Existing Annotations Review

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
GO:0051087 protein-folding chaperone binding	IBA GO_REF:0000033	ACCEPT	Summary: IBA annotation of PTGES3 to protein-folding chaperone binding (GO:0051087) is phylogenetically inferred. PTGES3/p23 directly binds HSP90, a protein-folding chaperone, in an ATP-dependent manner (PMID:10543959, PMID:9817749). This interaction is one of the most well-characterized aspects of PTGES3 function. Reason: PTGES3 binding to HSP90 (a protein-folding chaperone) is extensively documented. The protein binds specifically to the ATP-bound state of HSP90 and stabilizes the closed conformation (PMID:10543959, PMID:21183720). This is a core function appropriately captured at this level of specificity by IBA. 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	ACCEPT	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 secondary function of PTGES3 and the IBA annotation is appropriate. 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	ACCEPT	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 is concordant with the IBA. 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	ACCEPT	Summary: IEA annotation for cytoplasm from UniProt subcellular location mapping. PTGES3 is annotated to cytoplasm in UniProt based on sequence similarity evidence. The protein is primarily cytosolic. Reason: Cytoplasmic localization is well established for PTGES3. While cytosol (GO:0005829) is more specific and also annotated, the broader cytoplasm term from an IEA pipeline is not incorrect. It is simply less specific than the IBA and TAS annotations to cytosol.
GO:0006629 lipid metabolic process	IEA GO_REF:0000043	ACCEPT	Summary: IEA annotation for lipid metabolic process from UniProt keyword mapping. PTGES3 catalyzes conversion of PGH2 to PGE2, which is a lipid metabolic process. Reason: This is a broad but not incorrect annotation. PTGES3 participates in prostaglandin biosynthesis, which is a form of lipid metabolism. The more specific annotations to prostaglandin biosynthetic process (GO:0001516) and fatty acid biosynthetic process (GO:0006633) provide better granularity, but this IEA annotation is acceptable as a parent term.
GO:0006631 fatty acid metabolic process	IEA GO_REF:0000043	ACCEPT	Summary: IEA annotation for fatty acid metabolic process from UniProt keyword mapping. Prostaglandins are derived from arachidonic acid, a fatty acid. PTGES3 catalyzes the terminal step converting PGH2 to PGE2. Reason: Prostaglandins are eicosanoids derived from arachidonic acid (a fatty acid), so this broad IEA mapping is not incorrect. The more specific prostaglandin biosynthetic process annotation provides better specificity.
GO:0006633 fatty acid biosynthetic process	IEA GO_REF:0000043	ACCEPT	Summary: IEA annotation for fatty acid biosynthetic process from UniProt keyword mapping. PTGES3 catalyzes the isomerization of PGH2 to PGE2 in the prostaglandin biosynthetic pathway, which is derived from arachidonic acid metabolism. Reason: This IEA mapping from UniProt keywords is broadly acceptable since prostaglandins are fatty acid derivatives. However, prostaglandin biosynthesis is more accurately described as eicosanoid/prostanoid biosynthesis than as fatty acid biosynthesis per se. This is a tolerable IEA-level annotation given the more specific annotations exist.
GO:0006693 prostaglandin metabolic process	IEA GO_REF:0000043	ACCEPT	Summary: IEA annotation for prostaglandin metabolic process from UniProt keyword mapping. PTGES3 is a prostaglandin E synthase that converts PGH2 to PGE2 (PMID:10922363). Reason: This is a correct but broader annotation than the more specific prostaglandin biosynthetic process (GO:0001516) that is also annotated. Acceptable for an IEA-level annotation.
GO:0016853 isomerase activity	IEA GO_REF:0000043	ACCEPT	Summary: IEA annotation for isomerase activity from UniProt keyword mapping. The UniProt EC number for PTGES3 is 5.3.99.3 (prostaglandin-E synthase), which is classified as an isomerase. The conversion of PGH2 to PGE2 is an isomerization reaction. Reason: PTGES3 catalyzes the isomerization of PGH2 to PGE2 (EC 5.3.99.3), making isomerase activity a correct broad annotation. The more specific prostaglandin-E synthase activity (GO:0050220) is also annotated. This IEA annotation is acceptable as a parent MF term.
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...	MARK AS OVER ANNOTATED	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: Protein binding (GO:0005515) is uninformative for PTGES3, which has well-characterized specific binding interactions (Hsp90 protein binding, GO:0051879). The high-throughput nature of the study (large-scale mapping by mass spectrometry) and the vague term make this annotation of limited value. The specific binding functions of PTGES3 are better captured by GO:0051879 and GO:0051087.
GO:0005515 protein binding	IPI PMID:19875381 A proteomic investigation of ligand-dependent HSP90 complexe...	MARK AS OVER ANNOTATED	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: While PTGES3 was correctly identified in HSP90 complexes in this study, the annotation to the generic protein binding term is uninformative. The interaction with HSP90 is already well captured by GO:0051879 (Hsp90 protein binding). The generic protein binding annotation adds no value.
GO:0005515 protein binding	IPI PMID:21183720 N-terminal domain of human Hsp90 triggers binding to the coc...	MARK AS OVER ANNOTATED	Summary: IPI annotation for protein binding from Karagoz et al. (PMID:21183720) which characterized the p23-HSP90 interaction by NMR. This study specifically showed that Hsp90's N-terminal domain triggers binding to p23. Reason: PMID:21183720 demonstrated specific binding of p23 to HSP90's N-terminal domain, which is better captured by GO:0051879 (Hsp90 protein binding) than the generic protein binding term. The generic annotation is redundant and uninformative. 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...	MARK AS OVER ANNOTATED	Summary: IPI annotation for protein binding from a large-scale study of human liver protein interaction network. Reason: Generic protein binding annotation from a high-throughput interaction study. The specific molecular function binding terms (GO:0051879 Hsp90 protein binding, GO:0051087 protein-folding chaperone binding) are far more informative.
GO:0005515 protein binding	IPI PMID:23741051 Hsp90 cochaperones p23 and FKBP4 physically interact with hA...	MARK AS OVER ANNOTATED	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: While PMID:23741051 demonstrates a biologically interesting interaction (p23 with hAgo2 in RISC loading), the generic protein binding annotation does not capture this specificity. The interaction with hAgo2 occurs as part of PTGES3's HSP90 co-chaperone function, which is already well annotated. 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...	MARK AS OVER ANNOTATED	Summary: IPI annotation for protein binding from a study of human chromatin-related protein interactions. Reason: Generic protein binding annotation from a high-throughput interaction study. Uninformative given the well-characterized specific binding functions of PTGES3.
GO:0005515 protein binding	IPI PMID:25036637 A quantitative chaperone interaction network reveals the arc...	MARK AS OVER ANNOTATED	Summary: IPI annotation for protein binding from a quantitative chaperone interaction network study. This study mapped chaperone-client relationships. Reason: While this study provides useful information about PTGES3 in the chaperone network, the generic protein binding annotation is uninformative. PTGES3's chaperone binding is better captured by GO:0051879 and GO:0051087.
GO:0005515 protein binding	IPI PMID:33961781 Dual proteome-scale networks reveal cell-specific remodeling...	MARK AS OVER ANNOTATED	Summary: IPI annotation for protein binding from a dual proteome-scale network study of the human interactome. Reason: Generic protein binding from a high-throughput interactome study. The specific binding functions of PTGES3 are better captured by more informative terms already annotated.
GO:0005515 protein binding	IPI PMID:35271311 OpenCell: Endogenous tagging for the cartography of human ce...	MARK AS OVER ANNOTATED	Summary: IPI annotation for protein binding from the OpenCell endogenous tagging study. Reason: Generic protein binding from a large-scale cellular organization study. Uninformative for PTGES3 which has well-characterized specific binding partners.
GO:0005515 protein binding	IPI PMID:35914814 Chr21 protein-protein interactions: enrichment in proteins i...	MARK AS OVER ANNOTATED	Summary: IPI annotation for protein binding from a study of Chr21 protein-protein interactions related to intellectual disability and Alzheimer's disease. Reason: Generic protein binding from a focused interaction study. Uninformative for PTGES3 given existing specific binding annotations.
GO:0005515 protein binding	IPI PMID:9817749 In vivo function of Hsp90 is dependent on ATP binding and AT...	MARK AS OVER ANNOTATED	Summary: IPI annotation for protein binding from Obermann et al. (PMID:9817749), which demonstrated that p23 binding to HSP90 is ATP-dependent and that mutant HSP90 proteins defective in ATP binding/hydrolysis are defective in p23 cycling. Reason: PMID:9817749 specifically demonstrates the ATP-dependent interaction between p23 and HSP90, which is better captured by GO:0051879 (Hsp90 protein binding). The generic protein binding annotation is redundant. 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	ACCEPT	Summary: TAS annotation for prostanoid biosynthetic process from Reactome pathway R-HSA-2162123 (Synthesis of Prostaglandins and Thromboxanes). PTGES3 catalyzes the conversion of PGH2 to PGE2 as part of this pathway. Reason: Prostanoid biosynthetic process is a correct and appropriate annotation for PTGES3. PGE2 is a prostanoid, and PTGES3 catalyzes the terminal step in its biosynthesis (PMID:10922363). This is concordant with the prostaglandin biosynthetic process annotation and represents the same core enzymatic function.
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...	ACCEPT	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 consistent with the broader literature on PTGES3's role in telomerase assembly. 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...	ACCEPT	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 core secondary function of PTGES3. 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...	ACCEPT	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 correct. 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...	ACCEPT	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). 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 ...	ACCEPT	Summary: IMP annotation for protein-containing complex from Weikl et al. (PMID:10543959), which demonstrated that p23 forms complexes with HSP90 and that the C-terminal truncation affects complex formation with non-native proteins but not with HSP90. Reason: PTGES3 is demonstrated to exist in multiple protein complexes including HSP90 chaperone complexes (PMID:10543959) and the telomerase holoenzyme. While the term protein-containing complex is very broad, the annotation is correct and reflects experimental evidence. The more specific protein folding chaperone complex (GO:0101031) annotation provides better granularity.
GO:0032991 protein-containing complex	IMP PMID:10811660 Crystal structure and activity of human p23, a heat shock pr...	ACCEPT	Summary: IMP annotation for protein-containing complex from Weaver et al. (PMID:10811660), which determined the crystal structure of p23 and showed it exists in complexes with HSP90 and progesterone receptor. Reason: PTGES3 is a well-established component of HSP90-containing multi-protein complexes. Weaver et al. showed that p23 binds to HSP90 and to progesterone receptor complexes (PMID:10811660). This duplicates the annotation from PMID:10543959 but with independent evidence.
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
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
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...	ACCEPT	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 GO term is appropriate. 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 ...	MARK AS OVER ANNOTATED	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: PMID:27353360 demonstrates specific interactions of PTGES3 with HSP90AA1, FLCN, FNIP1, and FNIP2. These are biologically meaningful interactions in the context of the HSP90 chaperone cycle, but the generic protein binding annotation is uninformative. The HSP90 interaction is already captured by GO:0051879. 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
GO:0051082 unfolded protein binding	IDA PMID:12077419 Disassembly of transcriptional regulatory complexes by molec...	MARK AS OVER ANNOTATED	Summary: GO:0051082 "unfolded protein binding" is annotated to PTGES3 based on PMID:12077419 (Freeman & Yamamoto, 2002), which demonstrated that p23 acts as a molecular chaperone that localizes to genomic response elements and promotes disassembly of transcriptional regulatory complexes. However, this paper does not directly demonstrate binding to unfolded proteins. The paper shows that p23 disrupts receptor-mediated transcriptional activation by promoting disassembly of multicomponent regulatory complexes, functioning as an HSP90 co-chaperone rather than independently binding unfolded substrates. Separate evidence from PMID:10543959 (Weikl et al., 1999) does demonstrate that p23 has independent chaperone activity, showing that it "interacts specifically with non-native proteins" and prevents "non-specific aggregation." PMID:10811660 (Weaver et al., 2000) also confirmed the "passive chaperoning activity of p23 in assays measuring inhibition of heat-induced protein aggregation." However, this holdase-type activity is secondary to p23's primary role as an HSP90 co-chaperone, and the cited reference PMID:12077419 does not support "unfolded protein binding" as such. Furthermore, GO:0051082 is being obsoleted (go-ontology issue 30962) in favor of more specific terms such as GO:0044183 "protein folding chaperone." Given that PTGES3 already has annotations for Hsp90 protein binding (GO:0051879), protein folding (GO:0006457), protein-folding chaperone binding (GO:0051087), and membership in a protein folding chaperone complex (GO:0101031), the core chaperone functions are well-captured by existing annotations. The independent holdase activity demonstrated in PMID:10543959 and PMID:10811660 could be better represented by GO:0044183 "protein folding chaperone" if needed, but the current annotation to GO:0051082 based on PMID:12077419 is a misattribution of the cited evidence. Reason: The GO:0051082 "unfolded protein binding" annotation should be marked as over-annotated for three reasons. First, the cited reference PMID:12077419 does not demonstrate unfolded protein binding; it shows p23 promotes disassembly of transcriptional regulatory complexes as part of the HSP90 chaperone system. Second, while p23 does have a modest independent holdase-type chaperone activity preventing aggregation of non-native proteins (demonstrated in PMID:10543959 and PMID:10811660), this is secondary to its primary role as an HSP90 co-chaperone and is not the activity described in the cited reference. Third, GO:0051082 is being obsoleted (go-ontology issue 30962) because it conflates binding with chaperone activity. The core chaperone functions of PTGES3 are already well-represented by existing annotations to GO:0051879 (Hsp90 protein binding), GO:0006457 (protein folding), GO:0051087 (protein-folding chaperone binding), and GO:0101031 (protein folding chaperone complex). If the independent holdase activity needs representation, GO:0044183 "protein folding chaperone" would be more appropriate than the soon-to-be-obsoleted GO:0051082. Proposed replacements: protein folding chaperone 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...	ACCEPT	Summary: TAS annotation for telomere maintenance from Chang et al. (PMID:12135483), which examined the role of six telomerase subunits (hTR, TEP1, hTERT, hsp90, p23, dyskerin) in telomerase regulation. The study confirmed that p23 participates in full enzyme activity even though hTERT is the rate-limiting subunit. Reason: Telomere maintenance is well supported for PTGES3. The study showed that antisense treatment against p23 decreased telomerase activity (PMID:12135483). This is broader than but consistent with the more specific annotation to telomere maintenance via telomerase (GO:0007004). 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...	ACCEPT	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. 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

Core Functions

PTGES3 (cPGES/p23) catalyzes the GSH-dependent isomerization of PGH2 to PGE2 in the cytosol. It is functionally coupled with COX-1 (not COX-2) for immediate prostaglandin E2 biosynthesis with Km=14 uM for PGH2 and Vmax=190 nmol/min/mg.

Molecular Function:

prostaglandin-E synthase activity

Directly Involved In:

prostaglandin biosynthetic process

Cellular Locations:

cytosol

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.

PTGES3/p23 binds to the N-terminal domain of HSP90 in its ATP-bound conformation, stabilizing the "closed 2" HSP90 dimer state and inhibiting/reducing HSP90 ATPase activity, thereby regulating progression of the HSP90 chaperone cycle and shaping client maturation/release (DOI:10.1038/nrm.2017.20, DOI:10.3389/fimmu.2024.1436973). This co-chaperone activity is essential for maturation of steroid hormone receptors, hTERT, and other HSP90 client proteins. The CS domain in the N-terminal region of p23 mediates HSP90 binding, while the unstructured acidic C-terminal tail is important for its independent passive chaperoning activity preventing protein aggregation. Beyond the cytosol, nuclear p23 can function as an HSP90-independent transcription factor for COX-2 (PTGS2) in lung adenocarcinoma, driven by succinate-induced succinylation at K7/K33/K79 (DOI:10.1126/sciadv.ade0387).

Molecular Function:

Hsp90 protein binding

Directly Involved In:

protein folding chaperone-mediated protein complex assembly protein stabilization

Cellular Locations:

cytosol nucleoplasm

In Complex:

protein folding chaperone complex

Supporting Evidence:

PMID:10543959
p23 binds to Hsp90 in its ATP-bound state and, on its own, interacts specifically with non-native proteins.
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:21183720
it is Hsp90's nucleotide-binding domain that triggers the formation of the Hsp90(2)p23(2) complex.

PTGES3/p23 directly binds hTERT, the telomerase reverse transcriptase catalytic subunit, as part of the HSP90-dependent telomerase holoenzyme assembly pathway. Together with HSP90, p23 is required for assembly of active telomerase from its components and a significant fraction of cellular telomerase is associated with p23 and HSP90.

Molecular Function:

DNA polymerase binding

Directly Involved In:

telomere maintenance via telomerase telomerase holoenzyme complex assembly

Cellular Locations:

nucleoplasm

In Complex:

telomerase holoenzyme complex

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.
PMID:10197982
a significant fraction of active telomerase from cell extracts is associated with p23 and Hsp90.
PMID:19751963
curcumin treatment results in a substantial decrease in association of p23 and hTERT but does not affect the Hsp90 binding to hTERT.

References

GO_REF:0000002

Gene Ontology annotation through association of InterPro records with GO terms

GO_REF:0000033

Annotation inferences using phylogenetic trees

GO_REF:0000043

Gene Ontology annotation based on UniProtKB/Swiss-Prot keyword mapping

GO_REF:0000044

Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular Location vocabulary mapping, accompanied by conservative changes to GO terms applied by UniProt

GO_REF:0000120

Combined Automated Annotation using Multiple IEA Methods

PMID:10197982

Functional requirement of p23 and Hsp90 in telomerase complexes.

PMID:10543959

An unstructured C-terminal region of the Hsp90 co-chaperone p23 is important for its chaperone function.

PMID:10811660

Crystal structure and activity of human p23, a heat shock protein 90 co-chaperone.

PMID:10922363

Molecular identification of cytosolic prostaglandin E2 synthase that is functionally coupled with cyclooxygenase-1 in immediate prostaglandin E2 biosynthesis.

PMID:12077419

Disassembly of transcriptional regulatory complexes by molecular chaperones.

PMID:12135483

Differential regulation of telomerase activity by six telomerase subunits.

PMID:12853476

Cofactor Tpr2 combines two TPR domains and a J domain to regulate the Hsp70/Hsp90 chaperone system.

PMID:17353931

Large-scale mapping of human protein-protein interactions by mass spectrometry.

PMID:19740745

A truncated form of p23 down-regulates telomerase activity via disruption of Hsp90 function.

PMID:19751963

Curcumin inhibits nuclear localization of telomerase by dissociating the Hsp90 co-chaperone p23 from hTERT.

PMID:19875381

A proteomic investigation of ligand-dependent HSP90 complexes reveals CHORDC1 as a novel ADP-dependent HSP90-interacting protein.

PMID:21183720

N-terminal domain of human Hsp90 triggers binding to the cochaperone p23.

PMID:21630459

Proteomic characterization of the human sperm nucleus.

PMID:21988832

Toward an understanding of the protein interaction network of the human liver.

PMID:23741051

Hsp90 cochaperones p23 and FKBP4 physically interact with hAgo2 and activate RNA interference-mediated silencing in mammalian cells.

PMID:24981860

Human-chromatin-related protein interactions identify a demethylase complex required for chromosome segregation.

PMID:25036637

A quantitative chaperone interaction network reveals the architecture of cellular protein homeostasis pathways.

PMID:27353360

The FNIP co-chaperones decelerate the Hsp90 chaperone cycle and enhance drug binding.

PMID:29127155

Tumor suppressor Tsc1 is a new Hsp90 co-chaperone that facilitates folding of kinase and non-kinase clients.

PMID:33961781

Dual proteome-scale networks reveal cell-specific remodeling of the human interactome.

PMID:35271311

OpenCell: Endogenous tagging for the cartography of human cellular organization.

PMID:35914814

Chr21 protein-protein interactions: enrichment in proteins involved in intellectual disability, autism, and late-onset Alzheimer's disease.

PMID:8114727

Characterization of a novel 23-kilodalton protein of unactive progesterone receptor complexes.

PMID:9817749

In vivo function of Hsp90 is dependent on ATP binding and ATP hydrolysis.

Reactome:R-HSA-2162123

Synthesis of Prostaglandins (PG) and Thromboxanes (TX)

Reactome:R-HSA-265295

Prostaglandin E synthase isomerizes PGH2 to PGE2

Reactome:R-HSA-3371586

Dissociation of cytosolic HSF1:HSP90 complex

Reactome:R-HSA-5082409

Dissociation of HSF1:HSP90 complex in the nucleus

Reactome:R-HSA-5324617

HSP90:FKBP4:PTGES3 binds HSF1 trimer

Reactome:R-HSA-5324632

Dissociation of cytosolic HSF1:HSP90:HDAC6:PTGES3 upon sensing protein aggregates

Reactome:R-HSA-5618073

FKBP4 replaces FKBP5 within HSP90:ATP:FKBP5:unfolded protein

Reactome:R-HSA-5618080

HSP90:ATP:p23:FKBP52:SHR:SH translocates to the nucleus

Reactome:R-HSA-5618093

ATP hydrolysis by HSP90

Reactome:R-HSA-5618098

p23 (PTGES3) binds HSP90:ATP:FKBP5:nascent protein

Reactome:R-HSA-5618099

NR3C2 ligands bind NR3C2 (in the HSP90 chaperone complex)

Reactome:R-HSA-5618110

p23 (PTGES3) binds HSP90:ATP:FKBP4:nascent protein

Reactome:R-HSA-8936849

AHR:2xHSP90:AIP:PTGES3 binds TCDD

Reactome:R-HSA-8937169

AHR:TCDD:2xHSP90AB1:AIP:PTGES3 translocates from cytosol to nucleoplasm

Reactome:R-HSA-8937191

AHR:TCDD:2xHSP90AB1:AIP:PTGES3 dissociates

Reactome:R-HSA-8939203

HSP90-dependent ATP hydrolysis promotes release of ESR:ESTG from chaperone complex

Reactome:R-HSA-8939204

ESTG binds ESR1:chaperone complex

Reactome:R-HSA-9032751

Estrogen-independent phosphorylation of ESR1 S118 by MAPK1 and MAPK3

Reactome:R-HSA-9038161

Progesterone stimulation promotes PGR:P4 binding to ESR1:ESTG

Reactome:R-HSA-9678925

NR3C1 binds NR3C1 agonists

Reactome:R-HSA-9690534

NR3C1 ligands bind NR3C1 (in the HSP90 chaperone complex)

Reactome:R-HSA-9705925

Androgens binds AR (in the HSP90 chaperone complex)

Reactome:R-HSA-9705926

AR binds AR agonists

Reactome:R-HSA-9706837

AR binds AR antagonists

Reactome:R-HSA-9709547

ESTG binds ESR2:chaperone complex

Reactome:R-HSA-9716913

ESR1 binds ESR1 antagonists

Reactome:R-HSA-9716947

ESR1 binds ESR1 agonists

Reactome:R-HSA-9725855

NR3C2 binds NR3C2 antagonists

Reactome:R-HSA-9725885

P4 bind PGR (in the HSP90 chaperone complex)

Reactome:R-HSA-9726509

NR3C2 binds fludrocortisone

Reactome:R-HSA-9726580

PGR binds PGR agonists

Reactome:R-HSA-9726621

PGR binds PGR antagonists

DOI:10.1038/nrm.2017.20

The HSP90 chaperone machinery.

p23/PTGES3 stabilizes the HSP90 closed 2 conformational state and inhibits/reduces HSP90 ATPase activity, functioning as a late-stage co-chaperone regulator of the HSP90 cycle

DOI:10.1126/sciadv.ade0387

The p23 co-chaperone is a succinate-activated COX-2 transcription factor in lung adenocarcinoma tumorigenesis.

Nuclear p23/PTGES3 functions as an HSP90-independent transcription factor for COX-2 (PTGS2), driven by succinate-dependent lysine succinylation at K7, K33, and K79 that promotes nuclear translocation
Nuclear p23 expression was detected in >90% of lung adenocarcinoma tumor tissues versus ~5% of adjacent normal tissues
Small-molecule inhibitor M16 inhibits p23 succinylation and nuclear translocation, suppressing tumor growth in a p23-dependent manner

DOI:10.3389/fimmu.2024.1436973

HSP90 multi-functionality in cancer.

2024 review reiterating PTGES3/p23 mechanistic role in slowing HSP90 ATPase cycle by stabilizing the closed ATP-committed conformation

📚 Additional Documentation

Deep Research Falcon

(PTGES3-deep-research-falcon.md)

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Question

Gene Research for Functional Annotation

⚠️ CRITICAL: Gene/Protein Identification Context

BEFORE YOU BEGIN RESEARCH: You MUST verify you are researching the CORRECT gene/protein. Gene symbols can be ambiguous, especially for less well-characterized genes from non-model organisms.

Target Gene/Protein Identity (from UniProt):

UniProt Accession: Q15185
Protein Description: RecName: Full=Prostaglandin E synthase 3; EC=5.3.99.3 {ECO:0000269|PubMed:10922363}; AltName: Full=Cytosolic prostaglandin E2 synthase; Short=cPGES; AltName: Full=Hsp90 co-chaperone; AltName: Full=Progesterone receptor complex p23; AltName: Full=Telomerase-binding protein p23;
Gene Information: Name=PTGES3; Synonyms=P23, TEBP;
Organism (full): Homo sapiens (Human).
Protein Family: Belongs to the p23/wos2 family. .
Key Domains: CS_dom. (IPR007052); HSP20-like_chaperone. (IPR008978); p23-like. (IPR045250); CS (PF04969)

MANDATORY VERIFICATION STEPS:

Check if the gene symbol "PTGES3" matches the protein description above
Verify the organism is correct: Homo sapiens (Human).
Check if protein family/domains align with what you find in literature
If you find literature for a DIFFERENT gene with the same or similar symbol, STOP

If Gene Symbol is Ambiguous or You Cannot Find Relevant Literature:

DO NOT PROCEED WITH RESEARCH ON A DIFFERENT GENE. Instead:
- State clearly: "The gene symbol 'PTGES3' is ambiguous or literature is limited for this specific protein"
- Explain what you found (e.g., "Found extensive literature on a different gene with the same symbol in a different organism")
- Describe the protein based ONLY on the UniProt information provided above
- Suggest that the protein function can be inferred from domain/family information

Research Target:

Please provide a comprehensive research report on the gene PTGES3 (gene ID: PTGES3, UniProt: Q15185) in human.

The research report should be a detailed narrative explaining the function, biological processes, and localization of the gene product. Citations should be given for all claims.

You should prioritize authoritative reviews and primary scientific literature when conducting research. You can supplement
this with annotations you find in gene/protein databases, but these can be outdated or inaccurate.

We are specifically interested in the primary function of the gene - for enzymes, what reaction is catalyzed, and what is the substrate specificity? For transporters, what is the substrate? For structural proteins or adapters, what is the broader structural role? For signaling molecules, what is the role in the pathway.

We are interested in where in or outside the cell the gene product carries out its function.

We are also interested in the signaling or biochemical pathways in which the gene functions. We are less interested in broad pleiotropic effects, except where these elucidate the precise role.

Include evidence where possible. We are interested in both experimental evidence as well as inference from structure, evolution, or bioinformatic analysis. Precise studies should be prioritized over high-throughput, where available.

Output

Question: You are an expert researcher providing comprehensive, well-cited information.

Provide detailed information focusing on:
1. Key concepts and definitions with current understanding
2. Recent developments and latest research (prioritize 2023-2024 sources)
3. Current applications and real-world implementations
4. Expert opinions and analysis from authoritative sources
5. Relevant statistics and data from recent studies

Format as a comprehensive research report with proper citations. Include URLs and publication dates where available.
Always prioritize recent, authoritative sources and provide specific citations for all major claims.

Gene Research for Functional Annotation

⚠️ CRITICAL: Gene/Protein Identification Context

BEFORE YOU BEGIN RESEARCH: You MUST verify you are researching the CORRECT gene/protein. Gene symbols can be ambiguous, especially for less well-characterized genes from non-model organisms.

Target Gene/Protein Identity (from UniProt):

UniProt Accession: Q15185
Protein Description: RecName: Full=Prostaglandin E synthase 3; EC=5.3.99.3 {ECO:0000269|PubMed:10922363}; AltName: Full=Cytosolic prostaglandin E2 synthase; Short=cPGES; AltName: Full=Hsp90 co-chaperone; AltName: Full=Progesterone receptor complex p23; AltName: Full=Telomerase-binding protein p23;
Gene Information: Name=PTGES3; Synonyms=P23, TEBP;
Organism (full): Homo sapiens (Human).
Protein Family: Belongs to the p23/wos2 family. .
Key Domains: CS_dom. (IPR007052); HSP20-like_chaperone. (IPR008978); p23-like. (IPR045250); CS (PF04969)

MANDATORY VERIFICATION STEPS:

Check if the gene symbol "PTGES3" matches the protein description above
Verify the organism is correct: Homo sapiens (Human).
Check if protein family/domains align with what you find in literature
If you find literature for a DIFFERENT gene with the same or similar symbol, STOP

If Gene Symbol is Ambiguous or You Cannot Find Relevant Literature:

Research Target:

Please provide a comprehensive research report on the gene PTGES3 (gene ID: PTGES3, UniProt: Q15185) in human.

The research report should be a detailed narrative explaining the function, biological processes, and localization of the gene product. Citations should be given for all claims.

We are interested in where in or outside the cell the gene product carries out its function.

We are also interested in the signaling or biochemical pathways in which the gene functions. We are less interested in broad pleiotropic effects, except where these elucidate the precise role.

Title: Functional Annotation Report — Human PTGES3 (UniProt Q15185; p23/cPGES)

Target verification and nomenclature
Human PTGES3 encodes a 160-aa (~18.7 kDa) protein with UniProtKB accession Q15185, commonly referred to as p23 and also annotated as cytosolic prostaglandin E2 synthase (cPGES). (biringer2018theenzymesof pages 6-6, biringer2018theenzymesof pages 2-4, biringer2018theenzymesof media c64a4d06)
PTGES3/p23 belongs to the p23/WOS2 family and is described as a monomeric, glutathione-dependent cytosolic protein with an available structure (PDB 1EJF). (biringer2018theenzymesof pages 6-6)
This target is distinct from PTGES (mPGES-1; inducible/microsomal) and PTGES2 (mPGES-2). PTGES3 is among glutathione-requiring PGE synthase isoforms. (biringer2018theenzymesof pages 5-6)
Key concepts and current understanding (definitions and primary functions)
2.1 Enzymatic function in prostaglandin E2 biosynthesis (cPGES activity)
PTGES3/cPGES is annotated to catalyze the isomerization/conversion of prostaglandin H2 (PGH2) to prostaglandin E2 (PGE2): PGH2 → PGE2. (biringer2018theenzymesof pages 2-4, biringer2018theenzymesof media c64a4d06)
PTGES3 is described as glutathione-dependent in this enzymatic role. (biringer2018theenzymesof pages 6-6, biringer2018theenzymesof pages 5-6)
Functional channeling/coupling is reported between PTGES3 and cyclooxygenase-1 (PTGS1/COX-1), with PGH2 generated by PTGS1 stated to be preferred for PTGES3-mediated PGE2 production and with PTGES3/PTGS1 coupling reported. (biringer2018theenzymesof pages 6-6, biringer2018theenzymesof pages 6-8)

Interpretation: In current pathway models, PTGES3 functions as a constitutive, cytosolic PGE2 synthase whose activity can be shaped by cellular compartmentation and COX coupling, particularly favoring COX-1-derived PGH2 under certain contexts. (biringer2018theenzymesof pages 6-6, biringer2018theenzymesof pages 6-8)

2.2 Non-enzymatic function as an HSP90 co-chaperone (p23)
PTGES3 is explicitly identified as the co-chaperone p23 in authoritative HSP90 machinery literature. (schopf2017thehsp90chaperone pages 2-3)
Mechanistically, p23 stabilizes an HSP90 closed conformational state (often referred to as “closed 2”) and inhibits/reduces HSP90 ATPase activity, thereby regulating progression of the HSP90 chaperone cycle. (schopf2017thehsp90chaperone pages 2-3, schopf2017thehsp90chaperone pages 3-4)
A 2024 review reiterates that PTGES3/p23 slows the HSP90 ATPase cycle by stabilizing the closed ATP-committed conformation. (albakova2024hsp90multifunctionalityin pages 1-2)

Interpretation: p23 is widely viewed as a late-stage HSP90 cycle regulator that biases HSP90 toward an ATP-bound closed state and modulates client maturation/release, consistent with its broad effects on the activity of many HSP90 clients. (schopf2017thehsp90chaperone pages 2-3, schopf2017thehsp90chaperone pages 3-4, albakova2024hsp90multifunctionalityin pages 1-2)

Subcellular localization and molecular complexes
3.1 Cytosolic localization and constitutive roles
PTGES3 is described as cytosolic/cytoplasmic in enzymatic and chaperone contexts. (biringer2018theenzymesof pages 6-6)

3.2 Nuclear translocation and transcriptional roles (context-dependent)
A 2023 Science Advances study reports prominent nuclear localization of p23/PTGES3 in lung adenocarcinoma tissues and demonstrates that p23 can act as an HSP90-independent transcription factor for COX-2 (PTGS2), with nuclear localization driven by succinate-dependent lysine succinylation (K7, K33, K79). (yu2023thep23cochaperone pages 1-2)
The same study reports that >90% of tumor tissues exhibited nuclear p23 expression compared with ~5% in adjacent tissues, connecting localization with clinical tumor context. (yu2023thep23cochaperone pages 2-3)

3.3 Client complexes and interaction partners
HSP90 co-chaperone role: p23/PTGES3 binds HSP90 and stabilizes closed states, regulating ATPase cycling. (schopf2017thehsp90chaperone pages 2-3, schopf2017thehsp90chaperone pages 3-4)
Eicosanoid pathway coupling: functional coupling to PTGS1/COX-1 is reported for efficient use of PTGS1-derived PGH2. (biringer2018theenzymesof pages 6-6, biringer2018theenzymesof pages 6-8)
Steroid receptor/telomerase complexes: p23 is described as stabilizing HSP90 complexes with clients including estrogen receptor, androgen receptor, and telomerase. (yu2023thep23cochaperone pages 1-2)
Transcription factors/receptors (HSP90-independent interactions in cancer literature synthesis): PTGES3/p23 is described as interacting with transcription factor p53 independently of HSP90 and protecting the aryl hydrocarbon receptor from degradation. (wang2023comprehensivepancanceranalysis pages 12-13)

Pathway context
4.1 Prostaglandin biosynthesis
PTGES3 participates in the downstream prostanoid pathway by converting COX-derived PGH2 into PGE2. (biringer2018theenzymesof media c64a4d06, biringer2018theenzymesof pages 2-4)
PTGES3 is framed as a constitutive PGE2 synthase, in contrast to inducible microsomal PTGES (mPGES-1). (wang2023comprehensivepancanceranalysis pages 12-13, biringer2018theenzymesof pages 5-6)

4.2 Proteostasis and HSP90 client regulation
Within the HSP90 chaperone system, p23/PTGES3 is positioned as a co-chaperone that stabilizes the closed state and inhibits ATPase, shaping the HSP90 reaction cycle and affecting client maturation (including steroid receptor complexes). (schopf2017thehsp90chaperone pages 2-3, schopf2017thehsp90chaperone pages 3-4, albakova2024hsp90multifunctionalityin pages 1-2)

4.3 Cancer-associated metabolic–transcriptional axis (succinate–p23–COX-2)
In lung adenocarcinoma, intratumor succinate is reported to promote p23 succinylation that drives nuclear translocation and transcriptional activation of COX-2 (PTGS2), linking PTGES3 to inflammatory signaling pathways and tumorigenesis via COX-2 induction. (yu2023thep23cochaperone pages 1-2)

Recent developments (prioritized 2023–2024)
5.1 2023: p23/PTGES3 as an HSP90-independent transcription factor and druggable PTM axis
The 2023 Science Advances work reports a previously unidentified role for nuclear p23 as a transcription factor for COX-2, driven by succinate-induced succinylation at K7/K33/K79; the authors also report identification of a small-molecule inhibitor (M16) that inhibits p23 succinylation/nuclear translocation and suppresses tumor growth in a p23-dependent manner. (yu2023thep23cochaperone pages 1-2)

5.2 2024: review-level synthesis of mechanistic placement in the HSP90 cycle
A 2024 review reiterates the mechanistic role of PTGES3/p23 in slowing the HSP90 ATPase cycle by stabilizing the closed ATP-committed conformation, emphasizing its function as a co-chaperone regulator of HSP90 conformational dynamics. (albakova2024hsp90multifunctionalityin pages 1-2)

Current applications and real-world implementations
6.1 Biomarker associations in oncology (research/translation)
A 2023 pan-cancer analysis reports that PTGES3 expression is upregulated in many cancers and associates with survival endpoints in multiple tumor types; in hepatocellular carcinoma (HCC), higher PTGES3 expression is reported to associate with worse survival and was validated as higher PTGES3 protein expression by immunohistochemistry. (wang2023comprehensivepancanceranalysis pages 1-2, wang2023comprehensivepancanceranalysis pages 9-11)
The same analysis reports PTGES3 association with immune infiltration patterns (for example, positive association with Th2 and MDSC signatures and negative association with Th1/NKT signatures in some analyses) and co-expression with immune checkpoint genes across cancers. (wang2023comprehensivepancanceranalysis pages 4-9)

6.2 Therapeutic hypotheses/targeting approaches
Mechanism-based targeting of p23/PTGES3 is supported by (i) small-molecule inhibition of succinylation-dependent nuclear p23 function in lung adenocarcinoma (M16) and (ii) literature synthesis noting that certain small molecules (e.g., gedunin) can bind p23 and block function in malignant cells (as discussed in the HCC/pan-cancer synthesis). (yu2023thep23cochaperone pages 1-2, wang2023comprehensivepancanceranalysis pages 12-13)

6.3 Cardiovascular risk stratification (genetics)
In nephrosclerosis patients, PTGES3 tag-SNPs were evaluated as part of a COX/PGE2-pathway genetic risk model for cardiovascular events, suggesting potential use in refined risk prediction models (research-stage application). (gonzalez2023influenceofvariability pages 1-2, gonzalez2023influenceofvariability pages 2-3)

Quantitative data and statistics (recent studies)
7.1 Protein/structure metrics
PTGES3/cPGES is reported as 160 aa (~18.7 kDa) and has a solved structure (PDB 1EJF); a pathway table explicitly maps cPGES to UniProt Q15185 and the reaction PGH2→PGE2. (biringer2018theenzymesof pages 2-4, biringer2018theenzymesof media c64a4d06)

7.2 Nuclear localization prevalence in lung adenocarcinoma (2023)
In lung adenocarcinoma tissue, nuclear p23 expression was reported in >90% of tumor tissues versus ~5% of adjacent tissues. (yu2023thep23cochaperone pages 2-3)

7.3 Cardiovascular outcomes genetics (Scientific Reports, 2023)
In a cohort of 493 nephrosclerosis patients (716 controls) followed for a median of 47 months with 41 cardiovascular events (8.3%), PTGES3 rs2958155 and rs11300958 were associated with cardiovascular event–free survival in adjusted Cox models (HR 2.41 (1.15–5.04), p=0.02 for rs2958155; HR 2.20 (1.16–4.18), p=0.016 for rs11300958). (gonzalez2023influenceofvariability pages 2-3, gonzalez2023influenceofvariability pages 1-2)
Adding variants including these two PTGES3 SNPs to a traditional risk-factor model increased AUC from 78.6% to 87.4% (p=0.0003) in the patient group and from 84.7% to 87.3% (p=0.031) in the full cohort analysis. (gonzalez2023influenceofvariability pages 2-3)

7.4 Pan-cancer outcomes and drug association statistics (Frontiers in Oncology, 2023)
A Cox-model association reported PTGES3 with overall survival in several cancers, including a reported hazard ratio of 5.131 for KIRP in the pan-cancer Cox analysis excerpt. (wang2023comprehensivepancanceranalysis pages 4-9)
Drug-sensitivity analyses described 11 top drugs with PTGES3-associated IC50 relationships; TGX221 and NPK76-II-72-1 were reported with correlations >0.2, and 106 drugs were reported as differing between high- and low-PTGES3 HCC groups in one comparison. (wang2023comprehensivepancanceranalysis pages 4-9, wang2023comprehensivepancanceranalysis pages 3-4)

Expert interpretation and synthesis (authoritative perspectives)
8.1 Dual functional annotation is supported but context-dependent
An eicosanoid-pathway synthesis explicitly describes PTGES3 as a glutathione-dependent cytosolic PGE2 synthase and also notes its distinct (non-enzymatic) HSP90 co-chaperone functions, indicating that PTGES3 is commonly annotated as a bifunctional protein (enzyme + co-chaperone). (biringer2018theenzymesof pages 6-6)
8.2 Mechanistic consensus on HSP90 regulation
High-authority HSP90 chaperone machinery literature positions p23/PTGES3 as a co-chaperone that stabilizes the HSP90 closed 2 state and inhibits HSP90 ATPase activity, and a 2024 review concurs with this conceptual placement. (schopf2017thehsp90chaperone pages 2-3, schopf2017thehsp90chaperone pages 3-4, albakova2024hsp90multifunctionalityin pages 1-2)
8.3 Emerging view: p23 can directly regulate transcription in cancer
The 2023 Science Advances study provides mechanistic evidence supporting a model in which post-translational modification (succinylation) triggers nuclear translocation and enables p23/PTGES3 to function as a COX-2 transcription factor, expanding PTGES3 functional annotation beyond its traditional enzyme/co-chaperone roles in a tumor-metabolic context. (yu2023thep23cochaperone pages 1-2, yu2023thep23cochaperone pages 3-4)
Limitations and evidence gaps relevant to functional annotation
While the reaction PGH2→PGE2 and glutathione dependence are explicitly documented for PTGES3/cPGES in curated pathway summaries, the retrieved evidence here does not provide detailed enzymatic kinetics (Km/kcat), residue-level substrate specificity beyond PGH2, or conditions determining relative contributions versus other PGE synthases in specific human tissues. (biringer2018theenzymesof pages 2-4, biringer2018theenzymesof pages 6-6)
Similarly, although nuclear transcription-factor function is well-supported in a lung adenocarcinoma context, it remains unclear from the provided evidence how broadly this mechanism generalizes across normal tissues or other disease settings. (yu2023thep23cochaperone pages 2-3, yu2023thep23cochaperone pages 1-2)

Key source URLs (with publication dates)
• Schopf FH et al. “The HSP90 chaperone machinery.” Nature Reviews Molecular Cell Biology. Apr 2017. https://doi.org/10.1038/nrm.2017.20 (schopf2017thehsp90chaperone pages 2-3)
• Yu Z et al. “The p23 co-chaperone is a succinate-activated COX-2 transcription factor in lung adenocarcinoma tumorigenesis.” Science Advances. Jun 2023. https://doi.org/10.1126/sciadv.ade0387 (yu2023thep23cochaperone pages 1-2)
• Wang H et al. “Comprehensive pan-cancer analysis of PTGES3 and its prognostic role in hepatocellular carcinoma.” Frontiers in Oncology. May 2023. https://doi.org/10.3389/fonc.2023.1158490 (wang2023comprehensivepancanceranalysis pages 1-2)
• González LM et al. “Influence of variability in the cyclooxygenase pathway on cardiovascular outcomes of nephrosclerosis patients.” Scientific Reports. Jan 2023. https://doi.org/10.1038/s41598-022-27343-z (gonzalez2023influenceofvariability pages 1-2)
• Albakova Z. “HSP90 multi-functionality in cancer.” Frontiers in Immunology. Aug 2024. https://doi.org/10.3389/fimmu.2024.1436973 (albakova2024hsp90multifunctionalityin pages 1-2)

Visual evidence used
• Table and pathway schematic mapping PTGES3/cPGES to UniProt Q15185 and reaction PGH2→PGE2 (biringer2018theenzymesof media c64a4d06, biringer2018theenzymesof media 61fb2772)

References

(biringer2018theenzymesof pages 6-6): RG Biringer. The enzymes of the human eicosanoid pathway. Unknown journal, 2018.
(biringer2018theenzymesof pages 2-4): RG Biringer. The enzymes of the human eicosanoid pathway. Unknown journal, 2018.
(biringer2018theenzymesof media c64a4d06): RG Biringer. The enzymes of the human eicosanoid pathway. Unknown journal, 2018.
(biringer2018theenzymesof pages 5-6): RG Biringer. The enzymes of the human eicosanoid pathway. Unknown journal, 2018.
(biringer2018theenzymesof pages 6-8): RG Biringer. The enzymes of the human eicosanoid pathway. Unknown journal, 2018.
(schopf2017thehsp90chaperone pages 2-3): Florian H. Schopf, Maximilian M. Biebl, and Johannes Buchner. The hsp90 chaperone machinery. Nature Reviews Molecular Cell Biology, 18:345-360, Apr 2017. URL: https://doi.org/10.1038/nrm.2017.20, doi:10.1038/nrm.2017.20. This article has 1728 citations and is from a domain leading peer-reviewed journal.
(schopf2017thehsp90chaperone pages 3-4): Florian H. Schopf, Maximilian M. Biebl, and Johannes Buchner. The hsp90 chaperone machinery. Nature Reviews Molecular Cell Biology, 18:345-360, Apr 2017. URL: https://doi.org/10.1038/nrm.2017.20, doi:10.1038/nrm.2017.20. This article has 1728 citations and is from a domain leading peer-reviewed journal.
(albakova2024hsp90multifunctionalityin pages 1-2): Zarema Albakova. Hsp90 multi-functionality in cancer. Frontiers in Immunology, Aug 2024. URL: https://doi.org/10.3389/fimmu.2024.1436973, doi:10.3389/fimmu.2024.1436973. This article has 46 citations and is from a peer-reviewed journal.
(yu2023thep23cochaperone pages 1-2): Zhenlong Yu, Yulin Peng, Jian Gao, Meirong Zhou, Lei Shi, Feng Zhao, Chao Wang, Xiangge Tian, Lei Feng, Xiaokui Huo, Bao-jing Zhang, Min Liu, Deyu Fang, and Xiaochi Ma. The p23 co-chaperone is a succinate-activated cox-2 transcription factor in lung adenocarcinoma tumorigenesis. Science Advances, Jun 2023. URL: https://doi.org/10.1126/sciadv.ade0387, doi:10.1126/sciadv.ade0387. This article has 15 citations and is from a highest quality peer-reviewed journal.
(yu2023thep23cochaperone pages 2-3): Zhenlong Yu, Yulin Peng, Jian Gao, Meirong Zhou, Lei Shi, Feng Zhao, Chao Wang, Xiangge Tian, Lei Feng, Xiaokui Huo, Bao-jing Zhang, Min Liu, Deyu Fang, and Xiaochi Ma. The p23 co-chaperone is a succinate-activated cox-2 transcription factor in lung adenocarcinoma tumorigenesis. Science Advances, Jun 2023. URL: https://doi.org/10.1126/sciadv.ade0387, doi:10.1126/sciadv.ade0387. This article has 15 citations and is from a highest quality peer-reviewed journal.
(wang2023comprehensivepancanceranalysis pages 12-13): Han Wang, Peng Sun, Ruoyu Yao, Wenrui Zhang, Xiaoshuang Zhou, Jia Yao, and Kun He. Comprehensive pan-cancer analysis of ptges3 and its prognostic role in hepatocellular carcinoma. Frontiers in Oncology, May 2023. URL: https://doi.org/10.3389/fonc.2023.1158490, doi:10.3389/fonc.2023.1158490. This article has 7 citations.
(wang2023comprehensivepancanceranalysis pages 1-2): Han Wang, Peng Sun, Ruoyu Yao, Wenrui Zhang, Xiaoshuang Zhou, Jia Yao, and Kun He. Comprehensive pan-cancer analysis of ptges3 and its prognostic role in hepatocellular carcinoma. Frontiers in Oncology, May 2023. URL: https://doi.org/10.3389/fonc.2023.1158490, doi:10.3389/fonc.2023.1158490. This article has 7 citations.
(wang2023comprehensivepancanceranalysis pages 9-11): Han Wang, Peng Sun, Ruoyu Yao, Wenrui Zhang, Xiaoshuang Zhou, Jia Yao, and Kun He. Comprehensive pan-cancer analysis of ptges3 and its prognostic role in hepatocellular carcinoma. Frontiers in Oncology, May 2023. URL: https://doi.org/10.3389/fonc.2023.1158490, doi:10.3389/fonc.2023.1158490. This article has 7 citations.
(wang2023comprehensivepancanceranalysis pages 4-9): Han Wang, Peng Sun, Ruoyu Yao, Wenrui Zhang, Xiaoshuang Zhou, Jia Yao, and Kun He. Comprehensive pan-cancer analysis of ptges3 and its prognostic role in hepatocellular carcinoma. Frontiers in Oncology, May 2023. URL: https://doi.org/10.3389/fonc.2023.1158490, doi:10.3389/fonc.2023.1158490. This article has 7 citations.
(gonzalez2023influenceofvariability pages 1-2): Luz M. González, Nicolás R. Robles, Sonia Mota-Zamorano, José M. Valdivielso, Laura González-Rodríguez, Juan López-Gómez, and Guillermo Gervasini. Influence of variability in the cyclooxygenase pathway on cardiovascular outcomes of nephrosclerosis patients. Scientific Reports, Jan 2023. URL: https://doi.org/10.1038/s41598-022-27343-z, doi:10.1038/s41598-022-27343-z. This article has 3 citations and is from a peer-reviewed journal.
(gonzalez2023influenceofvariability pages 2-3): Luz M. González, Nicolás R. Robles, Sonia Mota-Zamorano, José M. Valdivielso, Laura González-Rodríguez, Juan López-Gómez, and Guillermo Gervasini. Influence of variability in the cyclooxygenase pathway on cardiovascular outcomes of nephrosclerosis patients. Scientific Reports, Jan 2023. URL: https://doi.org/10.1038/s41598-022-27343-z, doi:10.1038/s41598-022-27343-z. This article has 3 citations and is from a peer-reviewed journal.
(wang2023comprehensivepancanceranalysis pages 3-4): Han Wang, Peng Sun, Ruoyu Yao, Wenrui Zhang, Xiaoshuang Zhou, Jia Yao, and Kun He. Comprehensive pan-cancer analysis of ptges3 and its prognostic role in hepatocellular carcinoma. Frontiers in Oncology, May 2023. URL: https://doi.org/10.3389/fonc.2023.1158490, doi:10.3389/fonc.2023.1158490. This article has 7 citations.
(yu2023thep23cochaperone pages 3-4): Zhenlong Yu, Yulin Peng, Jian Gao, Meirong Zhou, Lei Shi, Feng Zhao, Chao Wang, Xiangge Tian, Lei Feng, Xiaokui Huo, Bao-jing Zhang, Min Liu, Deyu Fang, and Xiaochi Ma. The p23 co-chaperone is a succinate-activated cox-2 transcription factor in lung adenocarcinoma tumorigenesis. Science Advances, Jun 2023. URL: https://doi.org/10.1126/sciadv.ade0387, doi:10.1126/sciadv.ade0387. This article has 15 citations and is from a highest quality peer-reviewed journal.
(biringer2018theenzymesof media 61fb2772): RG Biringer. The enzymes of the human eicosanoid pathway. Unknown journal, 2018.

Citations

biringer2018theenzymesof pages 6-6
biringer2018theenzymesof pages 5-6
wang2023comprehensivepancanceranalysis pages 12-13
wang2023comprehensivepancanceranalysis pages 4-9
gonzalez2023influenceofvariability pages 2-3
wang2023comprehensivepancanceranalysis pages 1-2
gonzalez2023influenceofvariability pages 1-2
biringer2018theenzymesof pages 2-4
biringer2018theenzymesof pages 6-8
wang2023comprehensivepancanceranalysis pages 9-11
wang2023comprehensivepancanceranalysis pages 3-4
https://doi.org/10.1038/nrm.2017.20
https://doi.org/10.1126/sciadv.ade0387
https://doi.org/10.3389/fonc.2023.1158490
https://doi.org/10.1038/s41598-022-27343-z
https://doi.org/10.3389/fimmu.2024.1436973
https://doi.org/10.1038/nrm.2017.20,
https://doi.org/10.3389/fimmu.2024.1436973,
https://doi.org/10.1126/sciadv.ade0387,
https://doi.org/10.3389/fonc.2023.1158490,
https://doi.org/10.1038/s41598-022-27343-z,

📄 View Raw YAML

id: Q15185
gene_symbol: PTGES3
product_type: PROTEIN
status: IN_PROGRESS
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: >-
  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.
alternative_products:
- name: '1'
  id: Q15185-1
- name: '2'
  id: Q15185-2
  sequence_note: VSP_055363
- name: '3'
  id: Q15185-3
  sequence_note: VSP_055364
- name: '4'
  id: Q15185-4
  sequence_note: VSP_055365
existing_annotations:
- term:
    id: GO:0005634
    label: nucleus
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    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.
    action: ACCEPT
    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.
    supported_by:
    - reference_id: PMID:12077419
      supporting_text: >-
        the p23 molecular chaperone localizes in vivo to genomic response elements in a
        hormone-dependent manner
- term:
    id: GO:0006457
    label: protein folding
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    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).
    action: ACCEPT
    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.
    supported_by:
    - reference_id: PMID:10811660
      supporting_text: >-
        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
    - reference_id: PMID:10543959
      supporting_text: >-
        p23 binds to Hsp90 in its ATP-bound state and, on its own, interacts specifically
        with non-native proteins
- term:
    id: GO:0051087
    label: protein-folding chaperone binding
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: >-
      IBA annotation of PTGES3 to protein-folding chaperone binding (GO:0051087) is
      phylogenetically inferred. PTGES3/p23 directly binds HSP90, a protein-folding
      chaperone, in an ATP-dependent manner (PMID:10543959, PMID:9817749). This interaction
      is one of the most well-characterized aspects of PTGES3 function.
    action: ACCEPT
    reason: >-
      PTGES3 binding to HSP90 (a protein-folding chaperone) is extensively documented.
      The protein binds specifically to the ATP-bound state of HSP90 and stabilizes the
      closed conformation (PMID:10543959, PMID:21183720). This is a core function
      appropriately captured at this level of specificity by IBA.
    supported_by:
    - reference_id: PMID:10543959
      supporting_text: >-
        p23 binds to Hsp90 in its ATP-bound state
    - reference_id: PMID:21183720
      supporting_text: >-
        it is Hsp90's nucleotide-binding domain that triggers the formation of the
        Hsp90(2)p23(2) complex
- term:
    id: GO:0051131
    label: chaperone-mediated protein complex assembly
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    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).
    action: ACCEPT
    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.
    supported_by:
    - reference_id: PMID:10811660
      supporting_text: >-
        the tail is necessary for optimum active chaperoning of the progesterone receptor
    - reference_id: PMID:10197982
      supporting_text: >-
        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.
- term:
    id: GO:0051879
    label: Hsp90 protein binding
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    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).
    action: ACCEPT
    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.
    supported_by:
    - reference_id: PMID:21183720
      supporting_text: >-
        it is Hsp90's nucleotide-binding domain that triggers the formation of the
        Hsp90(2)p23(2) complex
    - reference_id: PMID:10543959
      supporting_text: >-
        p23 binds to Hsp90 in its ATP-bound state
- term:
    id: GO:0001516
    label: prostaglandin biosynthetic process
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    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).
    action: ACCEPT
    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.
    supported_by:
    - reference_id: PMID:10922363
      supporting_text: >-
        Recombinant p23 expressed in Escherichia coli and 293 cells exhibited all the
        features of PGES activity detected in rat brain cytosol
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    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.
    action: ACCEPT
    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.
    supported_by:
    - reference_id: PMID:10922363
      supporting_text: >-
        Here we report the molecular identification of cytosolic glutathione
        (GSH)-dependent prostaglandin (PG) E(2) synthase (cPGES)
- term:
    id: GO:0050220
    label: prostaglandin-E synthase activity
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    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.
    action: ACCEPT
    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.
    supported_by:
    - reference_id: PMID:10922363
      supporting_text: >-
        Recombinant p23 expressed in Escherichia coli and 293 cells exhibited all the
        features of PGES activity detected in rat brain cytosol
- term:
    id: GO:0007004
    label: telomere maintenance via telomerase
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    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.
    action: ACCEPT
    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 secondary function of PTGES3 and the IBA
      annotation is appropriate.
    supported_by:
    - reference_id: PMID:10197982
      supporting_text: >-
        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.
- term:
    id: GO:1905323
    label: telomerase holoenzyme complex assembly
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    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.
    action: ACCEPT
    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 is concordant with the IBA.
    supported_by:
    - reference_id: PMID:10197982
      supporting_text: >-
        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.
- term:
    id: GO:0001516
    label: prostaglandin biosynthetic process
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  review:
    summary: >-
      IEA annotation for prostaglandin biosynthetic process from combined automated methods.
      This is consistent with the core prostaglandin synthase function of PTGES3
      (PMID:10922363).
    action: ACCEPT
    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.
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  review:
    summary: >-
      IEA annotation for cytoplasm from UniProt subcellular location mapping. PTGES3 is
      annotated to cytoplasm in UniProt based on sequence similarity evidence. The protein
      is primarily cytosolic.
    action: ACCEPT
    reason: >-
      Cytoplasmic localization is well established for PTGES3. While cytosol (GO:0005829)
      is more specific and also annotated, the broader cytoplasm term from an IEA pipeline
      is not incorrect. It is simply less specific than the IBA and TAS annotations to
      cytosol.
- term:
    id: GO:0006629
    label: lipid metabolic process
  evidence_type: IEA
  original_reference_id: GO_REF:0000043
  review:
    summary: >-
      IEA annotation for lipid metabolic process from UniProt keyword mapping. PTGES3
      catalyzes conversion of PGH2 to PGE2, which is a lipid metabolic process.
    action: ACCEPT
    reason: >-
      This is a broad but not incorrect annotation. PTGES3 participates in prostaglandin
      biosynthesis, which is a form of lipid metabolism. The more specific annotations to
      prostaglandin biosynthetic process (GO:0001516) and fatty acid biosynthetic process
      (GO:0006633) provide better granularity, but this IEA annotation is acceptable as
      a parent term.
- term:
    id: GO:0006631
    label: fatty acid metabolic process
  evidence_type: IEA
  original_reference_id: GO_REF:0000043
  review:
    summary: >-
      IEA annotation for fatty acid metabolic process from UniProt keyword mapping.
      Prostaglandins are derived from arachidonic acid, a fatty acid. PTGES3 catalyzes the
      terminal step converting PGH2 to PGE2.
    action: ACCEPT
    reason: >-
      Prostaglandins are eicosanoids derived from arachidonic acid (a fatty acid), so
      this broad IEA mapping is not incorrect. The more specific prostaglandin biosynthetic
      process annotation provides better specificity.
- term:
    id: GO:0006633
    label: fatty acid biosynthetic process
  evidence_type: IEA
  original_reference_id: GO_REF:0000043
  review:
    summary: >-
      IEA annotation for fatty acid biosynthetic process from UniProt keyword mapping.
      PTGES3 catalyzes the isomerization of PGH2 to PGE2 in the prostaglandin biosynthetic
      pathway, which is derived from arachidonic acid metabolism.
    action: ACCEPT
    reason: >-
      This IEA mapping from UniProt keywords is broadly acceptable since prostaglandins are
      fatty acid derivatives. However, prostaglandin biosynthesis is more accurately described
      as eicosanoid/prostanoid biosynthesis than as fatty acid biosynthesis per se. This is a
      tolerable IEA-level annotation given the more specific annotations exist.
- term:
    id: GO:0006693
    label: prostaglandin metabolic process
  evidence_type: IEA
  original_reference_id: GO_REF:0000043
  review:
    summary: >-
      IEA annotation for prostaglandin metabolic process from UniProt keyword mapping.
      PTGES3 is a prostaglandin E synthase that converts PGH2 to PGE2 (PMID:10922363).
    action: ACCEPT
    reason: >-
      This is a correct but broader annotation than the more specific prostaglandin biosynthetic
      process (GO:0001516) that is also annotated. Acceptable for an IEA-level annotation.
- term:
    id: GO:0016853
    label: isomerase activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000043
  review:
    summary: >-
      IEA annotation for isomerase activity from UniProt keyword mapping. The UniProt EC
      number for PTGES3 is 5.3.99.3 (prostaglandin-E synthase), which is classified as an
      isomerase. The conversion of PGH2 to PGE2 is an isomerization reaction.
    action: ACCEPT
    reason: >-
      PTGES3 catalyzes the isomerization of PGH2 to PGE2 (EC 5.3.99.3), making isomerase
      activity a correct broad annotation. The more specific prostaglandin-E synthase activity
      (GO:0050220) is also annotated. This IEA annotation is acceptable as a parent MF term.
- term:
    id: GO:0050220
    label: prostaglandin-E synthase activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  review:
    summary: >-
      IEA annotation for prostaglandin-E synthase activity from combined automated methods.
      This is concordant with the experimentally demonstrated enzymatic activity
      (PMID:10922363).
    action: ACCEPT
    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.
- term:
    id: GO:0051879
    label: Hsp90 protein binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  review:
    summary: >-
      IEA annotation for Hsp90 protein binding from InterPro mapping. PTGES3 contains a CS
      domain (InterPro IPR007052) that mediates HSP90 binding.
    action: ACCEPT
    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.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:17353931
  review:
    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.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      Protein binding (GO:0005515) is uninformative for PTGES3, which has well-characterized
      specific binding interactions (Hsp90 protein binding, GO:0051879). The high-throughput
      nature of the study (large-scale mapping by mass spectrometry) and the vague term make
      this annotation of limited value. The specific binding functions of PTGES3 are better
      captured by GO:0051879 and GO:0051087.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:19875381
  review:
    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.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      While PTGES3 was correctly identified in HSP90 complexes in this study, the annotation
      to the generic protein binding term is uninformative. The interaction with HSP90 is
      already well captured by GO:0051879 (Hsp90 protein binding). The generic protein binding
      annotation adds no value.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:21183720
  review:
    summary: >-
      IPI annotation for protein binding from Karagoz et al. (PMID:21183720) which
      characterized the p23-HSP90 interaction by NMR. This study specifically showed that
      Hsp90's N-terminal domain triggers binding to p23.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      PMID:21183720 demonstrated specific binding of p23 to HSP90's N-terminal domain, which
      is better captured by GO:0051879 (Hsp90 protein binding) than the generic protein
      binding term. The generic annotation is redundant and uninformative.
    supported_by:
    - reference_id: PMID:21183720
      supporting_text: >-
        it is Hsp90's nucleotide-binding domain that triggers the formation of the
        Hsp90(2)p23(2) complex
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:21988832
  review:
    summary: >-
      IPI annotation for protein binding from a large-scale study of human liver protein
      interaction network.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      Generic protein binding annotation from a high-throughput interaction study. The specific
      molecular function binding terms (GO:0051879 Hsp90 protein binding, GO:0051087
      protein-folding chaperone binding) are far more informative.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:23741051
  review:
    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.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      While PMID:23741051 demonstrates a biologically interesting interaction (p23 with
      hAgo2 in RISC loading), the generic protein binding annotation does not capture this
      specificity. The interaction with hAgo2 occurs as part of PTGES3's HSP90 co-chaperone
      function, which is already well annotated.
    supported_by:
    - reference_id: PMID:23741051
      supporting_text: >-
        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
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:24981860
  review:
    summary: >-
      IPI annotation for protein binding from a study of human chromatin-related protein
      interactions.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      Generic protein binding annotation from a high-throughput interaction study. Uninformative
      given the well-characterized specific binding functions of PTGES3.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:25036637
  review:
    summary: >-
      IPI annotation for protein binding from a quantitative chaperone interaction network
      study. This study mapped chaperone-client relationships.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      While this study provides useful information about PTGES3 in the chaperone network, the
      generic protein binding annotation is uninformative. PTGES3's chaperone binding is
      better captured by GO:0051879 and GO:0051087.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:33961781
  review:
    summary: >-
      IPI annotation for protein binding from a dual proteome-scale network study of the
      human interactome.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      Generic protein binding from a high-throughput interactome study. The specific binding
      functions of PTGES3 are better captured by more informative terms already annotated.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:35271311
  review:
    summary: >-
      IPI annotation for protein binding from the OpenCell endogenous tagging study.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      Generic protein binding from a large-scale cellular organization study. Uninformative
      for PTGES3 which has well-characterized specific binding partners.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:35914814
  review:
    summary: >-
      IPI annotation for protein binding from a study of Chr21 protein-protein interactions
      related to intellectual disability and Alzheimer's disease.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      Generic protein binding from a focused interaction study. Uninformative for PTGES3
      given existing specific binding annotations.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:9817749
  review:
    summary: >-
      IPI annotation for protein binding from Obermann et al. (PMID:9817749), which
      demonstrated that p23 binding to HSP90 is ATP-dependent and that mutant HSP90
      proteins defective in ATP binding/hydrolysis are defective in p23 cycling.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      PMID:9817749 specifically demonstrates the ATP-dependent interaction between p23
      and HSP90, which is better captured by GO:0051879 (Hsp90 protein binding). The
      generic protein binding annotation is redundant.
    supported_by:
    - reference_id: PMID:9817749
      supporting_text: >-
        The mutant Hsp90 proteins tested are defective in the binding and ATP
        hydrolysis-dependent cycling of the co-chaperone p23
- term:
    id: GO:0046457
    label: prostanoid biosynthetic process
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-2162123
  review:
    summary: >-
      TAS annotation for prostanoid biosynthetic process from Reactome pathway
      R-HSA-2162123 (Synthesis of Prostaglandins and Thromboxanes). PTGES3 catalyzes the
      conversion of PGH2 to PGE2 as part of this pathway.
    action: ACCEPT
    reason: >-
      Prostanoid biosynthetic process is a correct and appropriate annotation for PTGES3.
      PGE2 is a prostanoid, and PTGES3 catalyzes the terminal step in its biosynthesis
      (PMID:10922363). This is concordant with the prostaglandin biosynthetic process
      annotation and represents the same core enzymatic function.
- term:
    id: GO:0050220
    label: prostaglandin-E synthase activity
  evidence_type: EXP
  original_reference_id: PMID:10922363
  review:
    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.
    action: ACCEPT
    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.
    supported_by:
    - reference_id: PMID:10922363
      supporting_text: >-
        Recombinant p23 expressed in Escherichia coli and 293 cells exhibited all the
        features of PGES activity detected in rat brain cytosol
- term:
    id: GO:0032212
    label: positive regulation of telomere maintenance via telomerase
  evidence_type: IDA
  original_reference_id: PMID:19740745
  review:
    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.
    action: ACCEPT
    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 consistent with the broader literature on PTGES3's role in
      telomerase assembly.
    supported_by:
    - reference_id: PMID:19740745
      supporting_text: >-
        overexpression of Delta p23 resulted in a decrease in hTERT levels, and a
        down-regulation in telomerase activity
- term:
    id: GO:0007004
    label: telomere maintenance via telomerase
  evidence_type: IDA
  original_reference_id: PMID:10197982
  review:
    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.
    action: ACCEPT
    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 core secondary function of PTGES3.
    supported_by:
    - reference_id: PMID:10197982
      supporting_text: >-
        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.
- term:
    id: GO:0070182
    label: DNA polymerase binding
  evidence_type: IPI
  original_reference_id: PMID:10197982
  review:
    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.
    action: ACCEPT
    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 correct.
    supported_by:
    - reference_id: PMID:10197982
      supporting_text: >-
        We have identified the molecular chaperones p23 and Hsp90 as proteins that bind to
        the catalytic subunit of telomerase
- term:
    id: GO:1905323
    label: telomerase holoenzyme complex assembly
  evidence_type: IDA
  original_reference_id: PMID:10197982
  review:
    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.
    action: ACCEPT
    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).
    supported_by:
    - reference_id: PMID:10197982
      supporting_text: >-
        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
- term:
    id: GO:0101031
    label: protein folding chaperone complex
  evidence_type: IDA
  original_reference_id: PMID:29127155
  review:
    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.
    action: ACCEPT
    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.
    supported_by:
    - reference_id: PMID:29127155
      supporting_text: >-
        Here, we show that Tsc1 is a new co-chaperone for Hsp90 that inhibits its ATPase
        activity
- term:
    id: GO:0000781
    label: chromosome, telomeric region
  evidence_type: IC
  original_reference_id: PMID:12135483
  review:
    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.
    action: KEEP_AS_NON_CORE
    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.
    supported_by:
    - reference_id: PMID:12135483
      supporting_text: >-
        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
- term:
    id: GO:0032991
    label: protein-containing complex
  evidence_type: IMP
  original_reference_id: PMID:10543959
  review:
    summary: >-
      IMP annotation for protein-containing complex from Weikl et al. (PMID:10543959),
      which demonstrated that p23 forms complexes with HSP90 and that the C-terminal
      truncation affects complex formation with non-native proteins but not with HSP90.
    action: ACCEPT
    reason: >-
      PTGES3 is demonstrated to exist in multiple protein complexes including HSP90
      chaperone complexes (PMID:10543959) and the telomerase holoenzyme. While the term
      protein-containing complex is very broad, the annotation is correct and reflects
      experimental evidence. The more specific protein folding chaperone complex (GO:0101031)
      annotation provides better granularity.
- term:
    id: GO:0032991
    label: protein-containing complex
  evidence_type: IMP
  original_reference_id: PMID:10811660
  review:
    summary: >-
      IMP annotation for protein-containing complex from Weaver et al. (PMID:10811660),
      which determined the crystal structure of p23 and showed it exists in complexes with
      HSP90 and progesterone receptor.
    action: ACCEPT
    reason: >-
      PTGES3 is a well-established component of HSP90-containing multi-protein complexes.
      Weaver et al. showed that p23 binds to HSP90 and to progesterone receptor complexes
      (PMID:10811660). This duplicates the annotation from PMID:10543959 but with
      independent evidence.
- term:
    id: GO:0050821
    label: protein stabilization
  evidence_type: IMP
  original_reference_id: PMID:10543959
  review:
    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.
    action: ACCEPT
    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.
    supported_by:
    - reference_id: PMID:10543959
      supporting_text: >-
        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
- term:
    id: GO:0050821
    label: protein stabilization
  evidence_type: IMP
  original_reference_id: PMID:10811660
  review:
    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.
    action: ACCEPT
    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.
    supported_by:
    - reference_id: PMID:10811660
      supporting_text: >-
        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
- term:
    id: GO:0051131
    label: chaperone-mediated protein complex assembly
  evidence_type: IMP
  original_reference_id: PMID:10811660
  review:
    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.
    action: ACCEPT
    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.
    supported_by:
    - reference_id: PMID:10811660
      supporting_text: >-
        the tail is necessary for optimum active chaperoning of the progesterone receptor
- term:
    id: GO:0051879
    label: Hsp90 protein binding
  evidence_type: IPI
  original_reference_id: PMID:10543959
  review:
    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.
    action: ACCEPT
    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).
    supported_by:
    - reference_id: PMID:10543959
      supporting_text: >-
        p23 binds to Hsp90 in its ATP-bound state
    - reference_id: PMID:10543959
      supporting_text: >-
        the binding site for Hsp90 is contained in the folded domain of p23
- term:
    id: GO:0051879
    label: Hsp90 protein binding
  evidence_type: IPI
  original_reference_id: PMID:10811660
  review:
    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.
    action: ACCEPT
    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).
    supported_by:
    - reference_id: PMID:10811660
      supporting_text: >-
        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
    - reference_id: PMID:10811660
      supporting_text: >-
        This tail is not needed for the binding of p23 to hsp90 or to complexes with the
        progesterone receptor
- term:
    id: GO:0070182
    label: DNA polymerase binding
  evidence_type: IPI
  original_reference_id: PMID:19751963
  review:
    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.
    action: ACCEPT
    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 GO term is appropriate.
    supported_by:
    - reference_id: PMID:19751963
      supporting_text: >-
        curcumin treatment results in a substantial decrease in association of p23 and
        hTERT but does not affect the Hsp90 binding to hTERT
- term:
    id: GO:0051879
    label: Hsp90 protein binding
  evidence_type: IPI
  original_reference_id: PMID:19740745
  review:
    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.
    action: ACCEPT
    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).
    supported_by:
    - reference_id: PMID:19740745
      supporting_text: >-
        The Hsp90-associated protein p23 modulates Hsp90 activity during the final
        stages of the chaperone pathway to facilitate maturation of client proteins
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:27353360
  review:
    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.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      PMID:27353360 demonstrates specific interactions of PTGES3 with HSP90AA1, FLCN,
      FNIP1, and FNIP2. These are biologically meaningful interactions in the context of
      the HSP90 chaperone cycle, but the generic protein binding annotation is uninformative.
      The HSP90 interaction is already captured by GO:0051879.
    supported_by:
    - reference_id: PMID:27353360
      supporting_text: >-
        tumour suppressor FLCN is an Hsp90 client protein and its binding partners
        FNIP1/FNIP2 function as co-chaperones
- term:
    id: GO:0005634
    label: nucleus
  evidence_type: HDA
  original_reference_id: PMID:21630459
  review:
    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.
    action: ACCEPT
    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.
- term:
    id: GO:0005654
    label: nucleoplasm
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-5082409
  review:
    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.
    action: ACCEPT
    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.
- term:
    id: GO:0005654
    label: nucleoplasm
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-5324617
  review:
    summary: >-
      TAS annotation for nucleoplasm from Reactome R-HSA-5324617 (HSP90:FKBP4:PTGES3 binds
      HSF1 trimer).
    action: ACCEPT
    reason: >-
      Duplicate nucleoplasm annotation from a different Reactome event. Consistent with
      PTGES3's nuclear function as part of HSP90 complexes.
- term:
    id: GO:0005654
    label: nucleoplasm
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-5618080
  review:
    summary: >-
      TAS annotation for nucleoplasm from Reactome R-HSA-5618080 (HSP90:ATP:p23:FKBP52:SHR:SH
      translocates to the nucleus).
    action: ACCEPT
    reason: >-
      Consistent nucleoplasm annotation reflecting PTGES3's role in nuclear translocation
      of steroid hormone receptor complexes.
- term:
    id: GO:0005654
    label: nucleoplasm
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-5618093
  review:
    summary: >-
      TAS annotation for nucleoplasm from Reactome R-HSA-5618093 (ATP hydrolysis by HSP90).
    action: ACCEPT
    reason: >-
      Consistent nucleoplasm annotation from Reactome pathway events.
- term:
    id: GO:0005654
    label: nucleoplasm
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-8937169
  review:
    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.
    action: ACCEPT
    reason: >-
      Consistent nucleoplasm annotation. PTGES3 translocates to the nucleus as part of
      the AHR signaling complex.
- term:
    id: GO:0005654
    label: nucleoplasm
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-8937191
  review:
    summary: >-
      TAS annotation for nucleoplasm from Reactome R-HSA-8937191 (AHR:TCDD:2xHSP90AB1:AIP:PTGES3
      dissociates).
    action: ACCEPT
    reason: >-
      Consistent nucleoplasm annotation from AHR signaling pathway.
- term:
    id: GO:0005654
    label: nucleoplasm
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-8939203
  review:
    summary: >-
      TAS annotation for nucleoplasm from Reactome R-HSA-8939203 (HSP90-dependent ATP
      hydrolysis promotes release of ESR:ESTG from chaperone complex).
    action: ACCEPT
    reason: >-
      Consistent nucleoplasm annotation from estrogen receptor signaling pathway.
- term:
    id: GO:0005654
    label: nucleoplasm
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-8939204
  review:
    summary: >-
      TAS annotation for nucleoplasm from Reactome R-HSA-8939204 (ESTG binds ESR1:chaperone
      complex).
    action: ACCEPT
    reason: >-
      Consistent nucleoplasm annotation from estrogen receptor signaling pathway.
- term:
    id: GO:0005654
    label: nucleoplasm
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9032751
  review:
    summary: >-
      TAS annotation for nucleoplasm from Reactome R-HSA-9032751 (Estrogen-independent
      phosphorylation of ESR1 S118 by MAPK1 and MAPK3).
    action: ACCEPT
    reason: >-
      Consistent nucleoplasm annotation from ESR-mediated signaling pathway.
- term:
    id: GO:0005654
    label: nucleoplasm
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9038161
  review:
    summary: >-
      TAS annotation for nucleoplasm from Reactome R-HSA-9038161 (Progesterone stimulation
      promotes PGR:P4 binding to ESR1:ESTG).
    action: ACCEPT
    reason: >-
      Consistent nucleoplasm annotation from estrogen-dependent gene expression pathway.
- term:
    id: GO:0005654
    label: nucleoplasm
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9709547
  review:
    summary: >-
      TAS annotation for nucleoplasm from Reactome R-HSA-9709547 (ESTG binds ESR2:chaperone
      complex).
    action: ACCEPT
    reason: >-
      Consistent nucleoplasm annotation from ESR2 signaling pathway.
- term:
    id: GO:0005654
    label: nucleoplasm
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9716913
  review:
    summary: >-
      TAS annotation for nucleoplasm from Reactome R-HSA-9716913 (ESR1 binds ESR1
      antagonists).
    action: ACCEPT
    reason: >-
      Consistent nucleoplasm annotation from ESR1 signaling pathway.
- term:
    id: GO:0005654
    label: nucleoplasm
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9716947
  review:
    summary: >-
      TAS annotation for nucleoplasm from Reactome R-HSA-9716947 (ESR1 binds ESR1
      agonists).
    action: ACCEPT
    reason: >-
      Consistent nucleoplasm annotation from ESR1 signaling pathway.
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-265295
  review:
    summary: >-
      TAS annotation for cytosol from Reactome R-HSA-265295 (Prostaglandin E synthase
      isomerizes PGH2 to PGE2). PTGES3 catalyzes PGE2 synthesis in the cytosol.
    action: ACCEPT
    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.
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-3371586
  review:
    summary: >-
      TAS annotation for cytosol from Reactome R-HSA-3371586 (Dissociation of cytosolic
      HSF1:HSP90 complex).
    action: ACCEPT
    reason: >-
      Consistent cytosol annotation from HSF1 activation pathway.
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-5324632
  review:
    summary: >-
      TAS annotation for cytosol from Reactome R-HSA-5324632 (Dissociation of cytosolic
      HSF1:HSP90:HDAC6:PTGES3 upon sensing protein aggregates).
    action: ACCEPT
    reason: >-
      Consistent cytosol annotation from heat stress response pathway.
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-5618073
  review:
    summary: >-
      TAS annotation for cytosol from Reactome R-HSA-5618073 (FKBP4 replaces FKBP5 within
      HSP90:ATP:FKBP5:unfolded protein).
    action: ACCEPT
    reason: >-
      Consistent cytosol annotation from HSP90 chaperone cycle for steroid receptors.
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-5618080
  review:
    summary: >-
      TAS annotation for cytosol from Reactome R-HSA-5618080 (HSP90:ATP:p23:FKBP52:SHR:SH
      translocates to the nucleus).
    action: ACCEPT
    reason: >-
      Consistent cytosol annotation. PTGES3 starts in the cytosol before translocation to
      the nucleus with the steroid receptor complex.
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-5618098
  review:
    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.
    action: ACCEPT
    reason: >-
      Consistent cytosol annotation. PTGES3 binds to HSP90 in the cytosol during steroid
      receptor maturation.
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-5618099
  review:
    summary: >-
      TAS annotation for cytosol from Reactome R-HSA-5618099 (NR3C2 ligands bind NR3C2 in
      the HSP90 chaperone complex).
    action: ACCEPT
    reason: >-
      Consistent cytosol annotation from mineralocorticoid receptor signaling.
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-5618110
  review:
    summary: >-
      TAS annotation for cytosol from Reactome R-HSA-5618110 (p23 (PTGES3) binds
      HSP90:ATP:FKBP4:nascent protein).
    action: ACCEPT
    reason: >-
      Consistent cytosol annotation from HSP90 chaperone cycle.
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-8936849
  review:
    summary: >-
      TAS annotation for cytosol from Reactome R-HSA-8936849 (AHR:2xHSP90:AIP:PTGES3
      binds TCDD).
    action: ACCEPT
    reason: >-
      Consistent cytosol annotation. PTGES3 is part of the cytosolic AHR complex before
      ligand-induced nuclear translocation.
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-8937169
  review:
    summary: >-
      TAS annotation for cytosol from Reactome R-HSA-8937169 (AHR:TCDD:2xHSP90AB1:AIP:PTGES3
      translocates from cytosol to nucleoplasm).
    action: ACCEPT
    reason: >-
      Consistent cytosol annotation for AHR complex translocation.
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9678925
  review:
    summary: >-
      TAS annotation for cytosol from Reactome R-HSA-9678925 (NR3C1 binds NR3C1 agonists).
    action: ACCEPT
    reason: >-
      Consistent cytosol annotation from glucocorticoid receptor signaling.
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9690534
  review:
    summary: >-
      TAS annotation for cytosol from Reactome R-HSA-9690534 (NR3C1 ligands bind NR3C1 in
      the HSP90 chaperone complex).
    action: ACCEPT
    reason: >-
      Consistent cytosol annotation from glucocorticoid receptor signaling.
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9705925
  review:
    summary: >-
      TAS annotation for cytosol from Reactome R-HSA-9705925 (Androgens bind AR in the
      HSP90 chaperone complex).
    action: ACCEPT
    reason: >-
      Consistent cytosol annotation from androgen receptor signaling.
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9705926
  review:
    summary: >-
      TAS annotation for cytosol from Reactome R-HSA-9705926 (AR binds AR agonists).
    action: ACCEPT
    reason: >-
      Consistent cytosol annotation from androgen receptor signaling.
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9706837
  review:
    summary: >-
      TAS annotation for cytosol from Reactome R-HSA-9706837 (AR binds AR antagonists).
    action: ACCEPT
    reason: >-
      Consistent cytosol annotation from androgen receptor signaling.
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9725855
  review:
    summary: >-
      TAS annotation for cytosol from Reactome R-HSA-9725855 (NR3C2 binds NR3C2
      antagonists).
    action: ACCEPT
    reason: >-
      Consistent cytosol annotation from mineralocorticoid receptor signaling.
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9725885
  review:
    summary: >-
      TAS annotation for cytosol from Reactome R-HSA-9725885 (P4 binds PGR in the HSP90
      chaperone complex).
    action: ACCEPT
    reason: >-
      Consistent cytosol annotation from progesterone receptor signaling.
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9726509
  review:
    summary: >-
      TAS annotation for cytosol from Reactome R-HSA-9726509 (NR3C2 binds fludrocortisone).
    action: ACCEPT
    reason: >-
      Consistent cytosol annotation from mineralocorticoid receptor signaling.
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9726580
  review:
    summary: >-
      TAS annotation for cytosol from Reactome R-HSA-9726580 (PGR binds PGR agonists).
    action: ACCEPT
    reason: >-
      Consistent cytosol annotation from progesterone receptor signaling.
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9726621
  review:
    summary: >-
      TAS annotation for cytosol from Reactome R-HSA-9726621 (PGR binds PGR antagonists).
    action: ACCEPT
    reason: >-
      Consistent cytosol annotation from progesterone receptor signaling.
- term:
    id: GO:0006457
    label: protein folding
  evidence_type: IDA
  original_reference_id: PMID:12853476
  review:
    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.
    action: ACCEPT
    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.
    supported_by:
    - reference_id: PMID:12853476
      supporting_text: >-
        Excess Tpr2 inhibits the Hsp90-dependent folding of GR in cell lysates
- term:
    id: GO:0051082
    label: unfolded protein binding
  evidence_type: IDA
  original_reference_id: PMID:12077419
  review:
    summary: >-
      GO:0051082 "unfolded protein binding" is annotated to PTGES3 based on PMID:12077419
      (Freeman & Yamamoto, 2002), which demonstrated that p23 acts as a molecular chaperone
      that localizes to genomic response elements and promotes disassembly of transcriptional
      regulatory complexes. However, this paper does not directly demonstrate binding to
      unfolded proteins. The paper shows that p23 disrupts receptor-mediated transcriptional
      activation by promoting disassembly of multicomponent regulatory complexes, functioning
      as an HSP90 co-chaperone rather than independently binding unfolded substrates.
      Separate evidence from PMID:10543959 (Weikl et al., 1999) does demonstrate that p23
      has independent chaperone activity, showing that it "interacts specifically with
      non-native proteins" and prevents "non-specific aggregation." PMID:10811660 (Weaver
      et al., 2000) also confirmed the "passive chaperoning activity of p23 in assays
      measuring inhibition of heat-induced protein aggregation." However, this holdase-type
      activity is secondary to p23's primary role as an HSP90 co-chaperone, and the cited
      reference PMID:12077419 does not support "unfolded protein binding" as such.
      Furthermore, GO:0051082 is being obsoleted (go-ontology issue 30962) in favor of
      more specific terms such as GO:0044183 "protein folding chaperone." Given that PTGES3
      already has annotations for Hsp90 protein binding (GO:0051879), protein folding
      (GO:0006457), protein-folding chaperone binding (GO:0051087), and membership in a
      protein folding chaperone complex (GO:0101031), the core chaperone functions are
      well-captured by existing annotations. The independent holdase activity demonstrated
      in PMID:10543959 and PMID:10811660 could be better represented by GO:0044183 "protein
      folding chaperone" if needed, but the current annotation to GO:0051082 based on
      PMID:12077419 is a misattribution of the cited evidence.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      The GO:0051082 "unfolded protein binding" annotation should be marked as
      over-annotated for three reasons. First, the cited reference PMID:12077419 does not
      demonstrate unfolded protein binding; it shows p23 promotes disassembly of
      transcriptional regulatory complexes as part of the HSP90 chaperone system.
      Second, while p23 does have a modest independent holdase-type chaperone activity
      preventing aggregation of non-native proteins (demonstrated in PMID:10543959 and
      PMID:10811660), this is secondary to its primary role as an HSP90 co-chaperone and
      is not the activity described in the cited reference. Third, GO:0051082 is being
      obsoleted (go-ontology issue 30962) because it conflates binding with chaperone
      activity. The core chaperone functions of PTGES3 are already well-represented by
      existing annotations to GO:0051879 (Hsp90 protein binding), GO:0006457 (protein
      folding), GO:0051087 (protein-folding chaperone binding), and GO:0101031 (protein
      folding chaperone complex). If the independent holdase activity needs representation,
      GO:0044183 "protein folding chaperone" would be more appropriate than the
      soon-to-be-obsoleted GO:0051082.
    proposed_replacement_terms:
    - id: GO:0044183
      label: protein folding chaperone
    additional_reference_ids:
    - PMID:10543959
    - PMID:10811660
    supported_by:
    - reference_id: PMID:12077419
      supporting_text: >-
        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
    - reference_id: PMID:10543959
      supporting_text: >-
        p23 binds to Hsp90 in its ATP-bound state and, on its own, interacts specifically
        with non-native proteins
    - reference_id: PMID:10543959
      supporting_text: >-
        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
    - reference_id: PMID:10811660
      supporting_text: >-
        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
- term:
    id: GO:0000723
    label: telomere maintenance
  evidence_type: TAS
  original_reference_id: PMID:12135483
  review:
    summary: >-
      TAS annotation for telomere maintenance from Chang et al. (PMID:12135483), which
      examined the role of six telomerase subunits (hTR, TEP1, hTERT, hsp90, p23, dyskerin)
      in telomerase regulation. The study confirmed that p23 participates in full enzyme
      activity even though hTERT is the rate-limiting subunit.
    action: ACCEPT
    reason: >-
      Telomere maintenance is well supported for PTGES3. The study showed that antisense
      treatment against p23 decreased telomerase activity (PMID:12135483). This is broader
      than but consistent with the more specific annotation to telomere maintenance via
      telomerase (GO:0007004).
    supported_by:
    - reference_id: PMID:12135483
      supporting_text: >-
        the other telomerase subunits (hTR, TEP1, hsp90, p23, dyskerin) participated in
        full enzyme activity
- term:
    id: GO:0003720
    label: telomerase activity
  evidence_type: IDA
  original_reference_id: PMID:12135483
  review:
    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.
    action: MODIFY
    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_replacement_terms:
    - id: GO:1905323
      label: telomerase holoenzyme complex assembly
    - id: GO:0005697
      label: telomerase holoenzyme complex
    supported_by:
    - reference_id: PMID:12135483
      supporting_text: >-
        Telomerase activity was decreased or abolished by antisense treatment
    - reference_id: PMID:10197982
      supporting_text: >-
        We have identified the molecular chaperones p23 and Hsp90 as proteins that bind to
        the catalytic subunit of telomerase
- term:
    id: GO:0005697
    label: telomerase holoenzyme complex
  evidence_type: IDA
  original_reference_id: PMID:12135483
  review:
    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.
    action: ACCEPT
    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.
    supported_by:
    - reference_id: PMID:12135483
      supporting_text: >-
        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
    - reference_id: PMID:10197982
      supporting_text: >-
        a significant fraction of active telomerase from cell extracts is associated with
        p23 and Hsp90
- term:
    id: GO:0001516
    label: prostaglandin biosynthetic process
  evidence_type: IDA
  original_reference_id: PMID:10922363
  review:
    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.
    action: ACCEPT
    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).
    supported_by:
    - reference_id: PMID:10922363
      supporting_text: >-
        Recombinant p23 expressed in Escherichia coli and 293 cells exhibited all the
        features of PGES activity detected in rat brain cytosol
    - reference_id: PMID:10922363
      supporting_text: >-
        cPGES/p23 was functionally linked with COX-1 in marked preference to COX-2 to
        produce PGE(2) from exogenous and endogenous arachidonic acid
- term:
    id: GO:0050220
    label: prostaglandin-E synthase activity
  evidence_type: IDA
  original_reference_id: PMID:10922363
  review:
    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.
    action: ACCEPT
    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).
    supported_by:
    - reference_id: PMID:10922363
      supporting_text: >-
        Here we report the molecular identification of cytosolic glutathione
        (GSH)-dependent prostaglandin (PG) E(2) synthase (cPGES)
- term:
    id: GO:0007165
    label: signal transduction
  evidence_type: TAS
  original_reference_id: PMID:8114727
  review:
    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.
    action: KEEP_AS_NON_CORE
    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.
    supported_by:
    - reference_id: PMID:8114727
      supporting_text: >-
        Immunoprecipitation of unactivated avian progesterone receptor results in the
        copurification of hsp90, hsp70, and three additional proteins, p54, p50, and p23
core_functions:
- molecular_function:
    id: GO:0050220
    label: prostaglandin-E synthase activity
  description: >-
    PTGES3 (cPGES/p23) catalyzes the GSH-dependent isomerization of PGH2 to PGE2 in the
    cytosol. It is functionally coupled with COX-1 (not COX-2) for immediate prostaglandin
    E2 biosynthesis with Km=14 uM for PGH2 and Vmax=190 nmol/min/mg.
  directly_involved_in:
    - id: GO:0001516
      label: prostaglandin biosynthetic process
  locations:
    - id: GO:0005829
      label: cytosol
  supported_by:
    - reference_id: PMID:10922363
      supporting_text: >-
        Recombinant p23 expressed in Escherichia coli and 293 cells exhibited all the
        features of PGES activity detected in rat brain cytosol.
    - reference_id: PMID:10922363
      supporting_text: >-
        cPGES/p23 was functionally linked with COX-1 in marked preference to COX-2 to
        produce PGE(2) from exogenous and endogenous arachidonic acid.
- molecular_function:
    id: GO:0051879
    label: Hsp90 protein binding
  description: >-
    PTGES3/p23 binds to the N-terminal domain of HSP90 in its ATP-bound conformation,
    stabilizing the "closed 2" HSP90 dimer state and inhibiting/reducing HSP90 ATPase
    activity, thereby regulating progression of the HSP90 chaperone cycle and shaping
    client maturation/release (DOI:10.1038/nrm.2017.20,
    DOI:10.3389/fimmu.2024.1436973). This co-chaperone activity is essential for
    maturation of steroid hormone receptors, hTERT, and other HSP90 client proteins.
    The CS domain in the N-terminal region of p23 mediates HSP90 binding, while the
    unstructured acidic C-terminal tail is important for its independent passive
    chaperoning activity preventing protein aggregation. Beyond the cytosol, nuclear
    p23 can function as an HSP90-independent transcription factor for COX-2 (PTGS2)
    in lung adenocarcinoma, driven by succinate-induced succinylation at K7/K33/K79
    (DOI:10.1126/sciadv.ade0387).
  directly_involved_in:
    - id: GO:0006457
      label: protein folding
    - id: GO:0051131
      label: chaperone-mediated protein complex assembly
    - id: GO:0050821
      label: protein stabilization
  locations:
    - id: GO:0005829
      label: cytosol
    - id: GO:0005654
      label: nucleoplasm
  in_complex:
    id: GO:0101031
    label: protein folding chaperone complex
  supported_by:
    - reference_id: PMID:10543959
      supporting_text: >-
        p23 binds to Hsp90 in its ATP-bound state and, on its own, interacts specifically
        with non-native proteins.
    - reference_id: PMID:10811660
      supporting_text: >-
        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.
    - reference_id: PMID:21183720
      supporting_text: >-
        it is Hsp90's nucleotide-binding domain that triggers the formation of the
        Hsp90(2)p23(2) complex.
- molecular_function:
    id: GO:0070182
    label: DNA polymerase binding
  description: >-
    PTGES3/p23 directly binds hTERT, the telomerase reverse transcriptase catalytic subunit,
    as part of the HSP90-dependent telomerase holoenzyme assembly pathway. Together with
    HSP90, p23 is required for assembly of active telomerase from its components and a
    significant fraction of cellular telomerase is associated with p23 and HSP90.
  directly_involved_in:
    - id: GO:0007004
      label: telomere maintenance via telomerase
    - id: GO:1905323
      label: telomerase holoenzyme complex assembly
  locations:
    - id: GO:0005654
      label: nucleoplasm
  in_complex:
    id: GO:0005697
    label: telomerase holoenzyme complex
  supported_by:
    - reference_id: PMID:10197982
      supporting_text: >-
        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.
    - reference_id: PMID:10197982
      supporting_text: >-
        a significant fraction of active telomerase from cell extracts is associated with
        p23 and Hsp90.
    - reference_id: PMID:19751963
      supporting_text: >-
        curcumin treatment results in a substantial decrease in association of p23 and
        hTERT but does not affect the Hsp90 binding to hTERT.
references:
- id: GO_REF:0000002
  title: Gene Ontology annotation through association of InterPro records with GO
    terms
  findings: []
- id: GO_REF:0000033
  title: Annotation inferences using phylogenetic trees
  findings: []
- id: GO_REF:0000043
  title: Gene Ontology annotation based on UniProtKB/Swiss-Prot keyword mapping
  findings: []
- id: GO_REF:0000044
  title: Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular Location
    vocabulary mapping, accompanied by conservative changes to GO terms applied by
    UniProt
  findings: []
- id: GO_REF:0000120
  title: Combined Automated Annotation using Multiple IEA Methods
  findings: []
- id: PMID:10197982
  title: Functional requirement of p23 and Hsp90 in telomerase complexes.
  findings: []
- id: PMID:10543959
  title: An unstructured C-terminal region of the Hsp90 co-chaperone p23 is important
    for its chaperone function.
  findings: []
- id: PMID:10811660
  title: Crystal structure and activity of human p23, a heat shock protein 90 co-chaperone.
  findings: []
- id: PMID:10922363
  title: Molecular identification of cytosolic prostaglandin E2 synthase that is functionally
    coupled with cyclooxygenase-1 in immediate prostaglandin E2 biosynthesis.
  findings: []
- id: PMID:12077419
  title: Disassembly of transcriptional regulatory complexes by molecular chaperones.
  findings: []
- id: PMID:12135483
  title: Differential regulation of telomerase activity by six telomerase subunits.
  findings: []
- id: PMID:12853476
  title: Cofactor Tpr2 combines two TPR domains and a J domain to regulate the Hsp70/Hsp90
    chaperone system.
  findings: []
- id: PMID:17353931
  title: Large-scale mapping of human protein-protein interactions by mass spectrometry.
  findings: []
- id: PMID:19740745
  title: A truncated form of p23 down-regulates telomerase activity via disruption
    of Hsp90 function.
  findings: []
- id: PMID:19751963
  title: Curcumin inhibits nuclear localization of telomerase by dissociating the
    Hsp90 co-chaperone p23 from hTERT.
  findings: []
- id: PMID:19875381
  title: A proteomic investigation of ligand-dependent HSP90 complexes reveals CHORDC1
    as a novel ADP-dependent HSP90-interacting protein.
  findings: []
- id: PMID:21183720
  title: N-terminal domain of human Hsp90 triggers binding to the cochaperone p23.
  findings: []
- id: PMID:21630459
  title: Proteomic characterization of the human sperm nucleus.
  findings: []
- id: PMID:21988832
  title: Toward an understanding of the protein interaction network of the human liver.
  findings: []
- id: PMID:23741051
  title: Hsp90 cochaperones p23 and FKBP4 physically interact with hAgo2 and activate
    RNA interference-mediated silencing in mammalian cells.
  findings: []
- id: PMID:24981860
  title: Human-chromatin-related protein interactions identify a demethylase complex
    required for chromosome segregation.
  findings: []
- id: PMID:25036637
  title: A quantitative chaperone interaction network reveals the architecture of
    cellular protein homeostasis pathways.
  findings: []
- id: PMID:27353360
  title: The FNIP co-chaperones decelerate the Hsp90 chaperone cycle and enhance drug
    binding.
  findings: []
- id: PMID:29127155
  title: Tumor suppressor Tsc1 is a new Hsp90 co-chaperone that facilitates folding
    of kinase and non-kinase clients.
  findings: []
- id: PMID:33961781
  title: Dual proteome-scale networks reveal cell-specific remodeling of the human
    interactome.
  findings: []
- id: PMID:35271311
  title: 'OpenCell: Endogenous tagging for the cartography of human cellular organization.'
  findings: []
- id: PMID:35914814
  title: 'Chr21 protein-protein interactions: enrichment in proteins involved in intellectual
    disability, autism, and late-onset Alzheimer''s disease.'
  findings: []
- id: PMID:8114727
  title: Characterization of a novel 23-kilodalton protein of unactive progesterone
    receptor complexes.
  findings: []
- id: PMID:9817749
  title: In vivo function of Hsp90 is dependent on ATP binding and ATP hydrolysis.
  findings: []
- id: Reactome:R-HSA-2162123
  title: Synthesis of Prostaglandins (PG) and Thromboxanes (TX)
  findings: []
- id: Reactome:R-HSA-265295
  title: Prostaglandin E synthase isomerizes PGH2 to PGE2
  findings: []
- id: Reactome:R-HSA-3371586
  title: Dissociation of cytosolic HSF1:HSP90 complex
  findings: []
- id: Reactome:R-HSA-5082409
  title: Dissociation of HSF1:HSP90 complex in the nucleus
  findings: []
- id: Reactome:R-HSA-5324617
  title: HSP90:FKBP4:PTGES3 binds HSF1 trimer
  findings: []
- id: Reactome:R-HSA-5324632
  title: Dissociation of cytosolic HSF1:HSP90:HDAC6:PTGES3 upon sensing protein aggregates
  findings: []
- id: Reactome:R-HSA-5618073
  title: FKBP4 replaces FKBP5 within HSP90:ATP:FKBP5:unfolded protein
  findings: []
- id: Reactome:R-HSA-5618080
  title: HSP90:ATP:p23:FKBP52:SHR:SH translocates to the nucleus
  findings: []
- id: Reactome:R-HSA-5618093
  title: ATP hydrolysis by HSP90
  findings: []
- id: Reactome:R-HSA-5618098
  title: p23 (PTGES3) binds HSP90:ATP:FKBP5:nascent protein
  findings: []
- id: Reactome:R-HSA-5618099
  title: NR3C2 ligands bind NR3C2 (in the HSP90 chaperone complex)
  findings: []
- id: Reactome:R-HSA-5618110
  title: p23 (PTGES3) binds HSP90:ATP:FKBP4:nascent protein
  findings: []
- id: Reactome:R-HSA-8936849
  title: AHR:2xHSP90:AIP:PTGES3 binds TCDD
  findings: []
- id: Reactome:R-HSA-8937169
  title: AHR:TCDD:2xHSP90AB1:AIP:PTGES3 translocates from cytosol to nucleoplasm
  findings: []
- id: Reactome:R-HSA-8937191
  title: AHR:TCDD:2xHSP90AB1:AIP:PTGES3 dissociates
  findings: []
- id: Reactome:R-HSA-8939203
  title: HSP90-dependent ATP hydrolysis promotes release of ESR:ESTG from chaperone
    complex
  findings: []
- id: Reactome:R-HSA-8939204
  title: ESTG binds ESR1:chaperone complex
  findings: []
- id: Reactome:R-HSA-9032751
  title: Estrogen-independent phosphorylation of ESR1 S118 by MAPK1 and MAPK3
  findings: []
- id: Reactome:R-HSA-9038161
  title: Progesterone stimulation promotes PGR:P4 binding to ESR1:ESTG
  findings: []
- id: Reactome:R-HSA-9678925
  title: NR3C1 binds NR3C1 agonists
  findings: []
- id: Reactome:R-HSA-9690534
  title: NR3C1 ligands bind NR3C1 (in the HSP90 chaperone complex)
  findings: []
- id: Reactome:R-HSA-9705925
  title: Androgens binds AR (in the HSP90 chaperone complex)
  findings: []
- id: Reactome:R-HSA-9705926
  title: AR binds AR agonists
  findings: []
- id: Reactome:R-HSA-9706837
  title: AR binds AR antagonists
  findings: []
- id: Reactome:R-HSA-9709547
  title: ESTG binds ESR2:chaperone complex
  findings: []
- id: Reactome:R-HSA-9716913
  title: ESR1 binds ESR1 antagonists
  findings: []
- id: Reactome:R-HSA-9716947
  title: ESR1 binds ESR1 agonists
  findings: []
- id: Reactome:R-HSA-9725855
  title: NR3C2 binds NR3C2 antagonists
  findings: []
- id: Reactome:R-HSA-9725885
  title: P4 bind PGR (in the HSP90 chaperone complex)
  findings: []
- id: Reactome:R-HSA-9726509
  title: NR3C2 binds fludrocortisone
  findings: []
- id: Reactome:R-HSA-9726580
  title: PGR binds PGR agonists
  findings: []
- id: Reactome:R-HSA-9726621
  title: PGR binds PGR antagonists
  findings: []
- id: DOI:10.1038/nrm.2017.20
  title: The HSP90 chaperone machinery.
  findings:
  - statement: >-
      p23/PTGES3 stabilizes the HSP90 closed 2 conformational state and
      inhibits/reduces HSP90 ATPase activity, functioning as a late-stage
      co-chaperone regulator of the HSP90 cycle
- id: DOI:10.1126/sciadv.ade0387
  title: The p23 co-chaperone is a succinate-activated COX-2 transcription factor in
    lung adenocarcinoma tumorigenesis.
  findings:
  - statement: >-
      Nuclear p23/PTGES3 functions as an HSP90-independent transcription
      factor for COX-2 (PTGS2), driven by succinate-dependent lysine
      succinylation at K7, K33, and K79 that promotes nuclear translocation
  - statement: >-
      Nuclear p23 expression was detected in >90% of lung adenocarcinoma
      tumor tissues versus ~5% of adjacent normal tissues
  - statement: >-
      Small-molecule inhibitor M16 inhibits p23 succinylation and nuclear
      translocation, suppressing tumor growth in a p23-dependent manner
- id: DOI:10.3389/fimmu.2024.1436973
  title: HSP90 multi-functionality in cancer.
  findings:
  - statement: >-
      2024 review reiterating PTGES3/p23 mechanistic role in slowing HSP90
      ATPase cycle by stabilizing the closed ATP-committed conformation

PTGES3

Gene Description

Existing Annotations Review

Core Functions

PTGES3 (cPGES/p23) catalyzes the GSH-dependent isomerization of PGH2 to PGE2 in the cytosol. It is functionally coupled with COX-1 (not COX-2) for immediate prostaglandin E2 biosynthesis with Km=14 uM for PGH2 and Vmax=190 nmol/min/mg.

References

📚 Additional Documentation

Deep Research Falcon

Question

Gene Research for Functional Annotation

⚠️ CRITICAL: Gene/Protein Identification Context

Target Gene/Protein Identity (from UniProt):

MANDATORY VERIFICATION STEPS:

If Gene Symbol is Ambiguous or You Cannot Find Relevant Literature:

Research Target:

Output

Gene Research for Functional Annotation

⚠️ CRITICAL: Gene/Protein Identification Context

Target Gene/Protein Identity (from UniProt):

MANDATORY VERIFICATION STEPS:

If Gene Symbol is Ambiguous or You Cannot Find Relevant Literature:

Research Target:

Citations

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