FKBP5 (FKBP51) is a cytoplasmic immunophilin and HSP90 co-chaperone of the FKBP family. It contains two FKBP-type peptidyl-prolyl cis-trans isomerase (PPIase/rotamase) domains (active site inhibited by FK506 and rapamycin) and three C-terminal tetratricopeptide (TPR) repeats that bind the EEVD motif of HSP90. As a component of unligated steroid hormone receptor heterocomplexes (with HSP90 and HSP70), it acts as a negative regulator of glucocorticoid and progesterone receptor signaling, lowering receptor hormone-binding affinity and retaining the unliganded receptor in the cytoplasm; upon hormone binding it is displaced by its paralog FKBP4 (FKBP52). FKBP5 is a glucocorticoid-induced gene that forms an ultra-short negative feedback loop on the HPA axis, and FKBP5 genetic variation is associated with stress-related psychiatric disorders. Beyond steroid signaling, FKBP5 scaffolds the AKT1-PHLPP1 interaction to promote AKT1 dephosphorylation, negatively regulating PI3K/AKT signaling, and it engages numerous protein kinases as HSP90 clients and the IKBKB/IKBKE (IKK) machinery. It localizes mainly to the cytoplasm/cytosol with a nuclear pool. In human prostate cancer cells, FKBP5 positively regulates androgen-receptor ligand-binding capacity, dimer formation and chromatin association. Thus, its inhibition of glucocorticoid receptor signaling cannot be generalized to androgen receptor signaling.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0006457 protein folding | IBA GO_REF:0000033 | ACCEPT | Summary: Core participation in protein folding through PPIase and co-chaperone activities. Reason: The protein performs proline isomerization and participates in the HSP90 client-maturation machinery. A contributing co-chaperone role is participation in folding; it need not be an autonomous ATP-driven foldase. The process is core even though its molecular activities are annotated separately. Supporting Evidence: PMID:11350175 the catalytic activity of prolyl isomerization corresponds well to that of the respective small PPIases. |
| GO:0003755 peptidyl-prolyl cis-trans isomerase activity | IBA GO_REF:0000033 | ACCEPT | Summary: FKBP5 is a peptidyl-prolyl cis-trans isomerase (rotamase, EC 5.2.1.8) inhibited by FK506/rapamycin. A defining core molecular function. Reason: Direct enzymology of human FKBP51 and FKBP52 supports the catalytic PPIase function (PMID:11350175); domain membership is corroborating evidence, not a substitute for that assay. Supporting Evidence: PMID:11350175 the catalytic activity of prolyl isomerization corresponds well to that of the respective small PPIases. |
| GO:0003755 peptidyl-prolyl cis-trans isomerase activity | IEA GO_REF:0000120 | ACCEPT | Summary: Electronic (InterPro/EC-based) annotation of PPIase activity, consistent with the experimentally and phylogenetically supported core catalytic function. Reason: Direct enzymology of human FKBP51 and FKBP52 supports the catalytic PPIase function (PMID:11350175); domain membership is corroborating evidence, not a substitute for that assay. Supporting Evidence: PMID:11350175 the catalytic activity of prolyl isomerization corresponds well to that of the respective small PPIases. |
| GO:0005528 FK506 binding | IEA GO_REF:0000117 | ACCEPT | Summary: FKBP5 binds FK506 (and rapamycin), which inhibits its PPIase activity; the defining property of the FKBP family. Reason: FK506 binding is documented (activity inhibited by FK506 and rapamycin; TAS PMID:9001212) and is a characteristic molecular function. Supporting Evidence: file:human/FKBP5/FKBP5-uniprot.txt ACTIVITY REGULATION: Inhibited by both FK506 and rapamycin. |
| GO:0005634 nucleus | IEA GO_REF:0000044 | KEEP AS NON CORE | Summary: A nuclear pool of FKBP5 is documented (by similarity to mouse Q64378), consistent with its role in steroid receptor regulation. Reason: Nuclear localization is real but secondary to the principal cytoplasmic site of co-chaperone action; retained as non-core. Supporting Evidence: file:human/FKBP5/FKBP5-uniprot.txt SUBCELLULAR LOCATION: Cytoplasm |
| GO:0005737 cytoplasm | IEA GO_REF:0000044 | MODIFY | Summary: Refine to the supported specific function or location. Reason: Refine the broad cytoplasm annotation to the separately supported cytosol location; this does not exclude the documented nuclear or other context-dependent pools. Proposed replacements: cytosol Supporting Evidence: file:human/FKBP5/FKBP5-uniprot.txt SUBCELLULAR LOCATION: Cytoplasm |
| GO:0006457 protein folding | IEA GO_REF:0000117 | ACCEPT | Summary: Core participation in protein folding through PPIase and co-chaperone activities. Reason: The protein performs proline isomerization and participates in the HSP90 client-maturation machinery. A contributing co-chaperone role is participation in folding; it need not be an autonomous ATP-driven foldase. The process is core even though its molecular activities are annotated separately. Supporting Evidence: PMID:11350175 the catalytic activity of prolyl isomerization corresponds well to that of the respective small PPIases. |
| GO:0031072 heat shock protein binding | IEA GO_REF:0000117 | MODIFY | Summary: Refine to the supported specific function or location. Reason: Direct HSP90 interaction is the specific supported co-chaperone binding activity; refine the broader heat-shock-protein term to Hsp90 protein binding, also supported by PMID:9660753. Proposed replacements: Hsp90 protein binding Supporting Evidence: file:human/FKBP5/FKBP5-uniprot.txt Part of a heteromultimeric cytoplasmic complex with HSP90AA1, HSPA1A/HSPA1B and steroid receptors. |
| GO:0005515 protein binding | IPI PMID:14676191 Comprehensive proteomic analysis of human Par protein comple... | REMOVE | Summary: IntAct interaction with STK11/LKB1 (Q15831), a kinase HSP90 client. Bare protein binding is uninformative. Reason: Bare GO:0005515 protein binding carries no functional information, so under the generic protein-binding policy this row is REMOVE. Removal does not mean the reported interaction is false; the summary and any supporting text keep it on record. |
| GO:0005515 protein binding | IPI PMID:14743216 A physical and functional map of the human TNF-alpha/NF-kapp... | REMOVE | Summary: IntAct interaction with CHUK/IKK-alpha (O15111). Bare protein binding is uninformative; FKBP5 engages the IKK machinery. Reason: Bare GO:0005515 protein binding carries no functional information, so under the generic protein-binding policy this row is REMOVE. Removal does not mean the reported interaction is false; the summary and any supporting text keep it on record. |
| GO:0005515 protein binding | IPI PMID:19615732 Defining the human deubiquitinating enzyme interaction lands... | REMOVE | Summary: IntAct interaction with USP49 (Q70CQ1). Bare protein binding is uninformative; an isolated interactome hit. Reason: Bare GO:0005515 protein binding carries no functional information, so under the generic protein-binding policy this row is REMOVE. Removal does not mean the reported interaction is false; the summary and any supporting text keep it on record. |
| GO:0005515 protein binding | IPI PMID:19875381 A proteomic investigation of ligand-dependent HSP90 complexe... | MODIFY | Summary: IntAct interaction with HSP90AA1 (P07900). Bare protein binding is uninformative; the partner is HSP90, the core co-chaperone interaction. Reason: Bare protein binding is uninformative; the WITH partner is HSP90AA1, so Hsp90 protein binding (GO:0051879) is the precise function. UniProt's curated interaction data record the FKBP5-HSP90AA1 interaction. Proposed replacements: Hsp90 protein binding Supporting Evidence: file:human/FKBP5/FKBP5-uniprot.txt Q13451; P07900: HSP90AA1; NbExp=9 PMID:19875381 Here we use tandem affinity purification and LC-MS/MS to investigate the proteome-wide effects of ATP, ADP, and geldanamycin on the constituents of the human HSP90 interactome. |
| GO:0005515 protein binding | IPI PMID:20562859 Network organization of the human autophagy system. | REMOVE | Summary: IntAct interaction with STK11/LKB1 (Q15831), a kinase HSP90 client. Bare protein binding is uninformative. Reason: Bare GO:0005515 protein binding carries no functional information, so under the generic protein-binding policy this row is REMOVE. Removal does not mean the reported interaction is false; the summary and any supporting text keep it on record. |
| GO:0005515 protein binding | IPI PMID:21170051 Mixed Hsp90-cochaperone complexes are important for the prog... | MODIFY | Summary: IntAct interaction with HSP90AB1 (P08238) from a study showing PPIase co-chaperones form mixed/asymmetric ternary Hsp90 complexes during the chaperone cycle. The partner is HSP90. Reason: Bare protein binding is uninformative; the WITH partner is HSP90AB1 and the study demonstrates incorporation of FKBP-type PPIases into the Hsp90 cycle, so Hsp90 protein binding (GO:0051879) is appropriate. Proposed replacements: Hsp90 protein binding Supporting Evidence: PMID:21170051 Mixed Hsp90-cochaperone complexes are important for the progression of the reaction cycle. |
| GO:0005515 protein binding | IPI PMID:21360678 Label-free quantitative proteomics and SAINT analysis enable... | MODIFY | Summary: IntAct interaction with HSP90AA1 (P07900). Bare protein binding is uninformative; the partner is HSP90. Reason: Bare protein binding is uninformative; the WITH partner is HSP90AA1, so Hsp90 protein binding (GO:0051879) is the precise function. UniProt's curated interaction data record the FKBP5-HSP90AA1 interaction. Proposed replacements: Hsp90 protein binding Supporting Evidence: file:human/FKBP5/FKBP5-uniprot.txt Q13451; P07900: HSP90AA1; NbExp=9 |
| GO:0005515 protein binding | IPI PMID:23455922 Interlaboratory reproducibility of large-scale human protein... | REMOVE | Summary: IntAct interaction with CDK9 (P50750), a kinase HSP90 client. Bare protein binding is uninformative. Reason: Bare GO:0005515 protein binding carries no functional information, so under the generic protein-binding policy this row is REMOVE. Removal does not mean the reported interaction is false; the summary and any supporting text keep it on record. |
| GO:0005515 protein binding | IPI PMID:23602568 The protein interaction landscape of the human CMGC kinase g... | REMOVE | Summary: IntAct interactions with CDK9 (P50750) and CDK15 (Q96Q40), kinase HSP90 clients. Bare protein binding is uninformative. Reason: Bare GO:0005515 protein binding carries no functional information, so under the generic protein-binding policy this row is REMOVE. Removal does not mean the reported interaction is false; the summary and any supporting text keep it on record. |
| GO:0005515 protein binding | IPI PMID:24169621 Elucidating novel hepatitis C virus-host interactions using ... | REMOVE | Summary: IntAct interaction with a viral protein (Q9WMX2 processed chain). Bare protein binding is uninformative; a cross-species interactome hit. Reason: Bare GO:0005515 protein binding carries no functional information, so under the generic protein-binding policy this row is REMOVE. Removal does not mean the reported interaction is false; the summary and any supporting text keep it on record. |
| GO:0005515 protein binding | IPI PMID:24981860 Human-chromatin-related protein interactions identify a deme... | REMOVE | Summary: IntAct interaction with CDK9 (P50750), a kinase HSP90 client. Bare protein binding is uninformative. Reason: Bare GO:0005515 protein binding carries no functional information, so under the generic protein-binding policy this row is REMOVE. Removal does not mean the reported interaction is false; the summary and any supporting text keep it on record. |
| GO:0005515 protein binding | IPI PMID:25036637 A quantitative chaperone interaction network reveals the arc... | MODIFY | Summary: Quantitative chaperone interaction network (Taipale et al.) capturing FKBP5 with HSP90AB1 (P08238) and many kinase clients (STK11, CDK9, EGFR, MOS, KSR2, CDK15, MCM7), placing it in the Hsp90 co-chaperone module. The central interaction is with HSP90. Reason: Bare protein binding is uninformative; the principal partner is HSP90AB1 within the Hsp90 co-chaperone network, so Hsp90 protein binding (GO:0051879) is appropriate. UniProt's curated interaction data record the FKBP5-HSP90AB1 interaction. Proposed replacements: Hsp90 protein binding Supporting Evidence: file:human/FKBP5/FKBP5-uniprot.txt Q13451; P08238: HSP90AB1; NbExp=17 PMID:25036637 surveying the physical interaction landscape of all known Hsp90 co-chaperones and several known Hsp70 cochaperones |
| GO:0005515 protein binding | IPI PMID:25852190 Integrative analysis of kinase networks in TRAIL-induced apo... | REMOVE | Summary: IntAct interaction with STK11/LKB1 (Q15831), a kinase HSP90 client. Bare protein binding is uninformative. Reason: Bare GO:0005515 protein binding carries no functional information, so under the generic protein-binding policy this row is REMOVE. Removal does not mean the reported interaction is false; the summary and any supporting text keep it on record. |
| GO:0005515 protein binding | IPI PMID:27086506 HiQuant: Rapid Postquantification Analysis of Large-Scale MS... | REMOVE | Summary: IntAct interaction with KSR2 (Q6VAB6), a kinase scaffold/HSP90 client. Bare protein binding is uninformative. Reason: Bare GO:0005515 protein binding carries no functional information, so under the generic protein-binding policy this row is REMOVE. Removal does not mean the reported interaction is false; the summary and any supporting text keep it on record. |
| GO:0005515 protein binding | IPI PMID:28514442 Architecture of the human interactome defines protein commun... | REMOVE | Summary: IntAct interactions with SGK1 (O00141), MOS (P00540) and STK11 (Q15831), kinase HSP90 clients. Bare protein binding is uninformative. Reason: Bare GO:0005515 protein binding carries no functional information, so under the generic protein-binding policy this row is REMOVE. Removal does not mean the reported interaction is false; the summary and any supporting text keep it on record. |
| GO:0005515 protein binding | IPI PMID:29079741 Combined x-ray crystallography and computational modeling ap... | MODIFY | Summary: IntAct interaction with HSP90AA1 (P07900). Bare protein binding is uninformative; the partner is HSP90. Reason: Bare protein binding is uninformative; the WITH partner is HSP90AA1, so Hsp90 protein binding (GO:0051879) is the precise function. Proposed replacements: Hsp90 protein binding Supporting Evidence: PMID:29079741 the Hsp90 C-terminal peptide binds to the TPR domain of FKBP51 with the help of di-carboxylate clamp file:human/FKBP5/FKBP5-uniprot.txt Q13451; P07900: HSP90AA1; NbExp=9 |
| GO:0005515 protein binding | IPI PMID:30021884 Histone Interaction Landscapes Visualized by Crosslinking Ma... | REMOVE | Summary: IntAct interaction with PYGB (P11216). Bare protein binding is uninformative; an isolated interactome hit. Reason: Bare GO:0005515 protein binding carries no functional information, so under the generic protein-binding policy this row is REMOVE. Removal does not mean the reported interaction is false; the summary and any supporting text keep it on record. |
| GO:0005515 protein binding | IPI PMID:30382094 Structure and pro-toxic mechanism of the human Hsp90/PPIase/... | MODIFY | Summary: IntAct interactions with HSP90AB1 (P08238) and MAPT/tau (P10636-8). The HSP90 partner is the core co-chaperone interaction; tau is a known FKBP-family interactor. Reason: Bare protein binding is uninformative; the principal WITH partner is HSP90AB1, so Hsp90 protein binding (GO:0051879) is the appropriate specific term. Proposed replacements: Hsp90 protein binding Supporting Evidence: PMID:30382094 we determined the solution structures of the human Hsp90/FKBP51 complex and the Hsp90/FKBP51 complex bound to its intrinsically disordered substrate Tau. file:human/FKBP5/FKBP5-uniprot.txt Q13451; P08238: HSP90AB1; NbExp=17 |
| GO:0005515 protein binding | IPI PMID:32707033 Kinase Interaction Network Expands Functional and Disease Ro... | REMOVE | Summary: A high-throughput screen reporting FKBP5 interactions with multiple kinases (MOS, CDK9, STK11, ULK3, KSR2, CILK1). Bare protein binding from a broad screen is uninformative. Reason: Bare GO:0005515 protein binding carries no functional information, so under the generic protein-binding policy this row is REMOVE. Removal does not mean the reported interaction is false; the summary and any supporting text keep it on record. |
| GO:0005515 protein binding | IPI PMID:33961781 Dual proteome-scale networks reveal cell-specific remodeling... | REMOVE | Summary: BioPlex affinity-purification interactome reporting many FKBP5 kinase-client interactions (SGK1, CHUK, MOS, CDK9, STK11, ULK3, CDK15, CILK1). Bare protein binding from a broad screen is uninformative. Reason: Bare GO:0005515 protein binding carries no functional information, so under the generic protein-binding policy this row is REMOVE. Removal does not mean the reported interaction is false; the summary and any supporting text keep it on record. |
| GO:0005515 protein binding | IPI PMID:34591612 A protein interaction landscape of breast cancer. | REMOVE | Summary: IntAct interactions with EGFR (P00533) and STK11 (Q15831), kinase HSP90 clients. Bare protein binding is uninformative. Reason: Bare GO:0005515 protein binding carries no functional information, so under the generic protein-binding policy this row is REMOVE. Removal does not mean the reported interaction is false; the summary and any supporting text keep it on record. |
| GO:0005515 protein binding | IPI PMID:35271311 OpenCell: Endogenous tagging for the cartography of human ce... | MODIFY | Summary: A high-throughput screen reporting FKBP5 with HSP90AA1/AB1 and several kinases (CHUK, CDK9, MCM7, PYGB). The HSP90 interactions are the core co-chaperone associations. Reason: Bare protein binding is uninformative; the principal partners include HSP90AA1/AB1, so Hsp90 protein binding (GO:0051879) is appropriate. UniProt's curated interaction data record FKBP5 interactions with both HSP90AA1 and HSP90AB1. Proposed replacements: Hsp90 protein binding Supporting Evidence: file:human/FKBP5/FKBP5-uniprot.txt Q13451; P07900: HSP90AA1; NbExp=9 file:human/FKBP5/FKBP5-uniprot.txt Q13451; P08238: HSP90AB1; NbExp=17 |
| GO:0005515 protein binding | IPI PMID:40205054 Multimodal cell maps as a foundation for structural and func... | REMOVE | Summary: Multimodal cell-maps interactome capturing FKBP5 with CDK9 (P50750) and STK11 (Q15831), kinase HSP90 clients. Bare protein binding is uninformative. Reason: Bare GO:0005515 protein binding carries no functional information, so under the generic protein-binding policy this row is REMOVE. Removal does not mean the reported interaction is false; the summary and any supporting text keep it on record. |
| GO:0005634 nucleus | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Nuclear localization inferred by sequence similarity from the mouse ortholog (Q64378). Reason: A real but secondary localization relative to the principal cytoplasmic site of action; retained as non-core. Supporting Evidence: file:human/FKBP5/FKBP5-uniprot.txt SUBCELLULAR LOCATION: Cytoplasm |
| GO:0005737 cytoplasm | ISS GO_REF:0000024 | MODIFY | Summary: Refine to the supported specific function or location. Reason: Refine the broad cytoplasm annotation to the separately supported cytosol location; this does not exclude the documented nuclear or other context-dependent pools. Proposed replacements: cytosol Supporting Evidence: file:human/FKBP5/FKBP5-uniprot.txt SUBCELLULAR LOCATION: Cytoplasm |
| GO:0005737 cytoplasm | IC PMID:28147277 Regulation of Serine-Threonine Kinase Akt Activation by NAD(... | MODIFY | Summary: Refine to the supported specific function or location. Reason: Refine the broad cytoplasm annotation to the separately supported cytosol location; this does not exclude the documented nuclear or other context-dependent pools. Proposed replacements: cytosol Supporting Evidence: file:human/FKBP5/FKBP5-uniprot.txt SUBCELLULAR LOCATION: Cytoplasm |
| GO:0030674 protein-macromolecule adaptor activity | IDA PMID:28147277 Regulation of Serine-Threonine Kinase Akt Activation by NAD(... | ACCEPT | Summary: FKBP5 acts as a scaffold/adaptor that promotes the AKT1-PHLPP1 interaction, enhancing AKT1 dephosphorylation. This adaptor activity is a genuine core molecular function (also the basis for its negative regulation of PI3K/AKT signaling). Reason: Directly demonstrated (IDA) scaffolding of the AKT1-PHLPP1 interaction; FKBP5 also acts as an adaptor bridging steroid receptors to HSP90. Supporting Evidence: file:human/FKBP5/FKBP5-uniprot.txt Acts as a regulator of Akt/AKT1 activity by promoting the interaction between Akt/AKT1 and PHLPP1 |
| GO:0051898 negative regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction | IDA PMID:28363942 USP49 negatively regulates tumorigenesis and chemoresistance... | ACCEPT | Summary: By scaffolding AKT1-PHLPP1, FKBP5 enhances AKT1 dephosphorylation and thereby negatively regulates PI3K/AKT signaling. A directly demonstrated biological process. Reason: Directly demonstrated (IDA); a genuine FKBP5 biological process linked to its scaffold/adaptor activity. Supporting Evidence: file:human/FKBP5/FKBP5-uniprot.txt enhancing dephosphorylation and subsequent activation of Akt/AKT1 |
| GO:0005829 cytosol | TAS Reactome:R-HSA-5618073 | ACCEPT | Summary: Reactome pathway annotation placing FKBP5 in the cytosol, consistent with its primary localization. Reason: Cytosol is a core location of the HSP90 co-chaperone. The term denotes the same supported localization across experimental, phylogenetic and pathway-derived rows. Supporting Evidence: file:human/FKBP5/FKBP5-uniprot.txt SUBCELLULAR LOCATION: Cytoplasm |
| GO:0005829 cytosol | TAS Reactome:R-HSA-5618098 | ACCEPT | Summary: Reactome pathway annotation placing FKBP5 in the cytosol; redundant with the primary localization. Reason: Cytosol is a core location of the HSP90 co-chaperone. The term denotes the same supported localization across experimental, phylogenetic and pathway-derived rows. Supporting Evidence: file:human/FKBP5/FKBP5-uniprot.txt SUBCELLULAR LOCATION: Cytoplasm |
| GO:0005829 cytosol | TAS Reactome:R-HSA-5618105 | ACCEPT | Summary: Reactome pathway annotation placing FKBP5 in the cytosol; redundant with the primary localization. Reason: Cytosol is a core location of the HSP90 co-chaperone. The term denotes the same supported localization across experimental, phylogenetic and pathway-derived rows. Supporting Evidence: file:human/FKBP5/FKBP5-uniprot.txt SUBCELLULAR LOCATION: Cytoplasm |
| GO:0005829 cytosol | TAS Reactome:R-HSA-9909510 | ACCEPT | Summary: Reactome pathway annotation placing FKBP5 in the cytosol; redundant with the primary localization. Reason: Cytosol is a core location of the HSP90 co-chaperone. The term denotes the same supported localization across experimental, phylogenetic and pathway-derived rows. Supporting Evidence: file:human/FKBP5/FKBP5-uniprot.txt SUBCELLULAR LOCATION: Cytoplasm |
| GO:0005829 cytosol | TAS Reactome:R-HSA-9909519 | ACCEPT | Summary: Reactome pathway annotation placing FKBP5 in the cytosol; redundant with the primary localization. Reason: Cytosol is a core location of the HSP90 co-chaperone. The term denotes the same supported localization across experimental, phylogenetic and pathway-derived rows. Supporting Evidence: file:human/FKBP5/FKBP5-uniprot.txt SUBCELLULAR LOCATION: Cytoplasm |
| GO:0016020 membrane | HDA PMID:19946888 Defining the membrane proteome of NK cells. | UNDECIDED | Summary: Membrane-fraction proteomics assignment requires target-level resolution. Reason: This UNDECIDED assessment supersedes the dated manual OMICS_EVIDENCE reassessment of 2026-10-10, which changed KEEP_AS_NON_CORE to MARK_AS_OVER_ANNOTATED. Absence of a membrane anchor does not exclude peripheral or transient membrane association. PMID:19946888 isolated an NK-cell membrane fraction containing many proteins predicted to associate transiently with membranes. The accessible abstract does not resolve the target-specific FKBP5 identification or contamination controls; the publisher full-text URL returned HTTP 403 on follow-up. The unresolved question is whether this fractionation establishes biologically meaningful FKBP5 membrane association, not whether FKBP5 is an integral membrane protein. Neither a negative localization conclusion nor automatic restoration is justified from the available source. Supporting Evidence: PMID:19946888 The remaining species were largely involved in cellular processes and molecular functions that could be predicted to be transiently associated with membranes. file:human/FKBP5/FKBP5-uniprot.txt SUBCELLULAR LOCATION: Cytoplasm |
| GO:0070062 extracellular exosome | HDA PMID:19056867 Large-scale proteomics and phosphoproteomics of urinary exos... | KEEP AS NON CORE | Summary: Detection of FKBP5 in extracellular exosome proteomics. As an abundant cytoplasmic protein, FKBP5 is frequently detected in exosome preparations. Reason: A high-throughput proteomic detection; peripheral to the gene's core cytoplasmic function. The cited study is a urinary-exosome proteome survey; this defers to the curator's reading of its data for FKBP5. Supporting Evidence: PMID:19056867 Here, we used LC-MS/MS to profile the proteome of human urinary exosomes. |
| GO:0003755 peptidyl-prolyl cis-trans isomerase activity | IDA PMID:11350175 Functional analysis of the Hsp90-associated human peptidyl p... | ACCEPT | Summary: Direct experimental demonstration of FKBP5 peptidyl-prolyl cis-trans isomerase activity. The core catalytic function. Reason: Direct enzymology of human FKBP51 and FKBP52 supports the catalytic PPIase function (PMID:11350175); domain membership is corroborating evidence, not a substitute for that assay. Supporting Evidence: PMID:11350175 the catalytic activity of prolyl isomerization corresponds well to that of the respective small PPIases. |
| GO:0006457 protein folding | IDA PMID:11350175 Functional analysis of the Hsp90-associated human peptidyl p... | ACCEPT | Summary: Core participation in protein folding through PPIase and co-chaperone activities. Reason: The protein performs proline isomerization and participates in the HSP90 client-maturation machinery. A contributing co-chaperone role is participation in folding; it need not be an autonomous ATP-driven foldase. The process is core even though its molecular activities are annotated separately. Supporting Evidence: PMID:11350175 the catalytic activity of prolyl isomerization corresponds well to that of the respective small PPIases. |
| GO:0031072 heat shock protein binding | IPI PMID:9660753 Specific binding of tetratricopeptide repeat proteins to the... | MODIFY | Summary: Refine to the supported specific function or location. Reason: Direct HSP90 interaction is the specific supported co-chaperone binding activity; refine the broader heat-shock-protein term to Hsp90 protein binding, also supported by PMID:9660753. Proposed replacements: Hsp90 protein binding Supporting Evidence: PMID:9660753 was found to mediate the interaction of hsp90 with TPR-containing sequences from the hsp90 cofactors FKBP51/54 and FKBP52. |
| GO:0005528 FK506 binding | TAS PMID:9001212 Molecular cloning of human FKBP51 and comparisons of immunop... | ACCEPT | Summary: Author-stated FK506 binding. FK506 binding is the defining property of the FKBP family and inhibits FKBP5's PPIase activity. Reason: FK506 binding is documented and characteristic of the FKBP family. Supporting Evidence: file:human/FKBP5/FKBP5-uniprot.txt ACTIVITY REGULATION: Inhibited by both FK506 and rapamycin. |
| GO:0006457 protein folding | TAS PMID:9001212 Molecular cloning of human FKBP51 and comparisons of immunop... | ACCEPT | Summary: Core participation in protein folding through PPIase and co-chaperone activities. Reason: The protein performs proline isomerization and participates in the HSP90 client-maturation machinery. A contributing co-chaperone role is participation in folding; it need not be an autonomous ATP-driven foldase. The process is core even though its molecular activities are annotated separately. Supporting Evidence: PMID:11350175 the catalytic activity of prolyl isomerization corresponds well to that of the respective small PPIases. |
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Download this section (compressed HTML)Q: How do FKBP5 and FKBP4 produce opposite effects on glucocorticoid receptor activity despite sharing the same TPR-HSP90 binding mode and overall domain architecture?
Q: Is FKBP5's PPIase catalytic activity required for its negative regulation of steroid receptors and for AKT1-PHLPP1 scaffolding, or are these adaptor functions catalysis-independent?
Q: How does glucocorticoid-induced FKBP5 expression quantitatively tune the HPA-axis negative feedback loop, and how do disease-associated FKBP5 variants alter this?
Experiment: Compare FKBP5 wild-type versus PPIase-dead and TPR-deletion constructs for their ability to suppress glucocorticoid receptor transcriptional activity and to scaffold AKT1-PHLPP1.
Experiment: Reconstitute steroid receptor-HSP90-FKBP5 versus -FKBP4 heterocomplexes in vitro and measure receptor hormone-binding affinity and the FKBP5-to-FKBP4 exchange upon ligand binding.
Experiment: Use FKBP5 knockout/knockdown with AKT phosphorylation readouts (and PHLPP1 co-depletion) to confirm the scaffold mechanism for negative regulation of PI3K/AKT signaling.
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