Dual-function protein (160 aa, ~18.7 kDa) that acts both as a cytosolic prostaglandin E synthase (cPGES) catalyzing the glutathione-dependent isomerization of PGH2 to PGE2, and as an HSP90 co-chaperone (p23) that stabilizes the HSP90-client protein complex in the ATP-bound closed conformation. As a co-chaperone, p23 inhibits/reduces HSP90 ATPase activity by stabilizing the "closed 2" conformational state, thereby regulating progression of the HSP90 chaperone cycle and shaping client maturation/release (DOI:10.1038/nrm.2017.20). PTGES3 participates in the maturation and stabilization of steroid hormone receptors, telomerase, and other HSP90 client proteins. As a PGE synthase, PTGES3/cPGES is functionally coupled with COX-1 (PTGS1) in preference to COX-2 for immediate PGE2 biosynthesis. Recent work reveals that PTGES3 can function as an HSP90-independent transcription factor for COX-2 (PTGS2) in lung adenocarcinoma, driven by succinate-dependent lysine succinylation (K7, K33, K79) that promotes nuclear translocation; nuclear p23 was detected in >90% of tumor tissues versus ~5% of adjacent normal tissues (DOI:10.1126/sciadv.ade0387). PTGES3 can also interact with p53 independently of HSP90 and protect the aryl hydrocarbon receptor from degradation. Contains a CS domain (CHORD-containing proteins and SGT1 domain) in the N-terminal region mediating HSP90 binding and an unstructured acidic C-terminal tail important for its independent passive chaperoning activity preventing protein aggregation. In human prostate cancer models, p23 supports androgen-receptor protein abundance, ligand-binding capacity and promoter occupancy; some AR effects persist when p23 cannot bind HSP90. These functions are distinct from its prostaglandin-synthase activity and need not imply an obligatory p23-dependent import step.
Definition: Binding to non-native proteins and preventing their aggregation without requiring ATP hydrolysis by the holdase; this activity does not by itself establish productive refolding.
Justification: Purified p23 anti-aggregation assays distinguish autonomous holdase activity from its HSP90-binding co-chaperone role.
Supporting Evidence:
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0005634 nucleus | IBA GO_REF:0000033 | ACCEPT | Summary: IBA annotation of PTGES3 to nucleus (GO:0005634) is phylogenetically inferred. PTGES3/p23 is predominantly cytoplasmic/cytosolic, but has been shown to localize to the nucleus, particularly when translocating with HSP90-client complexes such as steroid hormone receptors (PMID:12077419). Reactome documents multiple nuclear events involving PTGES3 (e.g., R-HSA-5618080 HSP90:ATP:p23:FKBP52:SHR:SH translocates to the nucleus). The HDA annotation from PMID:21630459 also detected PTGES3 in sperm nuclei by mass spectrometry. Reason: Nuclear localization is well supported. PTGES3 translocates to the nucleus as part of HSP90-steroid receptor complexes and also localizes to genomic response elements in a hormone-dependent manner (PMID:12077419). Multiple Reactome pathways place PTGES3 in the nucleoplasm. The IBA annotation at the level of nucleus is appropriate. Supporting Evidence: PMID:12077419 the p23 molecular chaperone localizes in vivo to genomic response elements in a hormone-dependent manner |
| GO:0006457 protein folding | IBA GO_REF:0000033 | ACCEPT | Summary: IBA annotation for protein folding is phylogenetically supported. PTGES3/p23 is a core HSP90 co-chaperone that participates in the folding of steroid receptors and other HSP90 client proteins (PMID:10811660, PMID:10543959). It also has independent chaperone activity preventing aggregation of non-native proteins (PMID:10543959). Reason: Protein folding is a well-established core function of PTGES3. As an HSP90 co-chaperone, p23 stabilizes the ATP-bound conformation of HSP90 needed for client protein folding (PMID:10811660). It also has independent passive chaperoning activity preventing heat-induced protein aggregation (PMID:10811660). This annotation is also supported by the IDA from PMID:12853476. Supporting Evidence: PMID:10811660 the tail is necessary for optimum active chaperoning of the progesterone receptor, as well as the passive chaperoning activity of p23 in assays measuring inhibition of heat-induced protein aggregation PMID:10543959 p23 binds to Hsp90 in its ATP-bound state and, on its own, interacts specifically with non-native proteins PMID:22899854 p23 increases activity of the AR, and this appears to involve steps both in the cytoplasm (increasing ligand-binding capacity, possibly via direct interaction with AR) and the nucleus (enhancing AR occupancy at target promoters). |
| GO:0051087 protein-folding chaperone binding | IBA GO_REF:0000033 | MODIFY | Summary: Refine protein-folding chaperone binding to Hsp90 protein binding, supported by the cited PTGES3 experiments. Reason: HSP90 is the experimentally established chaperone partner; refine the general protein-folding chaperone binding term to the existing specific Hsp90 protein binding annotation. Propagation Review Root cause: NO FAILURE CORE Sources checked: PANTHER:PTN000532593 · PTN000532593 UNRESOLVED The broad inherited claim is biologically sound; refinement uses the better-resolved target function or complex. Original PAINT node provenance is retained; the complete ancestral topology and MSA were not independently reconstructed. Target self-support is not circularity. Proposed replacements: Hsp90 protein binding Supporting Evidence: PMID:10543959 p23 binds to Hsp90 in its ATP-bound state PMID:21183720 it is Hsp90's nucleotide-binding domain that triggers the formation of the Hsp90(2)p23(2) complex |
| GO:0051131 chaperone-mediated protein complex assembly | IBA GO_REF:0000033 | ACCEPT | Summary: IBA annotation for chaperone-mediated protein complex assembly is phylogenetically inferred. PTGES3/p23, as part of the HSP90 chaperone system, facilitates the assembly of multiprotein complexes including steroid receptor complexes (PMID:8114727, PMID:10811660) and telomerase holoenzyme (PMID:10197982). Reason: PTGES3 participates in HSP90-mediated assembly of steroid receptor complexes and telomerase holoenzyme. The IMP evidence from PMID:10811660 directly demonstrates this for the progesterone receptor complex. This is a core function of the HSP90 co-chaperone activity of PTGES3. Supporting Evidence: PMID:10811660 the tail is necessary for optimum active chaperoning of the progesterone receptor PMID:10197982 We have identified the molecular chaperones p23 and Hsp90 as proteins that bind to the catalytic subunit of telomerase. Blockade of this interaction inhibits assembly of active telomerase in vitro. |
| GO:0051879 Hsp90 protein binding | IBA GO_REF:0000033 | ACCEPT | Summary: IBA annotation for Hsp90 protein binding is phylogenetically inferred. PTGES3/p23 is among the best-characterized HSP90 co-chaperones, binding directly to the N-terminal domain of HSP90 in its ATP-bound state (PMID:10543959, PMID:21183720). Reason: Hsp90 protein binding is a core molecular function of PTGES3. The interaction is extensively documented by crystal structures, NMR, and biochemical studies (PMID:10811660, PMID:10543959, PMID:21183720). Multiple IPI annotations from independent groups confirm this. Supporting Evidence: PMID:21183720 it is Hsp90's nucleotide-binding domain that triggers the formation of the Hsp90(2)p23(2) complex PMID:10543959 p23 binds to Hsp90 in its ATP-bound state |
| GO:0001516 prostaglandin biosynthetic process | IBA GO_REF:0000033 | ACCEPT | Summary: IBA annotation for prostaglandin biosynthetic process is phylogenetically inferred. PTGES3/p23 was identified as cytosolic prostaglandin E2 synthase (cPGES) that catalyzes conversion of PGH2 to PGE2, functionally coupled with COX-1 (PMID:10922363). Reason: Prostaglandin biosynthesis is a core function of PTGES3. The protein was molecularly identified as cPGES with demonstrated PGE synthase enzymatic activity (Km=14 uM for PGH2, Vmax=190 nmol/min/mg) (PMID:10922363). This is also supported by IDA evidence. Supporting Evidence: PMID:10922363 Recombinant p23 expressed in Escherichia coli and 293 cells exhibited all the features of PGES activity detected in rat brain cytosol |
| GO:0005829 cytosol | IBA GO_REF:0000033 | ACCEPT | Summary: IBA annotation for cytosol is phylogenetically inferred. PTGES3/p23 was originally identified as a cytosolic component of progesterone receptor complexes (PMID:8114727) and was later identified as a cytosolic PGE synthase (PMID:10922363). UniProt annotates it to cytoplasm. Reason: Cytosolic localization is one of the primary sites for PTGES3 function, both for its co-chaperone role in steroid receptor maturation and for its prostaglandin synthase activity. This is well established and concordant with the IBA inference. Supporting Evidence: PMID:10922363 Here we report the molecular identification of cytosolic glutathione (GSH)-dependent prostaglandin (PG) E(2) synthase (cPGES) |
| GO:0050220 prostaglandin-E synthase activity | IBA GO_REF:0000033 | ACCEPT | Summary: IBA annotation for prostaglandin-E synthase activity is phylogenetically inferred. This enzymatic activity was directly demonstrated by Tanioka et al. (PMID:10922363) who identified p23 as cytosolic PGES. This is a core molecular function. Reason: Prostaglandin-E synthase activity is a core molecular function of PTGES3, demonstrated by direct enzymatic assay with purified recombinant protein (PMID:10922363). The IBA annotation is concordant with multiple IDA and EXP annotations. Supporting Evidence: PMID:10922363 Recombinant p23 expressed in Escherichia coli and 293 cells exhibited all the features of PGES activity detected in rat brain cytosol |
| GO:0007004 telomere maintenance via telomerase | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: IBA annotation for telomere maintenance via telomerase is phylogenetically inferred. PTGES3/p23 and HSP90 were shown to be required for assembly and activity of telomerase (PMID:10197982). Inhibition of p23-HSP90 interaction blocks telomerase assembly. Reason: PTGES3 participates in telomere maintenance via telomerase through its role in assembling and stabilizing the telomerase holoenzyme complex with HSP90 (PMID:10197982, PMID:12135483). This is an established client-specific consequence of the p23/HSP90 co-chaperone role, not a core PTGES3 function. Supporting Evidence: PMID:10197982 We have identified the molecular chaperones p23 and Hsp90 as proteins that bind to the catalytic subunit of telomerase. Blockade of this interaction inhibits assembly of active telomerase in vitro. |
| GO:1905323 telomerase holoenzyme complex assembly | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: IBA annotation for telomerase holoenzyme complex assembly. PTGES3/p23 together with HSP90 is required for in vitro assembly of active telomerase from its components (PMID:10197982). The IDA from PMID:10197982 directly supports this. Reason: Telomerase holoenzyme complex assembly is a well-documented function of PTGES3 in concert with HSP90. Holt et al. (PMID:10197982) showed that p23 and HSP90 bind hTERT and are required for assembly of active telomerase. This should be kept as a non-core HSP90-client assembly consequence rather than elevated to a core function. Supporting Evidence: PMID:10197982 assembly of active telomerase from in vitro-synthesized components requires the contribution of proteins present in reticulocyte extracts. We have identified the molecular chaperones p23 and Hsp90 as proteins that bind to the catalytic subunit of telomerase. |
| GO:0001516 prostaglandin biosynthetic process | IEA GO_REF:0000120 | ACCEPT | Summary: IEA annotation for prostaglandin biosynthetic process from combined automated methods. This is consistent with the core prostaglandin synthase function of PTGES3 (PMID:10922363). Reason: This IEA annotation is consistent with the well-established prostaglandin E synthase activity of PTGES3 and is concordant with the IBA and IDA annotations for the same term. |
| GO:0005737 cytoplasm | IEA GO_REF:0000044 | MODIFY | Summary: Refine cytoplasm to cytosol, supported by the cited PTGES3 experiments. Reason: The separately supported cytosol is the more precise location for the cytoplasmic pool; nuclear localization is retained independently. Proposed replacements: cytosol |
| GO:0006629 lipid metabolic process | IEA GO_REF:0000043 | MODIFY | Summary: Refine lipid metabolic process to prostaglandin biosynthetic process, supported by the cited PTGES3 experiments. Reason: The directly supported PGH2-to-PGE2 isomerization participates in prostaglandin biosynthesis. Refine this broader lipid/prostanoid metabolic or biosynthetic term to the specific existing process rather than describing the ancestor as biologically false. Proposed replacements: prostaglandin biosynthetic process |
| GO:0006631 fatty acid metabolic process | IEA GO_REF:0000043 | MODIFY | Summary: Refine fatty acid metabolic process to prostaglandin biosynthetic process, supported by the cited PTGES3 experiments. Reason: The directly supported PGH2-to-PGE2 isomerization participates in prostaglandin biosynthesis. Refine this broader lipid/prostanoid metabolic or biosynthetic term to the specific existing process rather than describing the ancestor as biologically false. Proposed replacements: prostaglandin biosynthetic process |
| GO:0006633 fatty acid biosynthetic process | IEA GO_REF:0000043 | MODIFY | Summary: Refine fatty acid biosynthetic process to prostaglandin biosynthetic process, supported by the cited PTGES3 experiments. Reason: The directly supported PGH2-to-PGE2 isomerization participates in prostaglandin biosynthesis. Refine this broader lipid/prostanoid metabolic or biosynthetic term to the specific existing process rather than describing the ancestor as biologically false. Proposed replacements: prostaglandin biosynthetic process |
| GO:0006693 prostaglandin metabolic process | IEA GO_REF:0000043 | MODIFY | Summary: Refine prostaglandin metabolic process to prostaglandin biosynthetic process, supported by the cited PTGES3 experiments. Reason: The directly supported PGH2-to-PGE2 isomerization participates in prostaglandin biosynthesis. Refine this broader lipid/prostanoid metabolic or biosynthetic term to the specific existing process rather than describing the ancestor as biologically false. Proposed replacements: prostaglandin biosynthetic process |
| GO:0016853 isomerase activity | IEA GO_REF:0000043 | MODIFY | Summary: Refine isomerase activity to prostaglandin-E synthase activity, supported by the cited PTGES3 experiments. Reason: Refine general isomerase activity to the experimentally supported prostaglandin-E synthase activity already represented by IDA/EXP annotations. Proposed replacements: prostaglandin-E synthase activity |
| GO:0050220 prostaglandin-E synthase activity | IEA GO_REF:0000120 | ACCEPT | Summary: IEA annotation for prostaglandin-E synthase activity from combined automated methods. This is concordant with the experimentally demonstrated enzymatic activity (PMID:10922363). Reason: This IEA annotation is concordant with the directly demonstrated prostaglandin-E synthase activity of PTGES3 (PMID:10922363), which is also captured by IDA and EXP annotations. |
| GO:0051879 Hsp90 protein binding | IEA GO_REF:0000002 | ACCEPT | Summary: IEA annotation for Hsp90 protein binding from InterPro mapping. PTGES3 contains a CS domain (InterPro IPR007052) that mediates HSP90 binding. Reason: Hsp90 protein binding is a core function of PTGES3 well documented by multiple experimental studies (PMID:10543959, PMID:10811660, PMID:21183720). The IEA annotation from InterPro is concordant with IBA and IPI annotations. |
| GO:0005515 protein binding | IPI PMID:17353931 Large-scale mapping of human protein-protein interactions by... | REMOVE | Summary: IPI annotation for protein binding from large-scale mass spectrometry mapping of human protein-protein interactions. This is a high-throughput study without specific binding partner information in the GO annotation. Reason: Remove the uninformative generic protein-binding term under the protein-binding policy. This does not deny the reported interaction or mark the experimental evidence as false; no more specific molecular function is inferred from association alone. |
| GO:0005515 protein binding | IPI PMID:19875381 A proteomic investigation of ligand-dependent HSP90 complexe... | REMOVE | Summary: IPI annotation for protein binding from a proteomic study of ligand-dependent HSP90 complexes (PMID:19875381). PTGES3 was identified as a component of HSP90 complexes in this study. Reason: Remove the uninformative generic protein-binding term under the protein-binding policy. This does not deny the reported interaction or mark the experimental evidence as false; no more specific molecular function is inferred from association alone. |
| GO:0005515 protein binding | IPI PMID:21183720 N-terminal domain of human Hsp90 triggers binding to the coc... | MODIFY | Summary: Refine protein binding to Hsp90 protein binding, supported by the cited PTGES3 experiments. Reason: The cited primary experiment establishes p23-HSP90 binding, permitting refinement of generic protein binding to the specific Hsp90 protein-binding activity already present in this review. Proposed replacements: Hsp90 protein binding Supporting Evidence: PMID:21183720 it is Hsp90's nucleotide-binding domain that triggers the formation of the Hsp90(2)p23(2) complex |
| GO:0005515 protein binding | IPI PMID:21988832 Toward an understanding of the protein interaction network o... | REMOVE | Summary: IPI annotation for protein binding from a large-scale study of human liver protein interaction network. Reason: Remove the uninformative generic protein-binding term under the protein-binding policy. This does not deny the reported interaction or mark the experimental evidence as false; no more specific molecular function is inferred from association alone. |
| GO:0005515 protein binding | IPI PMID:23741051 Hsp90 cochaperones p23 and FKBP4 physically interact with hA... | REMOVE | Summary: IPI annotation for protein binding from Pare et al. (PMID:23741051), which showed that p23 and FKBP4 physically interact with hAgo2 and activate RNA interference. The specific interaction with hAgo2 in the context of the HSP90 chaperone cycle is noteworthy. Reason: Remove the uninformative generic protein-binding term under the protein-binding policy. This does not deny the reported interaction or mark the experimental evidence as false; no more specific molecular function is inferred from association alone. Supporting Evidence: PMID:23741051 Two of these cochaperones (FKBP4 and p23) form stable complexes with Hsp90 and hAgo2, and our data suggest that this interaction occurs before binding small RNAs |
| GO:0005515 protein binding | IPI PMID:24981860 Human-chromatin-related protein interactions identify a deme... | REMOVE | Summary: IPI annotation for protein binding from a study of human chromatin-related protein interactions. Reason: Remove the uninformative generic protein-binding term under the protein-binding policy. This does not deny the reported interaction or mark the experimental evidence as false; no more specific molecular function is inferred from association alone. |
| GO:0005515 protein binding | IPI PMID:25036637 A quantitative chaperone interaction network reveals the arc... | REMOVE | Summary: IPI annotation for protein binding from a quantitative chaperone interaction network study. This study mapped chaperone-client relationships. Reason: Remove the uninformative generic protein-binding term under the protein-binding policy. This does not deny the reported interaction or mark the experimental evidence as false; no more specific molecular function is inferred from association alone. |
| GO:0005515 protein binding | IPI PMID:33961781 Dual proteome-scale networks reveal cell-specific remodeling... | REMOVE | Summary: IPI annotation for protein binding from a dual proteome-scale network study of the human interactome. Reason: Remove the uninformative generic protein-binding term under the protein-binding policy. This does not deny the reported interaction or mark the experimental evidence as false; no more specific molecular function is inferred from association alone. |
| GO:0005515 protein binding | IPI PMID:35271311 OpenCell: Endogenous tagging for the cartography of human ce... | REMOVE | Summary: IPI annotation for protein binding from the OpenCell endogenous tagging study. Reason: Remove the uninformative generic protein-binding term under the protein-binding policy. This does not deny the reported interaction or mark the experimental evidence as false; no more specific molecular function is inferred from association alone. |
| GO:0005515 protein binding | IPI PMID:35914814 Chr21 protein-protein interactions: enrichment in proteins i... | REMOVE | Summary: IPI annotation for protein binding from a study of Chr21 protein-protein interactions related to intellectual disability and Alzheimer's disease. Reason: Remove the uninformative generic protein-binding term under the protein-binding policy. This does not deny the reported interaction or mark the experimental evidence as false; no more specific molecular function is inferred from association alone. |
| GO:0005515 protein binding | IPI PMID:9817749 In vivo function of Hsp90 is dependent on ATP binding and AT... | MODIFY | Summary: Refine protein binding to Hsp90 protein binding, supported by the cited PTGES3 experiments. Reason: The cited primary experiment establishes p23-HSP90 binding, permitting refinement of generic protein binding to the specific Hsp90 protein-binding activity already present in this review. Proposed replacements: Hsp90 protein binding Supporting Evidence: PMID:9817749 The mutant Hsp90 proteins tested are defective in the binding and ATP hydrolysis-dependent cycling of the co-chaperone p23 |
| GO:0046457 prostanoid biosynthetic process | TAS Reactome:R-HSA-2162123 | MODIFY | Summary: Refine prostanoid biosynthetic process to prostaglandin biosynthetic process, supported by the cited PTGES3 experiments. Reason: The directly supported PGH2-to-PGE2 isomerization participates in prostaglandin biosynthesis. Refine this broader lipid/prostanoid metabolic or biosynthetic term to the specific existing process rather than describing the ancestor as biologically false. Proposed replacements: prostaglandin biosynthetic process |
| GO:0050220 prostaglandin-E synthase activity | EXP PMID:10922363 Molecular identification of cytosolic prostaglandin E2 synth... | ACCEPT | Summary: EXP annotation for prostaglandin-E synthase activity based on the landmark paper by Tanioka et al. (PMID:10922363) that molecularly identified p23 as cytosolic PGES. Recombinant p23 demonstrated all features of PGES activity with Km=14 uM and Vmax=190 nmol/min/mg. Reason: This is a core enzymatic function of PTGES3 demonstrated by direct biochemical assay with purified recombinant protein (PMID:10922363). The enzyme was shown to catalyze GSH-dependent isomerization of PGH2 to PGE2 and to be functionally coupled with COX-1. Supporting Evidence: PMID:10922363 Recombinant p23 expressed in Escherichia coli and 293 cells exhibited all the features of PGES activity detected in rat brain cytosol |
| GO:0032212 positive regulation of telomere maintenance via telomerase | IDA PMID:19740745 A truncated form of p23 down-regulates telomerase activity v... | KEEP AS NON CORE | Summary: IDA annotation for positive regulation of telomere maintenance via telomerase based on Woo et al. (PMID:19740745). This study showed that overexpression of truncated p23 (Delta p23) down-regulated telomerase activity and decreased hTERT levels, implying that full-length p23 positively regulates telomerase maintenance. Reason: The study demonstrates that PTGES3 positively regulates telomerase activity through its HSP90 co-chaperone function. Truncation of p23 disrupts HSP90 function, leading to reduced telomerase activity, decreased hTERT stability, and inhibited cell growth (PMID:19740745). This is a non-core client-specific effect of the p23/HSP90 system. Supporting Evidence: PMID:19740745 overexpression of Delta p23 resulted in a decrease in hTERT levels, and a down-regulation in telomerase activity |
| GO:0007004 telomere maintenance via telomerase | IDA PMID:10197982 Functional requirement of p23 and Hsp90 in telomerase comple... | KEEP AS NON CORE | Summary: IDA annotation for telomere maintenance via telomerase from the seminal Holt et al. study (PMID:10197982) that demonstrated p23 and HSP90 are required for telomerase assembly and that a significant fraction of cellular telomerase is associated with p23 and HSP90. Reason: This is well-supported experimental evidence. Holt et al. showed that p23 and HSP90 bind hTERT, that blockade of their interaction inhibits telomerase assembly, and that active telomerase in cell extracts is associated with p23 and HSP90 (PMID:10197982). This represents a non-core HSP90-client consequence of PTGES3/p23. Supporting Evidence: PMID:10197982 a significant fraction of active telomerase from cell extracts is associated with p23 and Hsp90. Consistent with in vitro results, inhibition of Hsp90 function in cells blocks assembly of active telomerase. |
| GO:0070182 DNA polymerase binding | IPI PMID:10197982 Functional requirement of p23 and Hsp90 in telomerase comple... | KEEP AS NON CORE | Summary: IPI annotation for DNA polymerase binding based on PMID:10197982 (Holt et al., 1999). The study showed that p23 binds to hTERT, the reverse transcriptase catalytic subunit of telomerase. hTERT is a specialized reverse transcriptase (RNA-dependent DNA polymerase). The annotation captures p23's direct binding to this polymerase. Reason: PTGES3/p23 directly binds hTERT, the telomerase reverse transcriptase, which is a specialized DNA polymerase. This was demonstrated by co-immunoprecipitation in PMID:10197982. While hTERT is specifically a reverse transcriptase, the GO:0070182 (DNA polymerase binding) captures the binding to this enzyme class. The annotation is technically supported but non-core and should not be represented as a separate PTGES3 core function. Supporting Evidence: PMID:10197982 We have identified the molecular chaperones p23 and Hsp90 as proteins that bind to the catalytic subunit of telomerase |
| GO:1905323 telomerase holoenzyme complex assembly | IDA PMID:10197982 Functional requirement of p23 and Hsp90 in telomerase comple... | KEEP AS NON CORE | Summary: IDA annotation for telomerase holoenzyme complex assembly based on Holt et al. (PMID:10197982). The study demonstrated that p23 and HSP90 are required for in vitro assembly of active telomerase from purified components. Reason: This is directly demonstrated experimental evidence. Assembly of active telomerase from in vitro-synthesized components required p23 and HSP90 present in reticulocyte extracts. Blockade of the p23-HSP90 interaction inhibited telomerase assembly (PMID:10197982). Keep as a non-core client-specific outcome of the HSP90 co-chaperone function. Supporting Evidence: PMID:10197982 assembly of active telomerase from in vitro-synthesized components requires the contribution of proteins present in reticulocyte extracts. We have identified the molecular chaperones p23 and Hsp90 |
| GO:0101031 protein folding chaperone complex | IDA PMID:29127155 Tumor suppressor Tsc1 is a new Hsp90 co-chaperone that facil... | ACCEPT | Summary: IDA annotation for protein folding chaperone complex based on Woodford et al. (PMID:29127155). This study identified PTGES3 as part of a complex containing HSP90, HSP70, STIP1, CDC37, PPP5C, TSC1, and TSC2. The complex facilitates folding of kinase and non-kinase clients. Reason: PTGES3 is an established component of the HSP90 chaperone complex. The study (PMID:29127155) identified PTGES3 in a multi-protein chaperone complex with HSP90 and other co-chaperones. This is consistent with the well-known role of PTGES3 as an HSP90 co-chaperone. Supporting Evidence: PMID:29127155 Here, we show that Tsc1 is a new co-chaperone for Hsp90 that inhibits its ATPase activity |
| GO:0000781 chromosome, telomeric region | IC PMID:12135483 Differential regulation of telomerase activity by six telome... | KEEP AS NON CORE | Summary: IC annotation for chromosome, telomeric region based on Chang et al. (PMID:12135483), inferred from the role of p23 as a telomerase subunit. Since PTGES3 is part of the telomerase holoenzyme and telomerase acts at telomeres, localization to the telomeric region is a reasonable inference. Reason: This is an inferred localization based on PTGES3's role as a component of the telomerase holoenzyme complex (PMID:12135483, PMID:10197982). While the inference is reasonable, the primary localization sites of PTGES3 are the cytosol and nucleoplasm. Telomeric localization is secondary to its main co-chaperone and enzymatic functions. Supporting Evidence: PMID:12135483 Six subunits composing the telomerase complex have been cloned: hTR (human telomerase RNA), TEP1 (telomerase-associated protein 1), hTERT (human telomerase reverse transcriptase), hsp90 (heat shock protein 90), p23, and dyskerin |
| GO:0032991 protein-containing complex | IMP PMID:10543959 An unstructured C-terminal region of the Hsp90 co-chaperone ... | MODIFY | Summary: Refine protein-containing complex to protein folding chaperone complex and telomerase holoenzyme complex, supported by the cited PTGES3 experiments. Reason: Refine the general protein-containing complex annotation to the documented protein folding chaperone complex; p23 also has separately annotated telomerase-complex association. Proposed replacements: protein folding chaperone complex telomerase holoenzyme complex |
| GO:0032991 protein-containing complex | IMP PMID:10811660 Crystal structure and activity of human p23, a heat shock pr... | MODIFY | Summary: Refine protein-containing complex to protein folding chaperone complex and telomerase holoenzyme complex, supported by the cited PTGES3 experiments. Reason: Refine the general protein-containing complex annotation to the documented protein folding chaperone complex; p23 also has separately annotated telomerase-complex association. Proposed replacements: protein folding chaperone complex telomerase holoenzyme complex |
| GO:0050821 protein stabilization | IMP PMID:10543959 An unstructured C-terminal region of the Hsp90 co-chaperone ... | ACCEPT | Summary: IMP annotation for protein stabilization from Weikl et al. (PMID:10543959). p23 was shown to prevent non-specific aggregation of non-native proteins, acting as a holdase-type chaperone that stabilizes protein substrates. Reason: PTGES3 contributes to protein stabilization through two mechanisms: (1) as an HSP90 co-chaperone it stabilizes the HSP90-client complex in the mature conformation, and (2) independently it prevents aggregation of non-native proteins (PMID:10543959). This is a core aspect of its chaperone function. Supporting Evidence: PMID:10543959 truncation of the C-terminal 30 amino acid residues of p23 affects the ability of p23 to bind non-native proteins and to prevent their non-specific aggregation PMID:22899854 p23 increases activity of the AR, and this appears to involve steps both in the cytoplasm (increasing ligand-binding capacity, possibly via direct interaction with AR) and the nucleus (enhancing AR occupancy at target promoters). PMID:41193657 PTGES3 binds directly to AR, regulates AR protein stability and is necessary for AR function in the nucleus at AR target genes. |
| GO:0050821 protein stabilization | IMP PMID:10811660 Crystal structure and activity of human p23, a heat shock pr... | ACCEPT | Summary: IMP annotation for protein stabilization from Weaver et al. (PMID:10811660), which showed that the C-terminal tail of p23 is required for passive chaperoning activity in assays measuring inhibition of heat-induced protein aggregation. Reason: Independent evidence from PMID:10811660 confirming the protein stabilization function of PTGES3. The C-terminal tail is needed for both active chaperoning of progesterone receptor and passive chaperoning preventing protein aggregation. Supporting Evidence: PMID:10811660 the tail is necessary for optimum active chaperoning of the progesterone receptor, as well as the passive chaperoning activity of p23 in assays measuring inhibition of heat-induced protein aggregation PMID:22899854 p23 increases activity of the AR, and this appears to involve steps both in the cytoplasm (increasing ligand-binding capacity, possibly via direct interaction with AR) and the nucleus (enhancing AR occupancy at target promoters). PMID:41193657 PTGES3 binds directly to AR, regulates AR protein stability and is necessary for AR function in the nucleus at AR target genes. |
| GO:0051131 chaperone-mediated protein complex assembly | IMP PMID:10811660 Crystal structure and activity of human p23, a heat shock pr... | ACCEPT | Summary: IMP annotation for chaperone-mediated protein complex assembly from Weaver et al. (PMID:10811660). The study showed that p23 participates in the active chaperoning of the progesterone receptor, with the C-terminal tail required for optimum activity. Reason: PTGES3 participates in HSP90-mediated assembly of steroid receptor complexes. Weaver et al. demonstrated that p23's C-terminal tail is necessary for optimum active chaperoning of the progesterone receptor complex (PMID:10811660). This is a core function of PTGES3. Supporting Evidence: PMID:10811660 the tail is necessary for optimum active chaperoning of the progesterone receptor |
| GO:0051879 Hsp90 protein binding | IPI PMID:10543959 An unstructured C-terminal region of the Hsp90 co-chaperone ... | ACCEPT | Summary: IPI annotation for Hsp90 protein binding from Weikl et al. (PMID:10543959), which demonstrated that p23 binds HSP90 in its ATP-bound state and that the HSP90 binding site is contained in the folded N-terminal domain of p23. Reason: This is direct experimental evidence for a core molecular function of PTGES3. The study clearly demonstrated ATP-dependent binding of p23 to HSP90 and mapped the binding determinants (PMID:10543959). Supporting Evidence: PMID:10543959 p23 binds to Hsp90 in its ATP-bound state PMID:10543959 the binding site for Hsp90 is contained in the folded domain of p23 |
| GO:0051879 Hsp90 protein binding | IPI PMID:10811660 Crystal structure and activity of human p23, a heat shock pr... | ACCEPT | Summary: IPI annotation for Hsp90 protein binding from Weaver et al. (PMID:10811660), which determined the crystal structure of p23 and confirmed its binding to HSP90. The C-terminal tail is not needed for HSP90 binding. Reason: Independent structural and biochemical evidence confirming Hsp90 protein binding as a core function of PTGES3. The crystal structure identified a conserved surface region on p23 for HSP90 interaction (PMID:10811660). Supporting Evidence: PMID:10811660 Conserved residues are clustered on one face of the monomer and define a putative surface region and binding pocket for interaction(s) with hsp90 or protein substrates PMID:10811660 This tail is not needed for the binding of p23 to hsp90 or to complexes with the progesterone receptor |
| GO:0070182 DNA polymerase binding | IPI PMID:19751963 Curcumin inhibits nuclear localization of telomerase by diss... | KEEP AS NON CORE | Summary: IPI annotation for DNA polymerase binding from Lee & Chung (PMID:19751963), which demonstrated that p23 binds hTERT (telomerase reverse transcriptase) and that curcumin treatment dissociates p23 from hTERT. Reason: PTGES3/p23 directly binds hTERT, the reverse transcriptase subunit of telomerase. PMID:19751963 showed that curcumin treatment resulted in decreased association of p23 with hTERT. This is consistent with the earlier finding from PMID:10197982. hTERT is a DNA polymerase (reverse transcriptase), so the term is technically supported but should be kept non-core as a client-specific HSP90/p23 interaction. Supporting Evidence: PMID:19751963 curcumin treatment results in a substantial decrease in association of p23 and hTERT but does not affect the Hsp90 binding to hTERT |
| GO:0051879 Hsp90 protein binding | IPI PMID:19740745 A truncated form of p23 down-regulates telomerase activity v... | ACCEPT | Summary: IPI annotation for Hsp90 protein binding from Woo et al. (PMID:19740745). The study examined the effects of truncated p23 on HSP90 function and telomerase activity, demonstrating that the p23-HSP90 interaction is critical for telomerase regulation. Reason: Further experimental evidence for PTGES3 binding to HSP90, demonstrated in the context of telomerase regulation. The truncated form of p23 disrupts normal HSP90 function, confirming the functional importance of the p23-HSP90 interaction (PMID:19740745). Supporting Evidence: PMID:19740745 The Hsp90-associated protein p23 modulates Hsp90 activity during the final stages of the chaperone pathway to facilitate maturation of client proteins |
| GO:0005515 protein binding | IPI PMID:27353360 The FNIP co-chaperones decelerate the Hsp90 chaperone cycle ... | REMOVE | Summary: IPI annotation for protein binding from Woodford et al. (PMID:27353360), which demonstrated that PTGES3 interacts with HSP90AA1, FLCN, FNIP1, and FNIP2 in the context of the HSP90 chaperone cycle. Reason: Remove the uninformative generic protein-binding term under the protein-binding policy. This does not deny the reported interaction or mark the experimental evidence as false; no more specific molecular function is inferred from association alone. Supporting Evidence: PMID:27353360 tumour suppressor FLCN is an Hsp90 client protein and its binding partners FNIP1/FNIP2 function as co-chaperones |
| GO:0005634 nucleus | HDA PMID:21630459 Proteomic characterization of the human sperm nucleus. | ACCEPT | Summary: HDA annotation for nucleus from de Mateo et al. (PMID:21630459), a proteomic characterization of the human sperm nucleus that identified PTGES3 among 403 nuclear proteins by mass spectrometry. Reason: Nuclear localization of PTGES3 is supported by this high-throughput proteomics study (PMID:21630459) and is consistent with its known function in translocating to the nucleus as part of HSP90-steroid receptor complexes (PMID:12077419) and its role in transcriptional complex disassembly. |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-5082409 | ACCEPT | Summary: TAS annotation for nucleoplasm from Reactome pathway R-HSA-5082409 (Dissociation of HSF1:HSP90 complex in the nucleus). PTGES3 is part of the HSP90 complex that dissociates from HSF1 in the nucleus. Reason: PTGES3 is documented in multiple Reactome nuclear events as part of HSP90 chaperone complexes. This and the following nucleoplasm TAS annotations all reflect PTGES3's participation in HSP90-dependent processes in the nucleus. Accepting the first instance as representative. |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-5324617 | ACCEPT | Summary: TAS annotation for nucleoplasm from Reactome R-HSA-5324617 (HSP90:FKBP4:PTGES3 binds HSF1 trimer). Reason: Duplicate nucleoplasm annotation from a different Reactome event. Consistent with PTGES3's nuclear function as part of HSP90 complexes. |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-5618080 | ACCEPT | Summary: TAS annotation for nucleoplasm from Reactome R-HSA-5618080 (HSP90:ATP:p23:FKBP52:SHR:SH translocates to the nucleus). Reason: Consistent nucleoplasm annotation reflecting PTGES3's role in nuclear translocation of steroid hormone receptor complexes. |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-5618093 | ACCEPT | Summary: TAS annotation for nucleoplasm from Reactome R-HSA-5618093 (ATP hydrolysis by HSP90). Reason: Consistent nucleoplasm annotation from Reactome pathway events. |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-8937169 | ACCEPT | Summary: TAS annotation for nucleoplasm from Reactome R-HSA-8937169 (AHR:TCDD:2xHSP90AB1:AIP:PTGES3 translocates from cytosol to nucleoplasm). PTGES3 is part of the aryl hydrocarbon receptor complex that translocates to the nucleus. Reason: Consistent nucleoplasm annotation. PTGES3 translocates to the nucleus as part of the AHR signaling complex. |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-8937191 | ACCEPT | Summary: TAS annotation for nucleoplasm from Reactome R-HSA-8937191 (AHR:TCDD:2xHSP90AB1:AIP:PTGES3 dissociates). Reason: Consistent nucleoplasm annotation from AHR signaling pathway. |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-8939203 | ACCEPT | Summary: TAS annotation for nucleoplasm from Reactome R-HSA-8939203 (HSP90-dependent ATP hydrolysis promotes release of ESR:ESTG from chaperone complex). Reason: Consistent nucleoplasm annotation from estrogen receptor signaling pathway. |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-8939204 | ACCEPT | Summary: TAS annotation for nucleoplasm from Reactome R-HSA-8939204 (ESTG binds ESR1:chaperone complex). Reason: Consistent nucleoplasm annotation from estrogen receptor signaling pathway. |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-9032751 | ACCEPT | Summary: TAS annotation for nucleoplasm from Reactome R-HSA-9032751 (Estrogen-independent phosphorylation of ESR1 S118 by MAPK1 and MAPK3). Reason: Consistent nucleoplasm annotation from ESR-mediated signaling pathway. |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-9038161 | ACCEPT | Summary: TAS annotation for nucleoplasm from Reactome R-HSA-9038161 (Progesterone stimulation promotes PGR:P4 binding to ESR1:ESTG). Reason: Consistent nucleoplasm annotation from estrogen-dependent gene expression pathway. |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-9709547 | ACCEPT | Summary: TAS annotation for nucleoplasm from Reactome R-HSA-9709547 (ESTG binds ESR2:chaperone complex). Reason: Consistent nucleoplasm annotation from ESR2 signaling pathway. |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-9716913 | ACCEPT | Summary: TAS annotation for nucleoplasm from Reactome R-HSA-9716913 (ESR1 binds ESR1 antagonists). Reason: Consistent nucleoplasm annotation from ESR1 signaling pathway. |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-9716947 | ACCEPT | Summary: TAS annotation for nucleoplasm from Reactome R-HSA-9716947 (ESR1 binds ESR1 agonists). Reason: Consistent nucleoplasm annotation from ESR1 signaling pathway. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-265295 | ACCEPT | Summary: TAS annotation for cytosol from Reactome R-HSA-265295 (Prostaglandin E synthase isomerizes PGH2 to PGE2). PTGES3 catalyzes PGE2 synthesis in the cytosol. Reason: Cytosolic localization of PTGES3 for its prostaglandin synthase activity is well established (PMID:10922363). Accepting as representative of the many cytosol TAS annotations from Reactome. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-3371586 | ACCEPT | Summary: TAS annotation for cytosol from Reactome R-HSA-3371586 (Dissociation of cytosolic HSF1:HSP90 complex). Reason: Consistent cytosol annotation from HSF1 activation pathway. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-5324632 | ACCEPT | Summary: TAS annotation for cytosol from Reactome R-HSA-5324632 (Dissociation of cytosolic HSF1:HSP90:HDAC6:PTGES3 upon sensing protein aggregates). Reason: Consistent cytosol annotation from heat stress response pathway. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-5618073 | ACCEPT | Summary: TAS annotation for cytosol from Reactome R-HSA-5618073 (FKBP4 replaces FKBP5 within HSP90:ATP:FKBP5:unfolded protein). Reason: Consistent cytosol annotation from HSP90 chaperone cycle for steroid receptors. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-5618080 | ACCEPT | Summary: TAS annotation for cytosol from Reactome R-HSA-5618080 (HSP90:ATP:p23:FKBP52:SHR:SH translocates to the nucleus). Reason: Consistent cytosol annotation. PTGES3 starts in the cytosol before translocation to the nucleus with the steroid receptor complex. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-5618098 | ACCEPT | Summary: TAS annotation for cytosol from Reactome R-HSA-5618098 (p23 (PTGES3) binds HSP90:ATP:FKBP5:nascent protein). PTGES3 binds to the HSP90 complex in the cytosol. Reason: Consistent cytosol annotation. PTGES3 binds to HSP90 in the cytosol during steroid receptor maturation. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-5618099 | ACCEPT | Summary: TAS annotation for cytosol from Reactome R-HSA-5618099 (NR3C2 ligands bind NR3C2 in the HSP90 chaperone complex). Reason: Consistent cytosol annotation from mineralocorticoid receptor signaling. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-5618110 | ACCEPT | Summary: TAS annotation for cytosol from Reactome R-HSA-5618110 (p23 (PTGES3) binds HSP90:ATP:FKBP4:nascent protein). Reason: Consistent cytosol annotation from HSP90 chaperone cycle. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-8936849 | ACCEPT | Summary: TAS annotation for cytosol from Reactome R-HSA-8936849 (AHR:2xHSP90:AIP:PTGES3 binds TCDD). Reason: Consistent cytosol annotation. PTGES3 is part of the cytosolic AHR complex before ligand-induced nuclear translocation. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-8937169 | ACCEPT | Summary: TAS annotation for cytosol from Reactome R-HSA-8937169 (AHR:TCDD:2xHSP90AB1:AIP:PTGES3 translocates from cytosol to nucleoplasm). Reason: Consistent cytosol annotation for AHR complex translocation. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-9678925 | ACCEPT | Summary: TAS annotation for cytosol from Reactome R-HSA-9678925 (NR3C1 binds NR3C1 agonists). Reason: Consistent cytosol annotation from glucocorticoid receptor signaling. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-9690534 | ACCEPT | Summary: TAS annotation for cytosol from Reactome R-HSA-9690534 (NR3C1 ligands bind NR3C1 in the HSP90 chaperone complex). Reason: Consistent cytosol annotation from glucocorticoid receptor signaling. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-9705925 | ACCEPT | Summary: TAS annotation for cytosol from Reactome R-HSA-9705925 (Androgens bind AR in the HSP90 chaperone complex). Reason: Consistent cytosol annotation from androgen receptor signaling. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-9705926 | ACCEPT | Summary: TAS annotation for cytosol from Reactome R-HSA-9705926 (AR binds AR agonists). Reason: Consistent cytosol annotation from androgen receptor signaling. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-9706837 | ACCEPT | Summary: TAS annotation for cytosol from Reactome R-HSA-9706837 (AR binds AR antagonists). Reason: Consistent cytosol annotation from androgen receptor signaling. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-9725855 | ACCEPT | Summary: TAS annotation for cytosol from Reactome R-HSA-9725855 (NR3C2 binds NR3C2 antagonists). Reason: Consistent cytosol annotation from mineralocorticoid receptor signaling. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-9725885 | ACCEPT | Summary: TAS annotation for cytosol from Reactome R-HSA-9725885 (P4 binds PGR in the HSP90 chaperone complex). Reason: Consistent cytosol annotation from progesterone receptor signaling. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-9726509 | ACCEPT | Summary: TAS annotation for cytosol from Reactome R-HSA-9726509 (NR3C2 binds fludrocortisone). Reason: Consistent cytosol annotation from mineralocorticoid receptor signaling. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-9726580 | ACCEPT | Summary: TAS annotation for cytosol from Reactome R-HSA-9726580 (PGR binds PGR agonists). Reason: Consistent cytosol annotation from progesterone receptor signaling. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-9726621 | ACCEPT | Summary: TAS annotation for cytosol from Reactome R-HSA-9726621 (PGR binds PGR antagonists). Reason: Consistent cytosol annotation from progesterone receptor signaling. |
| GO:0006457 protein folding | IDA PMID:12853476 Cofactor Tpr2 combines two TPR domains and a J domain to reg... | ACCEPT | Summary: IDA annotation for protein folding from Brychzy et al. (PMID:12853476). This study examined the co-chaperone Tpr2 and its regulation of the Hsp70/Hsp90 chaperone system. PTGES3/p23 was part of the HSP90-dependent folding system studied. The paper examined glucocorticoid receptor folding in the context of the multi-chaperone machinery including p23. Reason: Protein folding is a core function of PTGES3 as an HSP90 co-chaperone. While this paper focuses on Tpr2, it demonstrates p23's involvement in HSP90-dependent protein folding of glucocorticoid receptor (PMID:12853476). This is consistent with multiple other lines of evidence. Supporting Evidence: PMID:12853476 Excess Tpr2 inhibits the Hsp90-dependent folding of GR in cell lysates PMID:22899854 p23 increases activity of the AR, and this appears to involve steps both in the cytoplasm (increasing ligand-binding capacity, possibly via direct interaction with AR) and the nucleus (enhancing AR occupancy at target promoters). |
| GO:0051082 unfolded protein binding | IDA PMID:12077419 Disassembly of transcriptional regulatory complexes by molec... | MODIFY | Summary: Represent independently demonstrated anti-aggregation activity with a proposed holdase function. Reason: PMID:10543959 and PMID:10811660 directly demonstrate binding to non-native proteins and suppression of aggregation. That positive activity is not negated by the different transcription-complex focus of PMID:12077419. Anti-aggregation alone does not establish autonomous productive folding, so use a proposed ATP-independent protein holdase activity rather than forcing the protein-folding chaperone term. Proposed replacements: ATP-independent protein holdase activity Supporting Evidence: PMID:12077419 the p23 molecular chaperone localizes in vivo to genomic response elements in a hormone-dependent manner, disrupting receptor-mediated transcriptional activation in vivo and in vitro; Hsp90 weakly displayed similar activities PMID:10543959 p23 binds to Hsp90 in its ATP-bound state and, on its own, interacts specifically with non-native proteins PMID:10543959 truncation of the C-terminal 30 amino acid residues of p23 affects the ability of p23 to bind non-native proteins and to prevent their non-specific aggregation PMID:10811660 the tail is necessary for optimum active chaperoning of the progesterone receptor, as well as the passive chaperoning activity of p23 in assays measuring inhibition of heat-induced protein aggregation |
| GO:0000723 telomere maintenance | TAS PMID:12135483 Differential regulation of telomerase activity by six telome... | MODIFY | Summary: Refine telomere maintenance to telomere maintenance via telomerase, supported by the cited PTGES3 experiments. Reason: The source and the existing specific annotation support telomerase-dependent telomere maintenance, a peripheral client system; refine the broader telomere-maintenance claim. Proposed replacements: telomere maintenance via telomerase Supporting Evidence: PMID:12135483 the other telomerase subunits (hTR, TEP1, hsp90, p23, dyskerin) participated in full enzyme activity |
| GO:0003720 telomerase activity | IDA PMID:12135483 Differential regulation of telomerase activity by six telome... | MODIFY | Summary: IDA annotation for telomerase activity from Chang et al. (PMID:12135483). The study identified p23 as one of six telomerase subunits and showed that antisense treatment against p23 abolished telomerase activity. However, PTGES3 does not itself have telomerase catalytic activity; hTERT is the catalytic reverse transcriptase subunit. PTGES3 is a non-catalytic component of the holoenzyme complex. Reason: GO:0003720 (telomerase activity) implies catalytic reverse transcriptase activity, which is performed by hTERT, not by PTGES3/p23. PTGES3 is a structural/regulatory component of the telomerase holoenzyme, required for its assembly and activity, but does not contribute the catalytic function itself. The role of PTGES3 is better described by the existing annotations to telomerase holoenzyme complex assembly (GO:1905323) and telomerase holoenzyme complex (GO:0005697). Annotating PTGES3 to telomerase activity is an over-attribution of catalytic function to a non-catalytic subunit. Proposed replacements: telomerase holoenzyme complex assembly telomerase holoenzyme complex Supporting Evidence: PMID:12135483 Telomerase activity was decreased or abolished by antisense treatment PMID:10197982 We have identified the molecular chaperones p23 and Hsp90 as proteins that bind to the catalytic subunit of telomerase |
| GO:0005697 telomerase holoenzyme complex | IDA PMID:12135483 Differential regulation of telomerase activity by six telome... | KEEP AS NON CORE | Summary: IDA annotation for telomerase holoenzyme complex from Chang et al. (PMID:12135483), which identified p23 as one of the six subunits of the telomerase complex. Earlier work (PMID:10197982) showed that a significant fraction of active telomerase is associated with p23 and HSP90. Reason: PTGES3/p23 is a confirmed component of the telomerase holoenzyme complex. Multiple studies demonstrate its presence in active telomerase complexes (PMID:10197982, PMID:12135483). This localization annotation appropriately captures PTGES3's role in the telomerase complex, but the role is client-specific and non-core. Supporting Evidence: PMID:12135483 Six subunits composing the telomerase complex have been cloned: hTR (human telomerase RNA), TEP1 (telomerase-associated protein 1), hTERT (human telomerase reverse transcriptase), hsp90 (heat shock protein 90), p23, and dyskerin PMID:10197982 a significant fraction of active telomerase from cell extracts is associated with p23 and Hsp90 |
| GO:0001516 prostaglandin biosynthetic process | IDA PMID:10922363 Molecular identification of cytosolic prostaglandin E2 synth... | ACCEPT | Summary: IDA annotation for prostaglandin biosynthetic process from the landmark study by Tanioka et al. (PMID:10922363) that identified p23 as cytosolic PGE2 synthase. The study demonstrated that recombinant p23 catalyzes GSH-dependent PGE2 synthesis and is functionally coupled with COX-1. Reason: This is direct experimental evidence for a core enzymatic function of PTGES3. The study demonstrated that p23 is the cytosolic PGES, with all features of PGES activity including GSH-dependence, COX-1 coupling, and kinetic parameters (PMID:10922363). Supporting Evidence: PMID:10922363 Recombinant p23 expressed in Escherichia coli and 293 cells exhibited all the features of PGES activity detected in rat brain cytosol PMID:10922363 cPGES/p23 was functionally linked with COX-1 in marked preference to COX-2 to produce PGE(2) from exogenous and endogenous arachidonic acid |
| GO:0050220 prostaglandin-E synthase activity | IDA PMID:10922363 Molecular identification of cytosolic prostaglandin E2 synth... | ACCEPT | Summary: IDA annotation for prostaglandin-E synthase activity from Tanioka et al. (PMID:10922363). Same landmark study demonstrating enzymatic activity of PTGES3 with Km=14 uM for PGH2 and Vmax=190 nmol/min/mg. Reason: Core enzymatic function directly demonstrated with purified recombinant protein. The catalytic parameters were determined and the enzyme was shown to be GSH-dependent and functionally coupled with COX-1 (PMID:10922363). Supporting Evidence: PMID:10922363 Here we report the molecular identification of cytosolic glutathione (GSH)-dependent prostaglandin (PG) E(2) synthase (cPGES) |
| GO:0007165 signal transduction | TAS PMID:8114727 Characterization of a novel 23-kilodalton protein of unactiv... | KEEP AS NON CORE | Summary: TAS annotation for signal transduction from Johnson et al. (PMID:8114727), the original characterization of p23 as a component of unactive progesterone receptor complexes. The annotation reflects PTGES3's role in steroid hormone signaling through its association with steroid receptor complexes. Reason: PTGES3 participates in signal transduction indirectly through its role as an HSP90 co-chaperone in steroid receptor maturation. However, signal transduction is very broad and PTGES3 is not a signaling molecule itself; it is a chaperone/enzyme. The annotation is not wrong but represents a downstream biological consequence rather than a core function. The specific chaperone functions (protein folding, chaperone-mediated protein complex assembly) better capture its role. Supporting Evidence: PMID:8114727 Immunoprecipitation of unactivated avian progesterone receptor results in the copurification of hsp90, hsp70, and three additional proteins, p54, p50, and p23 |
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