PTGES3

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 file:human/PTGES3/PTGES3-deep-research-falcon.md PTGES3/cPGES catalyzes the glutathione-dependent isomerization of PGH2 to PGE2 and is functionally coupled with COX-1-derived PGH2 in current pathway models.
GO:0007004 telomere maintenance via telomerase	IBA GO_REF:0000033	KEEP AS NON CORE	Summary: IBA annotation for telomere maintenance via telomerase is phylogenetically inferred. PTGES3/p23 and HSP90 were shown to be required for assembly and activity of telomerase (PMID:10197982). Inhibition of p23-HSP90 interaction blocks telomerase assembly. Reason: PTGES3 participates in telomere maintenance via telomerase through its role in assembling and stabilizing the telomerase holoenzyme complex with HSP90 (PMID:10197982, PMID:12135483). This is an established client-specific consequence of the p23/HSP90 co-chaperone role, not a core PTGES3 function. Supporting Evidence: PMID:10197982 We have identified the molecular chaperones p23 and Hsp90 as proteins that bind to the catalytic subunit of telomerase. Blockade of this interaction inhibits assembly of active telomerase in vitro.
GO:1905323 telomerase holoenzyme complex assembly	IBA GO_REF:0000033	KEEP AS NON CORE	Summary: IBA annotation for telomerase holoenzyme complex assembly. PTGES3/p23 together with HSP90 is required for in vitro assembly of active telomerase from its components (PMID:10197982). The IDA from PMID:10197982 directly supports this. Reason: Telomerase holoenzyme complex assembly is a well-documented function of PTGES3 in concert with HSP90. Holt et al. (PMID:10197982) showed that p23 and HSP90 bind hTERT and are required for assembly of active telomerase. This should be kept as a non-core HSP90-client assembly consequence rather than elevated to a core function. Supporting Evidence: PMID:10197982 assembly of active telomerase from in vitro-synthesized components requires the contribution of proteins present in reticulocyte extracts. We have identified the molecular chaperones p23 and Hsp90 as proteins that bind to the catalytic subunit of telomerase.
GO:0001516 prostaglandin biosynthetic process	IEA GO_REF:0000120	ACCEPT	Summary: IEA annotation for prostaglandin biosynthetic process from combined automated methods. This is consistent with the core prostaglandin synthase function of PTGES3 (PMID:10922363). Reason: This IEA annotation is consistent with the well-established prostaglandin E synthase activity of PTGES3 and is concordant with the IBA and IDA annotations for the same term.
GO:0005737 cytoplasm	IEA GO_REF:0000044	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 and metabolic process annotations provide better granularity. The separate fatty acid biosynthetic process annotation overstates this terminal prostanoid-synthesis step.
GO:0006631 fatty acid metabolic process	IEA GO_REF:0000043	MARK AS OVER ANNOTATED	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: PTGES3/cPGES converts PGH2 to PGE2 in prostanoid metabolism; it does not broadly participate in fatty acid metabolism. This parent term is therefore too broad for the terminal prostaglandin synthase activity, and the existing prostaglandin biosynthetic and metabolic process annotations provide better specificity.
GO:0006633 fatty acid biosynthetic process	IEA GO_REF:0000043	MARK AS OVER ANNOTATED	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: PTGES3 catalyzes the terminal isomerization of PGH2 to PGE2 in prostaglandin biosynthesis; it does not synthesize fatty acids. This keyword-derived IEA annotation is therefore too broad and biologically misleading compared with the existing prostaglandin biosynthetic process annotation. Proposed replacements: prostaglandin biosynthetic process
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...	KEEP AS NON CORE	Summary: IDA annotation for positive regulation of telomere maintenance via telomerase based on Woo et al. (PMID:19740745). This study showed that overexpression of truncated p23 (Delta p23) down-regulated telomerase activity and decreased hTERT levels, implying that full-length p23 positively regulates telomerase maintenance. Reason: The study demonstrates that PTGES3 positively regulates telomerase activity through its HSP90 co-chaperone function. Truncation of p23 disrupts HSP90 function, leading to reduced telomerase activity, decreased hTERT stability, and inhibited cell growth (PMID:19740745). This is a non-core client-specific effect of the p23/HSP90 system. Supporting Evidence: PMID:19740745 overexpression of Delta p23 resulted in a decrease in hTERT levels, and a down-regulation in telomerase activity
GO:0007004 telomere maintenance via telomerase	IDA PMID:10197982 Functional requirement of p23 and Hsp90 in telomerase comple...	KEEP AS NON CORE	Summary: IDA annotation for telomere maintenance via telomerase from the seminal Holt et al. study (PMID:10197982) that demonstrated p23 and HSP90 are required for telomerase assembly and that a significant fraction of cellular telomerase is associated with p23 and HSP90. Reason: This is well-supported experimental evidence. Holt et al. showed that p23 and HSP90 bind hTERT, that blockade of their interaction inhibits telomerase assembly, and that active telomerase in cell extracts is associated with p23 and HSP90 (PMID:10197982). This represents a non-core HSP90-client consequence of PTGES3/p23. Supporting Evidence: PMID:10197982 a significant fraction of active telomerase from cell extracts is associated with p23 and Hsp90. Consistent with in vitro results, inhibition of Hsp90 function in cells blocks assembly of active telomerase.
GO:0070182 DNA polymerase binding	IPI PMID:10197982 Functional requirement of p23 and Hsp90 in telomerase comple...	KEEP AS NON CORE	Summary: IPI annotation for DNA polymerase binding based on PMID:10197982 (Holt et al., 1999). The study showed that p23 binds to hTERT, the reverse transcriptase catalytic subunit of telomerase. hTERT is a specialized reverse transcriptase (RNA-dependent DNA polymerase). The annotation captures p23's direct binding to this polymerase. Reason: PTGES3/p23 directly binds hTERT, the telomerase reverse transcriptase, which is a specialized DNA polymerase. This was demonstrated by co-immunoprecipitation in PMID:10197982. While hTERT is specifically a reverse transcriptase, the GO:0070182 (DNA polymerase binding) captures the binding to this enzyme class. The annotation is technically supported but non-core and should not be represented as a separate PTGES3 core function. Supporting Evidence: PMID:10197982 We have identified the molecular chaperones p23 and Hsp90 as proteins that bind to the catalytic subunit of telomerase
GO:1905323 telomerase holoenzyme complex assembly	IDA PMID:10197982 Functional requirement of p23 and Hsp90 in telomerase comple...	KEEP AS NON CORE	Summary: IDA annotation for telomerase holoenzyme complex assembly based on Holt et al. (PMID:10197982). The study demonstrated that p23 and HSP90 are required for in vitro assembly of active telomerase from purified components. Reason: This is directly demonstrated experimental evidence. Assembly of active telomerase from in vitro-synthesized components required p23 and HSP90 present in reticulocyte extracts. Blockade of the p23-HSP90 interaction inhibited telomerase assembly (PMID:10197982). Keep as a non-core client-specific outcome of the HSP90 co-chaperone function. Supporting Evidence: PMID:10197982 assembly of active telomerase from in vitro-synthesized components requires the contribution of proteins present in reticulocyte extracts. We have identified the molecular chaperones p23 and Hsp90
GO:0101031 protein folding chaperone complex	IDA PMID:29127155 Tumor suppressor Tsc1 is a new Hsp90 co-chaperone that facil...	ACCEPT	Summary: IDA annotation for protein folding chaperone complex based on Woodford et al. (PMID:29127155). This study identified PTGES3 as part of a complex containing HSP90, HSP70, STIP1, CDC37, PPP5C, TSC1, and TSC2. The complex facilitates folding of kinase and non-kinase clients. Reason: PTGES3 is an established component of the HSP90 chaperone complex. The study (PMID:29127155) identified PTGES3 in a multi-protein chaperone complex with HSP90 and other co-chaperones. This is consistent with the well-known role of PTGES3 as an HSP90 co-chaperone. Supporting Evidence: PMID:29127155 Here, we show that Tsc1 is a new co-chaperone for Hsp90 that inhibits its ATPase activity
GO:0000781 chromosome, telomeric region	IC PMID:12135483 Differential regulation of telomerase activity by six telome...	KEEP AS NON CORE	Summary: IC annotation for chromosome, telomeric region based on Chang et al. (PMID:12135483), inferred from the role of p23 as a telomerase subunit. Since PTGES3 is part of the telomerase holoenzyme and telomerase acts at telomeres, localization to the telomeric region is a reasonable inference. Reason: This is an inferred localization based on PTGES3's role as a component of the telomerase holoenzyme complex (PMID:12135483, PMID:10197982). While the inference is reasonable, the primary localization sites of PTGES3 are the cytosol and nucleoplasm. Telomeric localization is secondary to its main co-chaperone and enzymatic functions. Supporting Evidence: PMID:12135483 Six subunits composing the telomerase complex have been cloned: hTR (human telomerase RNA), TEP1 (telomerase-associated protein 1), hTERT (human telomerase reverse transcriptase), hsp90 (heat shock protein 90), p23, and dyskerin
GO:0032991 protein-containing complex	IMP PMID:10543959 An unstructured C-terminal region of the Hsp90 co-chaperone ...	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...	KEEP AS NON CORE	Summary: IPI annotation for DNA polymerase binding from Lee & Chung (PMID:19751963), which demonstrated that p23 binds hTERT (telomerase reverse transcriptase) and that curcumin treatment dissociates p23 from hTERT. Reason: PTGES3/p23 directly binds hTERT, the reverse transcriptase subunit of telomerase. PMID:19751963 showed that curcumin treatment resulted in decreased association of p23 with hTERT. This is consistent with the earlier finding from PMID:10197982. hTERT is a DNA polymerase (reverse transcriptase), so the term is technically supported but should be kept non-core as a client-specific HSP90/p23 interaction. Supporting Evidence: PMID:19751963 curcumin treatment results in a substantial decrease in association of p23 and hTERT but does not affect the Hsp90 binding to hTERT
GO:0051879 Hsp90 protein binding	IPI PMID:19740745 A truncated form of p23 down-regulates telomerase activity v...	ACCEPT	Summary: IPI annotation for Hsp90 protein binding from Woo et al. (PMID:19740745). The study examined the effects of truncated p23 on HSP90 function and telomerase activity, demonstrating that the p23-HSP90 interaction is critical for telomerase regulation. Reason: Further experimental evidence for PTGES3 binding to HSP90, demonstrated in the context of telomerase regulation. The truncated form of p23 disrupts normal HSP90 function, confirming the functional importance of the p23-HSP90 interaction (PMID:19740745). Supporting Evidence: PMID:19740745 The Hsp90-associated protein p23 modulates Hsp90 activity during the final stages of the chaperone pathway to facilitate maturation of client proteins
GO:0005515 protein binding	IPI PMID:27353360 The FNIP co-chaperones decelerate the Hsp90 chaperone cycle ...	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 now formally obsolete (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 now formally obsolete (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...	KEEP AS NON CORE	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), and should be treated as non-core because it reflects one HSP90-client system rather than PTGES3's primary molecular function. Supporting Evidence: PMID:12135483 the other telomerase subunits (hTR, TEP1, hsp90, p23, dyskerin) participated in full enzyme activity
GO:0003720 telomerase activity	IDA PMID:12135483 Differential regulation of telomerase activity by six telome...	MODIFY	Summary: IDA annotation for telomerase activity from Chang et al. (PMID:12135483). The study identified p23 as one of six telomerase subunits and showed that antisense treatment against p23 abolished telomerase activity. However, PTGES3 does not itself have telomerase catalytic activity; hTERT is the catalytic reverse transcriptase subunit. PTGES3 is a non-catalytic component of the holoenzyme complex. Reason: GO:0003720 (telomerase activity) implies catalytic reverse transcriptase activity, which is performed by hTERT, not by PTGES3/p23. PTGES3 is a structural/regulatory component of the telomerase holoenzyme, required for its assembly and activity, but does not contribute the catalytic function itself. The role of PTGES3 is better described by the existing annotations to telomerase holoenzyme complex assembly (GO:1905323) and telomerase holoenzyme complex (GO:0005697). Annotating PTGES3 to telomerase activity is an over-attribution of catalytic function to a non-catalytic subunit. Proposed replacements: telomerase holoenzyme complex assembly telomerase holoenzyme complex Supporting Evidence: PMID:12135483 Telomerase activity was decreased or abolished by antisense treatment PMID:10197982 We have identified the molecular chaperones p23 and Hsp90 as proteins that bind to the catalytic subunit of telomerase
GO:0005697 telomerase holoenzyme complex	IDA PMID:12135483 Differential regulation of telomerase activity by six telome...	KEEP AS NON CORE	Summary: IDA annotation for telomerase holoenzyme complex from Chang et al. (PMID:12135483), which identified p23 as one of the six subunits of the telomerase complex. Earlier work (PMID:10197982) showed that a significant fraction of active telomerase is associated with p23 and HSP90. Reason: PTGES3/p23 is a confirmed component of the telomerase holoenzyme complex. Multiple studies demonstrate its presence in active telomerase complexes (PMID:10197982, PMID:12135483). This localization annotation appropriately captures PTGES3's role in the telomerase complex, but the role is client-specific and non-core. Supporting Evidence: PMID:12135483 Six subunits composing the telomerase complex have been cloned: hTR (human telomerase RNA), TEP1 (telomerase-associated protein 1), hTERT (human telomerase reverse transcriptase), hsp90 (heat shock protein 90), p23, and dyskerin PMID:10197982 a significant fraction of active telomerase from cell extracts is associated with p23 and Hsp90
GO:0001516 prostaglandin biosynthetic process	IDA PMID:10922363 Molecular identification of cytosolic prostaglandin E2 synth...	ACCEPT	Summary: IDA annotation for prostaglandin biosynthetic process from the landmark study by Tanioka et al. (PMID:10922363) that identified p23 as cytosolic PGE2 synthase. The study demonstrated that recombinant p23 catalyzes GSH-dependent PGE2 synthesis and is functionally coupled with COX-1. Reason: This is direct experimental evidence for a core enzymatic function of PTGES3. The study demonstrated that p23 is the cytosolic PGES, with all features of PGES activity including GSH-dependence, COX-1 coupling, and kinetic parameters (PMID:10922363). Supporting Evidence: PMID:10922363 Recombinant p23 expressed in Escherichia coli and 293 cells exhibited all the features of PGES activity detected in rat brain cytosol PMID:10922363 cPGES/p23 was functionally linked with COX-1 in marked preference to COX-2 to produce PGE(2) from exogenous and endogenous arachidonic acid
GO:0050220 prostaglandin-E synthase activity	IDA PMID:10922363 Molecular identification of cytosolic prostaglandin E2 synth...	ACCEPT	Summary: IDA annotation for prostaglandin-E synthase activity from Tanioka et al. (PMID:10922363). Same landmark study demonstrating enzymatic activity of PTGES3 with Km=14 uM for PGH2 and Vmax=190 nmol/min/mg. Reason: Core enzymatic function directly demonstrated with purified recombinant protein. The catalytic parameters were determined and the enzyme was shown to be GSH-dependent and functionally coupled with COX-1 (PMID:10922363). Supporting Evidence: PMID:10922363 Here we report the molecular identification of cytosolic glutathione (GSH)-dependent prostaglandin (PG) E(2) synthase (cPGES)
GO:0007165 signal transduction	TAS PMID:8114727 Characterization of a novel 23-kilodalton protein of unactiv...	KEEP AS NON CORE	Summary: TAS annotation for signal transduction from Johnson et al. (PMID:8114727), the original characterization of p23 as a component of unactive progesterone receptor complexes. The annotation reflects PTGES3's role in steroid hormone signaling through its association with steroid receptor complexes. Reason: PTGES3 participates in signal transduction indirectly through its role as an HSP90 co-chaperone in steroid receptor maturation. However, signal transduction is very broad and PTGES3 is not a signaling molecule itself; it is a chaperone/enzyme. The annotation is not wrong but represents a downstream biological consequence rather than a core function. The specific chaperone functions (protein folding, chaperone-mediated protein complex assembly) better capture its role. Supporting Evidence: PMID:8114727 Immunoprecipitation of unactivated avian progesterone receptor results in the copurification of hsp90, hsp70, and three additional proteins, p54, p50, and p23

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

Deep Research

Falcon

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