fibrotic lungs and activated myofibroblasts, and enhanced formation of PA200-proteasome complexes occurs in experimental fibrosis; transient silencing and overexpression establish a functional role. siRNA silencing and overexpression of PA200 in primary human lung myofibroblasts, in vivo fibrosis models, Western blot, complex formation assay Scientific reports Medium 31645612
2020 Human PA200 binds to N-terminal Huntingtin fragments (N-Htt). Loss of PA200 in human cells increases mutant N-Htt aggregate formation and cellular toxicity. In yeast, Blm10 in vitro accelerates proteasomal degradation of soluble N-Htt, identifying N-Htt as a substrate of Blm10/PA200-proteasomes. Co-immunoprecipitation (PA200 binding to N-Htt), cell-based aggregate formation assay, in vitro proteasome degradation assay with Blm10, PA200 KO/KD cellular toxicity assay Biomolecules Medium 33233776
2020 PA200 occupies genomic regions near transcription start sites in neuroblastoma cells, as shown by ChIP-seq. Selective mitochondrial inhibitors induce PA200 redistribution in the genome, suggesting a transcriptional regulatory role for PA200 in addition to its proteasome activation function. Chromatin immunoprecipitation (ChIP) and ChIP-seq in SH-SY5Y cells, gene ontology analysis Journal of cellular and molecular medicine Low 32368861
2020 The cryo-EM structure of human PA200-20S at 2.72 Å shows PA200 uses its C-terminal YYA motif (Tyr-Tyr-Ala) to induce alpha-ring rearrangements and partial gate opening of the 20S. PA200 contains two apertures with positively charged residues that bind (5,6[PP]2-InsP4) and InsP6 respectively. PA200's bromodomain-like (BRDL) domain has only 82 residues with a short ZA loop, distinct from all eight canonical human bromodomain families. Cryo-EM at 2.72 Å and 3.75 Å resolution, structural analysis, C-terminal YYA motif identification PLoS biology High 32134919
2021 PA200 promotes transcription-coupled degradation of core histones (H4 and H3.3) in an acetylation-dependent manner; the putative acetyl-lysine-binding region of PA200 is required for histone degradation in G1-arrested cells. Deletion of PA200 alters deposition of active transcriptional marks (H3K4me3 and H3K56ac), perturbs transcription, and accelerates cellular aging. PA200-deficient mice display aging-related deteriorations including immune malfunction and shorter lifespan. Metabolic pulse-chase labeling + genome-wide sequencing of histone degradation, RNA-seq, ChIP-seq, PA200 acetyl-lysine binding domain mutants, PA200 KO mouse phenotyping Theranostics High 33391545
2021 Stable PA200 knockdown in neuroblastoma cells shifts metabolism from oxidative phosphorylation to glycolysis. PA200 depletion reduces spare respiratory capacity and proton leak, increases glycolysis and glycolytic capacity, and alters Opa1 proteolytic cleavage with reduced OMA1 levels during oligomycin-induced stress, suggesting PA200 regulates metabolic adaptation to mitochondrial dysfunction. shRNA knockdown, Seahorse metabolic flux assay, RNA-seq, Western blot for Opa1/OMA1 International journal of molecular sciences Low 33562813
2022 Nuclear PSME4 (PA200) recognizes and degrades acetylated YAP1 in the nucleus of mesenchymal stem cells via a ubiquitination-independent mechanism. HDAC6 regulates YAP1 acetylation and subcellular localization. PSME4 null MSCs fail to degrade nuclear YAP1, leading to impaired cardiac commitment and in vivo cardiac dysfunction. Subcellular fractionation, co-immunoprecipitation, PSME4 KO mouse MSC assay, lentiviral knockdown, acetylation-dead YAP1 mutant, HDAC inhibitor treatment, in vivo myocardial injection Pharmaceutics Medium 36015285
2023 PA200 in mouse epididymal sperm localizes specifically to the midpiece (while partner protein ECPAS localizes to the acrosome). Double knockout of PA200 and ECPAS dramatically reduces proteasome activity in testes and epididymides and causes infertility with disorganization of the mitochondrial sheath. Mass spectrometry and immunoblotting identify LPIN1 as a target protein for PA200 and ECPAS. Double KO mouse generation, immunostaining for localization, proteasome activity assay, mass spectrometry, immunoblotting Biomolecules Medium 37189334
2023 PSME4 promotes cardiac commitment of mesenchymal stem cells by degrading acetylated YAP1 in the nucleus downstream of HDAC inhibition. PSME4 KO or knockdown prevents YAP1 nuclear clearance and blocks cardiac commitment; overexpression of acetylation-resistant YAP1 also impedes cardiac commitment, epistatic to PSME4. PSME4 KO mouse MSC assay, lentiviral knockdown, HDAC6 siRNA, tubastatin A treatment, acetylation-resistant YAP1 overexpression, immunofluorescence, Western blot The Korean journal of physiology & pharmacology Medium 37386838
2023 PSME4 (PA200) upregulation in NSCLC tumors alters proteasome activity, attenuates the diversity of presented antigenic peptides, and associates with lack of response to immunotherapy, as established by profiling the degradation landscape of patient-derived tumor samples. Proteasome degradome profiling of patient-derived NSCLC samples, mass spectrometry, antigen presentation analysis Nature cancer Medium 37217651
2024 In the S63del mouse model of CMT1B neuropathy, PA200 and PA200-bound proteasomes are upregulated in peripheral nerves. Genetic deletion of PA200 in S63del mice unexpectedly increases proteasomal protein degradation, reduces polyubiquitinated proteins and unfolded protein response markers, increases assembled active 26S proteasomes, and restores myelin thickness and nerve conduction to wild-type levels. PA200 upregulation is thus maladaptive in this disease context. Genetic PA200 KO combined with S63del disease model, proteasomal activity assay, Western blot for UPR markers, nerve conduction velocity, electron microscopy of myelin Life science alliance Medium 38320810
2026 Deletion of PA200 in two NSCLC lung cancer cell lines causes cell-line-specific alterations in proteasome composition and activities, inhibits tumor cell migration and invasion, and downregulates integrin ITGB3 with transcriptional dysregulation of cell adhesion and extracellular matrix regulators. PA200 interactome analysis revealed a cell-context-dependent profile of PA200-interacting proteins. CRISPR/genetic deletion of PA200, migration and invasion assays, proteasome activity assay, transcriptome profiling, interactome (co-IP/MS) analysis Journal of cell science Medium 41784105
2026 Blm10/PA200-capped 20S proteasomes efficiently degrade both monomeric and oligomeric alpha-synuclein in vitro. Overexpression of BLM10 or PA200 reduces alpha-synuclein aggregation and enhances its turnover via 20S proteasome activation in yeast and mammalian cells. Alpha-synuclein expression increases Blm10 protein stability through autophagy inhibition dependent on S129 phosphorylation in yeast. PA200-capped proteasomes retain proteolytic activity in the presence of alpha-synuclein, showing resistance to alpha-synuclein-induced inhibition unlike 20S or 26S alone. In vitro proteasome degradation assay, yeast and mammalian cell overexpression, aggregate quantification, autophagy inhibition experiments, S129 phosphorylation mutants Aging cell Medium 42206954
2025 Cryo-EM structures of singly- and doubly-capped immunoproteasome (i20S)-PA200 complexes show that PA200 binding to i20S is mechanistically similar to s20S binding but the first PA200 binding event triggers a long-range allosteric bending of the i20S barrel not seen in s20S-PA200 complexes, causing major structural rearrangements in the opposite unbound alpha ring (atom displacement up to 5.4 Å) and increasing occupancy of the second PA200 binding site. Mass photometry confirmed higher occupancy of PA200 on i20S versus s20S. PA200 binding to i20S enhances proteasomal activation more than on s20S. Cryo-EM of i20S-PA200 complexes, mass photometry, cell co-expression analysis bioRxivpreprint Medium

Source papers

Stage 0 corpus · 28 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2002 PA200, a nuclear proteasome activator involved in DNA repair. The EMBO journal 281 12093752
2012 Differential roles of proteasome and immunoproteasome regulators Pa28αβ, Pa28γ and Pa200 in the degradation of oxidized proteins. Archives of biochemistry and biophysics 127 22564544
2006 Proteasome activator PA200 is required for normal spermatogenesis. Molecular and cellular biology 125 16581775
2019 Characterization of Fully Recombinant Human 20S and 20S-PA200 Proteasome Complexes. Molecular cell 90 31473102
2005 The axial channel of the 20S proteasome opens upon binding of the PA200 activator. Journal of molecular biology 89 15713476
2008 Role for proteasome activator PA200 and postglutamyl proteasome activity in genomic stability. Proceedings of the National Academy of Sciences of the United States of America 87 18845680
2016 Proteasome activators, PA28γ and PA200, play indispensable roles in male fertility. Scientific reports 55 27003159
2007 Proteasomes and proteasome activator 200 kDa (PA200) accumulate on chromatin in response to ionizing radiation. Radiation research 47 17523843
2018 DNA damage-induced replication stress results in PA200-proteasome-mediated degradation of acetylated histones. EMBO reports 45 30104204
2020 Cryo-EM structures of the human PA200 and PA200-20S complex reveal regulation of proteasome gate opening and two PA200 apertures. PLoS biology 37 32134919
2012 The proteasome activator PA200 regulates tumor cell responsiveness to glutamine and resistance to ionizing radiation. Molecular cancer research : MCR 27 22550082
2023 The proteasome regulator PSME4 modulates proteasome activity and antigen diversity to abrogate antitumor immunity in NSCLC. Nature cancer 26 37217651
2005 Purification and assay of proteasome activator PA200. Methods in enzymology 17 16275339
2022 The Proteasome Activator PA200/PSME4: An Emerging New Player in Health and Disease. Biomolecules 16 36009043
2019 Proteasome activator PA200 regulates myofibroblast differentiation. Scientific reports 16 31645612
2021 Proteasome activator PA200 maintains stability of histone marks during transcription and aging. Theranostics 15 33391545
2020 The Proteasome Activators Blm10/PA200 Enhance the Proteasomal Degradation of N-Terminal Huntingtin. Biomolecules 15 33233776
2022 PSME4 Activates mTOR Signaling and Promotes the Malignant Progression of Hepatocellular Carcinoma. International journal of general medicine 12 35115815
2023 Proteasome-Associated Proteins, PA200 and ECPAS, Are Essential for Murine Spermatogenesis. Biomolecules 11 37189334
2020 The proteasome activator PA200 regulates expression of genes involved in cell survival upon selective mitochondrial inhibition in neuroblastoma cells. Journal of cellular and molecular medicine 8 32368861
2022 PSME4 Degrades Acetylated YAP1 in the Nucleus of Mesenchymal Stem Cells. Pharmaceutics 7 36015285
2021 Cells Lacking PA200 Adapt to Mitochondrial Dysfunction by Enhancing Glycolysis via Distinct Opa1 Processing. International journal of molecular sciences 6 33562813
2024 PA200-Mediated Proteasomal Protein Degradation and Regulation of Cellular Senescence. International journal of molecular sciences 4 38891826
2023 PSME4 determines mesenchymal stem cell fate towards cardiac commitment through YAP1 degradation. The Korean journal of physiology & pharmacology : official journal of the Korean Physiological Society and the Korean Society of Pharmacology 4 37386838
2024 Knockout of PA200 improves proteasomal degradation and myelination in a proteotoxic neuropathy. Life science alliance 3 38320810
2023 The role of proteasome activators PA28αβ and PA200 in brown adipocyte differentiation and function. Frontiers in endocrinology 2 37201100
2026 PA200 differentially regulates the proteasome and inhibits migration of NSCLC cells. Journal of cell science 0 41784105
2026 Blm10/PA200-Activated 20S Proteasomes Promote α-Synuclein Degradation and Bypass Proteasome Inhibition in Parkinson's Disease Models. Aging cell 0 42206954

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