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.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0006457 protein folding | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: Phylogenetic (IBA) annotation of protein folding for an FKBP-family PPIase/co-chaperone. FKBP5 has rotamase activity and acts as an HSP90 co-chaperone; the molecular activity (PPIase / HSP90 binding) is the more informative annotation. Reason: FKBP5 contributes to client maturation via PPIase/co-chaperone activity, but the catalytic and binding MFs are the core; protein folding is a downstream/contributory process. Supporting Evidence: file:human/FKBP5/FKBP5-uniprot.txt Immunophilin protein with PPIase and co-chaperone activities |
| 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: PPIase activity is directly demonstrated (IDA PMID:11350175; EC 5.2.1.8) and is core; IBA transfer is consistent with experimental evidence. Supporting Evidence: file:human/FKBP5/FKBP5-uniprot.txt RecName: Full=Peptidyl-prolyl cis-trans isomerase FKBP5 |
| 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: Agrees with stronger IDA/IBA evidence; the FKBP-type domain signature reliably predicts this activity. Supporting Evidence: file:human/FKBP5/FKBP5-uniprot.txt RecName: Full=Peptidyl-prolyl cis-trans isomerase FKBP5 |
| 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 | ACCEPT | Summary: Electronic annotation of cytoplasmic localization (UniProt subcellular-location), the principal site of FKBP5 action. Reason: Correct primary localization; agrees with IDA/HPA cytosol and IC evidence. Supporting Evidence: file:human/FKBP5/FKBP5-uniprot.txt SUBCELLULAR LOCATION: Cytoplasm |
| GO:0006457 protein folding | IEA GO_REF:0000117 | KEEP AS NON CORE | Summary: Electronic annotation of protein folding, duplicating the IBA/IDA/TAS folding annotations. The informative function is the PPIase/co-chaperone activity. Reason: A downstream/contributory process rather than the core molecular function. Supporting Evidence: file:human/FKBP5/FKBP5-uniprot.txt Immunophilin protein with PPIase and co-chaperone activities |
| GO:0031072 heat shock protein binding | IEA GO_REF:0000117 | ACCEPT | Summary: FKBP5 binds HSP90 (via its TPR domain) and is part of a cytoplasmic complex with HSP90AA1 and HSP70. A core molecular function of FKBP5 as an HSP90 co-chaperone. Reason: HSP90 binding is directly documented (IPI PMID:9660753) and central to FKBP5's co-chaperone role. 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... | KEEP AS NON CORE | Summary: IntAct interaction with STK11/LKB1 (Q15831), a kinase HSP90 client. Bare protein binding is uninformative. Reason: A real interaction with a kinase client, but recorded as bare protein binding; consistent with FKBP5's HSP90 co-chaperone role but not individually a core annotation. Supporting Evidence: file:human/FKBP5/FKBP5-goa.tsv GO:0005515 protein binding IPI PMID:14676191 UniProtKB:Q15831 |
| GO:0005515 protein binding | IPI PMID:14743216 A physical and functional map of the human TNF-alpha/NF-kapp... | KEEP AS NON CORE | Summary: IntAct interaction with CHUK/IKK-alpha (O15111). Bare protein binding is uninformative; FKBP5 engages the IKK machinery. Reason: A real interaction (IKK component) recorded as bare protein binding; relevant to FKBP5's NF-kB role but not a core MF annotation. Supporting Evidence: file:human/FKBP5/FKBP5-goa.tsv GO:0005515 protein binding IPI PMID:14743216 UniProtKB:O15111 |
| GO:0005515 protein binding | IPI PMID:19615732 Defining the human deubiquitinating enzyme interaction lands... | KEEP AS NON CORE | Summary: IntAct interaction with USP49 (Q70CQ1). Bare protein binding is uninformative; an isolated interactome hit. Reason: An isolated interaction recorded as bare protein binding; uninformative and not core. Supporting Evidence: file:human/FKBP5/FKBP5-goa.tsv GO:0005515 protein binding IPI PMID:19615732 UniProtKB:Q70CQ1 |
| 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. Proposed replacements: Hsp90 protein binding Supporting Evidence: file:human/FKBP5/FKBP5-goa.tsv GO:0005515 protein binding IPI PMID:19875381 UniProtKB:P07900 |
| GO:0005515 protein binding | IPI PMID:20562859 Network organization of the human autophagy system. | KEEP AS NON CORE | Summary: IntAct interaction with STK11/LKB1 (Q15831), a kinase HSP90 client. Bare protein binding is uninformative. Reason: A real kinase-client interaction recorded as bare protein binding; consistent with the co-chaperone role but not individually core. Supporting Evidence: file:human/FKBP5/FKBP5-goa.tsv GO:0005515 protein binding IPI PMID:20562859 UniProtKB:Q15831 |
| 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. file:human/FKBP5/FKBP5-goa.tsv GO:0005515 protein binding IPI PMID:21170051 UniProtKB:P08238 |
| 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. Proposed replacements: Hsp90 protein binding Supporting Evidence: file:human/FKBP5/FKBP5-goa.tsv GO:0005515 protein binding IPI PMID:21360678 UniProtKB:P07900 |
| GO:0005515 protein binding | IPI PMID:23455922 Interlaboratory reproducibility of large-scale human protein... | KEEP AS NON CORE | Summary: IntAct interaction with CDK9 (P50750), a kinase HSP90 client. Bare protein binding is uninformative. Reason: A real kinase-client interaction recorded as bare protein binding; consistent with the co-chaperone role but not individually core. Supporting Evidence: file:human/FKBP5/FKBP5-goa.tsv GO:0005515 protein binding IPI PMID:23455922 UniProtKB:P50750 |
| GO:0005515 protein binding | IPI PMID:23602568 The protein interaction landscape of the human CMGC kinase g... | KEEP AS NON CORE | Summary: IntAct interactions with CDK9 (P50750) and CDK15 (Q96Q40), kinase HSP90 clients. Bare protein binding is uninformative. Reason: Real kinase-client interactions recorded as bare protein binding; consistent with the co-chaperone role but not individually core. Supporting Evidence: file:human/FKBP5/FKBP5-goa.tsv GO:0005515 protein binding IPI PMID:23602568 UniProtKB:P50750 |
| GO:0005515 protein binding | IPI PMID:24169621 Elucidating novel hepatitis C virus-host interactions using ... | KEEP AS NON CORE | Summary: IntAct interaction with a viral protein (Q9WMX2 processed chain). Bare protein binding is uninformative; a cross-species interactome hit. Reason: An isolated cross-species interaction recorded as bare protein binding; uninformative and not core. Supporting Evidence: file:human/FKBP5/FKBP5-goa.tsv GO:0005515 protein binding IPI PMID:24169621 UniProtKB:Q9WMX2-PRO_0000037552 |
| GO:0005515 protein binding | IPI PMID:24981860 Human-chromatin-related protein interactions identify a deme... | KEEP AS NON CORE | Summary: IntAct interaction with CDK9 (P50750), a kinase HSP90 client. Bare protein binding is uninformative. Reason: A real kinase-client interaction recorded as bare protein binding; not individually core. Supporting Evidence: file:human/FKBP5/FKBP5-goa.tsv GO:0005515 protein binding IPI PMID:24981860 UniProtKB:P50750 |
| 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. Proposed replacements: Hsp90 protein binding Supporting Evidence: file:human/FKBP5/FKBP5-goa.tsv GO:0005515 protein binding IPI PMID:25036637 UniProtKB:P08238 |
| GO:0005515 protein binding | IPI PMID:25852190 Integrative analysis of kinase networks in TRAIL-induced apo... | KEEP AS NON CORE | Summary: IntAct interaction with STK11/LKB1 (Q15831), a kinase HSP90 client. Bare protein binding is uninformative. Reason: A real kinase-client interaction recorded as bare protein binding; not individually core. Supporting Evidence: file:human/FKBP5/FKBP5-goa.tsv GO:0005515 protein binding IPI PMID:25852190 UniProtKB:Q15831 |
| GO:0005515 protein binding | IPI PMID:27086506 HiQuant: Rapid Postquantification Analysis of Large-Scale MS... | KEEP AS NON CORE | Summary: IntAct interaction with KSR2 (Q6VAB6), a kinase scaffold/HSP90 client. Bare protein binding is uninformative. Reason: A real kinase-client interaction recorded as bare protein binding; not individually core. Supporting Evidence: file:human/FKBP5/FKBP5-goa.tsv GO:0005515 protein binding IPI PMID:27086506 UniProtKB:Q6VAB6 |
| GO:0005515 protein binding | IPI PMID:28514442 Architecture of the human interactome defines protein commun... | KEEP AS NON CORE | Summary: IntAct interactions with SGK1 (O00141), MOS (P00540) and STK11 (Q15831), kinase HSP90 clients. Bare protein binding is uninformative. Reason: Real kinase-client interactions recorded as bare protein binding; consistent with the co-chaperone role but not individually core. Supporting Evidence: file:human/FKBP5/FKBP5-goa.tsv GO:0005515 protein binding IPI PMID:28514442 UniProtKB:O00141 |
| 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: file:human/FKBP5/FKBP5-goa.tsv GO:0005515 protein binding IPI PMID:29079741 UniProtKB:P07900 |
| GO:0005515 protein binding | IPI PMID:30021884 Histone Interaction Landscapes Visualized by Crosslinking Ma... | KEEP AS NON CORE | Summary: IntAct interaction with PYGB (P11216). Bare protein binding is uninformative; an isolated interactome hit. Reason: An isolated interaction recorded as bare protein binding; uninformative and not core. Supporting Evidence: file:human/FKBP5/FKBP5-goa.tsv GO:0005515 protein binding IPI PMID:30021884 UniProtKB:P11216 |
| 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: file:human/FKBP5/FKBP5-goa.tsv GO:0005515 protein binding IPI PMID:30382094 UniProtKB:P08238 |
| GO:0005515 protein binding | IPI PMID:32707033 Kinase Interaction Network Expands Functional and Disease Ro... | KEEP AS NON CORE | 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 protein binding from one high-throughput screen with many kinase partners not independently validated; uninformative and not individually core. Supporting Evidence: file:human/FKBP5/FKBP5-goa.tsv GO:0005515 protein binding IPI PMID:32707033 UniProtKB:P50750 |
| GO:0005515 protein binding | IPI PMID:33961781 Dual proteome-scale networks reveal cell-specific remodeling... | KEEP AS NON CORE | 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 protein binding from one high-throughput interactome with many partners not independently validated; uninformative and not individually core. Supporting Evidence: file:human/FKBP5/FKBP5-goa.tsv GO:0005515 protein binding IPI PMID:33961781 UniProtKB:P50750 |
| GO:0005515 protein binding | IPI PMID:34591612 A protein interaction landscape of breast cancer. | KEEP AS NON CORE | Summary: IntAct interactions with EGFR (P00533) and STK11 (Q15831), kinase HSP90 clients. Bare protein binding is uninformative. Reason: Real kinase-client interactions recorded as bare protein binding; not individually core. Supporting Evidence: file:human/FKBP5/FKBP5-goa.tsv GO:0005515 protein binding IPI PMID:34591612 UniProtKB:P00533 |
| 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. Proposed replacements: Hsp90 protein binding Supporting Evidence: file:human/FKBP5/FKBP5-goa.tsv GO:0005515 protein binding IPI PMID:35271311 UniProtKB:P07900 |
| GO:0005515 protein binding | IPI PMID:40205054 Multimodal cell maps as a foundation for structural and func... | KEEP AS NON CORE | Summary: Multimodal cell-maps interactome capturing FKBP5 with CDK9 (P50750) and STK11 (Q15831), kinase HSP90 clients. Bare protein binding is uninformative. Reason: Real kinase-client interactions recorded as bare protein binding; not individually core. Supporting Evidence: file:human/FKBP5/FKBP5-goa.tsv GO:0005515 protein binding IPI PMID:40205054 UniProtKB:P50750 |
| 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 | ACCEPT | Summary: Cytoplasmic localization inferred by sequence similarity from the mouse ortholog, consistent with the principal site of FKBP5 action. Reason: Correct primary localization, corroborated by IC, IDA/HPA and IEA evidence. 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(... | ACCEPT | Summary: Curator-inferred (IC) cytoplasmic site of action from the study showing FKBP5 scaffolds the AKT1-PHLPP1 interaction. The cytoplasm is where FKBP5 acts. Reason: The cytoplasm is the principal site where FKBP5 acts as a co-chaperone and AKT1-PHLPP1 scaffold; well supported. 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: Curated cytosolic localization consistent with the principal site of FKBP5 action. Supporting Evidence: file:human/FKBP5/FKBP5-uniprot.txt SUBCELLULAR LOCATION: Cytoplasm |
| GO:0005829 cytosol | TAS Reactome:R-HSA-5618098 | KEEP AS NON CORE | Summary: Reactome pathway annotation placing FKBP5 in the cytosol; redundant with the primary localization. Reason: Redundant curated cytosol annotation; consistent but duplicative. Supporting Evidence: file:human/FKBP5/FKBP5-uniprot.txt SUBCELLULAR LOCATION: Cytoplasm |
| GO:0005829 cytosol | TAS Reactome:R-HSA-5618105 | KEEP AS NON CORE | Summary: Reactome pathway annotation placing FKBP5 in the cytosol; redundant with the primary localization. Reason: Redundant curated cytosol annotation; consistent but duplicative. Supporting Evidence: file:human/FKBP5/FKBP5-uniprot.txt SUBCELLULAR LOCATION: Cytoplasm |
| GO:0005829 cytosol | TAS Reactome:R-HSA-9909510 | KEEP AS NON CORE | Summary: Reactome pathway annotation placing FKBP5 in the cytosol; redundant with the primary localization. Reason: Redundant curated cytosol annotation; consistent but duplicative. Supporting Evidence: file:human/FKBP5/FKBP5-uniprot.txt SUBCELLULAR LOCATION: Cytoplasm |
| GO:0005829 cytosol | TAS Reactome:R-HSA-9909519 | KEEP AS NON CORE | Summary: Reactome pathway annotation placing FKBP5 in the cytosol; redundant with the primary localization. Reason: Redundant curated cytosol annotation; consistent but duplicative. Supporting Evidence: file:human/FKBP5/FKBP5-uniprot.txt SUBCELLULAR LOCATION: Cytoplasm |
| GO:0016020 membrane | HDA PMID:19946888 Defining the membrane proteome of NK cells. | KEEP AS NON CORE | Summary: High-throughput proteomic detection of FKBP5 in a membrane fraction. FKBP5 is a soluble cytoplasmic protein; this is not a characterized membrane localization. Reason: A high-throughput proteomic detection; plausible co-fractionation but peripheral to the gene's core cytoplasmic function. Supporting Evidence: file:human/FKBP5/FKBP5-goa.tsv GO:0016020 membrane HDA PMID:19946888 |
| 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. Supporting Evidence: file:human/FKBP5/FKBP5-goa.tsv GO:0070062 extracellular exosome HDA PMID:19056867 |
| 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: IDA evidence directly supports PPIase activity (EC 5.2.1.8), a defining core molecular function of FKBP5. Supporting Evidence: file:human/FKBP5/FKBP5-uniprot.txt RecName: Full=Peptidyl-prolyl cis-trans isomerase FKBP5 |
| GO:0006457 protein folding | IDA PMID:11350175 Functional analysis of the Hsp90-associated human peptidyl p... | KEEP AS NON CORE | Summary: Direct experimental evidence linking FKBP5 to protein folding via its rotamase/PPIase activity. The molecular function (PPIase) is the more informative annotation. Reason: FKBP5 contributes to folding through PPIase/co-chaperone activity, but the catalytic PPIase MF is the core; folding is retained as a non-core process. Supporting Evidence: file:human/FKBP5/FKBP5-uniprot.txt Immunophilin protein with PPIase and co-chaperone activities |
| GO:0031072 heat shock protein binding | IPI PMID:9660753 Specific binding of tetratricopeptide repeat proteins to the... | ACCEPT | Summary: Direct interaction (IPI) with HSP90AA1 (P07900), the principal heat shock protein partner of FKBP5. A core co-chaperone molecular function. Reason: Experimentally documented HSP90 binding (the basis of FKBP5's TPR-mediated co-chaperone role) supports heat shock protein binding as a core function. Supporting Evidence: file:human/FKBP5/FKBP5-goa.tsv GO:0031072 heat shock protein binding IPI PMID:9660753 UniProtKB:P07900 |
| 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... | KEEP AS NON CORE | Summary: Author-stated (TAS) involvement of FKBP5 in protein folding. The informative function is its PPIase/co-chaperone activity. Reason: A contributory process downstream of FKBP5's PPIase/co-chaperone activity; the catalytic and binding MFs are the core. Supporting Evidence: file:human/FKBP5/FKBP5-uniprot.txt Immunophilin protein with PPIase and co-chaperone activities |
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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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