FKBP5

UniProt ID: Q13451
Organism: Homo sapiens
Review Status: COMPLETE
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Gene Description

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.

Existing Annotations Review

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

Core Functions

Peptidyl-prolyl cis-trans isomerase (rotamase, EC 5.2.1.8), the catalytic activity of the FKBP domain, inhibited by FK506 and rapamycin.

Molecular Function:
peptidyl-prolyl cis-trans isomerase activity
Cellular Locations:
cytoplasm
Supporting Evidence:
  • file:human/FKBP5/FKBP5-uniprot.txt
    RecName: Full=Peptidyl-prolyl cis-trans isomerase FKBP5

HSP90 co-chaperone that binds HSP90 via its TPR domain and is part of unligated steroid hormone receptor heterocomplexes; negative regulator of glucocorticoid and progesterone receptor signaling (antagonist of FKBP4).

Molecular Function:
heat shock protein binding
Cellular Locations:
cytoplasm
Supporting Evidence:
  • file:human/FKBP5/FKBP5-uniprot.txt
    Part of a heteromultimeric cytoplasmic complex with HSP90AA1, HSPA1A/HSPA1B and steroid receptors.
  • file:human/FKBP5/FKBP5-goa.tsv
    GO:0031072 heat shock protein binding IPI PMID:9660753 UniProtKB:P07900

Scaffold/adaptor that promotes the AKT1-PHLPP1 interaction, enhancing PHLPP1-mediated AKT1 dephosphorylation and thereby negatively regulating PI3K/AKT signaling.

Molecular Function:
protein-macromolecule adaptor activity
Cellular Locations:
cytoplasm
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

References

GO_REF:0000024
Manual transfer of experimentally-verified manual GO annotation data to orthologs by curator judgment of sequence similarity
GO_REF:0000033
Annotation inferences using phylogenetic trees
GO_REF:0000044
Gene Ontology annotation through association of InterPro records with GO terms
GO_REF:0000117
Electronic Gene Ontology annotations created by ARBA machine learning models
GO_REF:0000120
Combined Automated Annotation using Multiple IEA Methods
PMID:11350175
Functional analysis of the Hsp90-associated human peptidyl prolyl cis/trans isomerases FKBP51, FKBP52 and Cyp40.
  • Direct demonstration of FKBP5/FKBP51 peptidyl-prolyl cis-trans isomerase (rotamase) activity.
PMID:14676191
Comprehensive proteomic analysis of human Par protein complexes reveals an interconnected protein network.
PMID:14743216
A physical and functional map of the human TNF-alpha/NF-kappa B signal transduction pathway.
PMID:19056867
Large-scale proteomics and phosphoproteomics of urinary exosomes.
PMID:19615732
Defining the human deubiquitinating enzyme interaction landscape.
PMID:19875381
A proteomic investigation of ligand-dependent HSP90 complexes reveals CHORDC1 as a novel ADP-dependent HSP90-interacting protein.
PMID:19946888
Defining the membrane proteome of NK cells.
PMID:20562859
Network organization of the human autophagy system.
PMID:21170051
Mixed Hsp90-cochaperone complexes are important for the progression of the reaction cycle.
  • PPIase co-chaperones such as FKBP5 are incorporated into asymmetric mixed Hsp90-cochaperone complexes during the chaperone reaction cycle.
PMID:21360678
Label-free quantitative proteomics and SAINT analysis enable interactome mapping for the human Ser/Thr protein phosphatase 5.
PMID:23455922
Interlaboratory reproducibility of large-scale human protein-complex analysis by standardized AP-MS.
PMID:23602568
The protein interaction landscape of the human CMGC kinase group.
PMID:24169621
Elucidating novel hepatitis C virus-host interactions using combined mass spectrometry and functional genomics approaches.
PMID:24981860
Human-chromatin-related protein interactions identify a demethylase complex required for chromosome segregation.
PMID:25036637
A quantitative chaperone interaction network reveals the architecture of cellular protein homeostasis pathways.
  • FKBP5 is part of the Hsp90 co-chaperone module, interacting with HSP90 and numerous protein kinase clients.
PMID:25852190
Integrative analysis of kinase networks in TRAIL-induced apoptosis provides a source of potential targets for combination therapy.
PMID:27086506
HiQuant: Rapid Postquantification Analysis of Large-Scale MS-Generated Proteomics Data.
PMID:28147277
Regulation of Serine-Threonine Kinase Akt Activation by NAD(+)-Dependent Deacetylase SIRT7.
  • FKBP5 (FKBP51) promotes the interaction between AKT1 and PHLPP1, acting as a scaffold/adaptor to enhance AKT1 dephosphorylation; acetylation regulates this scaffolding.
PMID:28363942
USP49 negatively regulates tumorigenesis and chemoresistance through FKBP51-AKT signaling.
  • FKBP5 negatively regulates PI3K/AKT signal transduction by enhancing PHLPP1-mediated AKT1 dephosphorylation.
PMID:28514442
Architecture of the human interactome defines protein communities and disease networks.
PMID:29079741
Combined x-ray crystallography and computational modeling approach to investigate the Hsp90 C-terminal peptide binding to FKBP51.
PMID:30021884
Histone Interaction Landscapes Visualized by Crosslinking Mass Spectrometry in Intact Cell Nuclei.
PMID:30382094
Structure and pro-toxic mechanism of the human Hsp90/PPIase/Tau complex.
PMID:32707033
Kinase Interaction Network Expands Functional and Disease Roles of Human Kinases.
PMID:33961781
Dual proteome-scale networks reveal cell-specific remodeling of the human interactome.
  • BioPlex affinity-purification interactome capturing FKBP5 interactions with numerous protein kinase clients.
PMID:34591612
A protein interaction landscape of breast cancer.
PMID:35271311
OpenCell: Endogenous tagging for the cartography of human cellular organization.
PMID:40205054
Multimodal cell maps as a foundation for structural and functional genomics.
  • Multimodal cell-maps interactome capturing FKBP5 interactions with kinase clients.
PMID:9001212
Molecular cloning of human FKBP51 and comparisons of immunophilin interactions with Hsp90 and progesterone receptor.
  • FKBP5 (FKBP51) is an FK506-binding immunophilin with rotamase/PPIase activity.
PMID:9660753
Specific binding of tetratricopeptide repeat proteins to the C-terminal 12-kDa domain of Hsp90.
  • FKBP5 directly binds HSP90AA1.
Reactome:R-HSA-5618073
Reactome: FKBP5 in cytosol.
Reactome:R-HSA-5618098
Reactome: FKBP5 in cytosol.
Reactome:R-HSA-5618105
Reactome: FKBP5 in cytosol.
Reactome:R-HSA-9909510
Reactome: FKBP5 in cytosol.
Reactome:R-HSA-9909519
Reactome: FKBP5 in cytosol.
file:human/FKBP5/FKBP5-uniprot.txt
UniProt entry Q13451 (FKBP5_HUMAN), Peptidyl-prolyl cis-trans isomerase FKBP5 / FKBP51
  • Immunophilin with PPIase and co-chaperone activities; component of unligated steroid receptor heterocomplexes via HSP90 (negative regulator, displaced by FKBP4 on ligand binding); scaffolds AKT1-PHLPP1 to negatively regulate PI3K/AKT; engages IKBKB/IKBKE; cytoplasmic and nuclear localization.

Suggested Questions for Experts

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?

Suggested Experiments

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.

📚 Additional Documentation

Notes

(FKBP5-notes.md)

FKBP5 (FKBP51) research notes

UniProt: Q13451. EC 5.2.1.8 (peptidyl-prolyl cis-trans isomerase). Two FKBP-type PPIase
domains + three TPR repeats. Two isoforms (Q13451-1 displayed; -2 = VSP_044820/VSP_044821).

Core biology (well-established)

  • Immunophilin with PPIase + co-chaperone activities [PMID:11350175; uniprot "Immunophilin
    protein with PPIase and co-chaperone activities"]. PPIase directly demonstrated (IDA PMID:11350175);
    EC 5.2.1.8; inhibited by FK506 and rapamycin.
  • Component of unligated steroid receptor heterocomplexes via HSP90; maintains complex in
    cytoplasm when unliganded [uniprot "Component of unligated steroid receptors heterocomplexes...
    maintaining the complex into the cytoplasm when unliganded"]. NEGATIVE regulator of GR/PR
    (contrast FKBP4/FKBP52 positive). Upon ligand binding FKBP5 dissociates and FKBP4 takes its
    place [uniprot "Upon ligand binding dissociates from the complex and FKBP4 takes its place"].
  • Part of heteromultimeric cytoplasmic complex with HSP90AA1, HSPA1A/B and steroid receptors.
  • Regulator of Akt/AKT1: scaffolds AKT1-PHLPP1 to enhance AKT1 dephosphorylation -> negative
    regulation of PI3K/AKT signaling [PMID:28147277, PMID:28363942; uniprot "Acts as a regulator
    of Akt/AKT1 activity by promoting the interaction between Akt/AKT1 and PHLPP1"]. This is the
    basis for GO:0030674 adaptor activity (IDA) and GO:0051898 neg reg PI3K/AKT (IDA).
  • IKK assembly: interacts with IKBKE/IKBKB, facilitates IKK complex assembly, NF-kB activation,
    IFN production [PMID:26101251, PMID:31434731].
  • Stress/psychiatric genetics: FKBP5 polymorphisms (rs1360780) implicated in HPA-axis regulation,
    PTSD/depression risk (GR negative feedback). (Well-established in literature, not in GOA terms.)

Subcellular location

Cytoplasm (primary), nucleus (both ISS from mouse Q64378; cytosol IDA HPA). Membrane (HDA) and
extracellular exosome (HDA) are high-throughput proteomics — non-core.

Interactome IPI partners (bare protein binding)

Many are kinase clients consistent with HSP90 co-chaperone role: STK11/LKB1 (Q15831), CDK9 (P50750),
CDK15 (Q96Q40), MOS (P00540), SGK1 (O00141), EGFR (P00533), KSR2 (Q6VAB6), CILK1 (Q9UPZ9),
ULK3 (Q6PHR2), MCM7 (P33993), PYGB (P11216), CHUK/IKK-alpha (O15111), MAPT/tau (P10636-8),
USP49 (Q70CQ1), MCMBP (Q9BTE3-2). HSP90AA1 (P07900), HSP90AB1 (P08238). 9660753=HSP90 IPI.

Action plan

  • PPIase activity GO:0003755 (IDA/IBA/IEA): ACCEPT core MF.
  • protein folding GO:0006457 (IBA/IEA/IDA/TAS): KEEP_AS_NON_CORE.
  • FK506 binding GO:0005528 (IEA/TAS): ACCEPT.
  • heat shock protein binding GO:0031072 (IPI 9660753 HSP90; IEA): ACCEPT core MF.
  • adaptor activity GO:0030674 (IDA 28147277, AKT1-PHLPP1 scaffold): ACCEPT core MF.
  • neg reg PI3K/AKT GO:0051898 (IDA 28363942): ACCEPT (real BP).
  • cytoplasm/cytosol/nucleus: ACCEPT primary; redundant Reactome cytosol KEEP_AS_NON_CORE.
  • membrane/exosome HDA: KEEP_AS_NON_CORE.
  • protein binding IPI block: KEEP_AS_NON_CORE generally; MODIFY HSP90 partners (P07900/P08238)
    to Hsp90 protein binding; MARK_AS_OVER_ANNOTATED the broad multi-partner screens.

Pn Notes

(FKBP5-pn-notes.md)

FKBP5 PN Consistency Notes

  • Generated: 2026-06-18
  • Project: PROTEOSTASIS
  • Scope: PN consistency rereview against local AIGR review and available deep-research artifacts
  • UniProt: Q13451
  • AIGR review status: COMPLETE
  • Review batch: proteostasis-batch-2026-06-07b
  • Batch change status: added

Source Files Checked

Deep Research Files

  • No *-deep-research*.md file found in this gene directory.

AIGR Review Snapshot

  • Description: 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.
  • Existing/core annotation action counts: ACCEPT: 13; KEEP_AS_NON_CORE: 28; MODIFY: 7

PN Consistency Summary

  • Consistency: Good on the chaperone/enzyme core. Review, notes and PN agree: active FKBP PPIase (FK506/rapamycin-inhibited) + HSP90 co-chaperone in steroid-receptor heterocomplexes (negative regulator, FKBP4 antagonist) + AKT1-PHLPP1 scaffold (neg reg PI3K/AKT, GO:0051898 IDA). Core MFs GO:0003755, GO:0031072, GO:0030674 — catalytic vs scaffold both captured. One gap: PN row 3 documents an autophagy-enhancing/BECN1 role that has NO counterpart in the review (autophagy appears only as a reference title).
  • PN story / NEW pressure: Two MF projections (GO:0003755, GO:0051879) are already in the review (GO:0051879 present ×14) → already captured. The autophagy/BECN1 story (FKBP5 enhances autophagy via BECN1) is real PN content but its node is deliberately context_only / too_broad_to_propagate (GO:0035032 PI3K-III complex, GO:0016236 macroautophagy) → PN projects no GO term, matching the TRAPP/overpropagation precedent. So no NEW GO term is asserted; over-reach correctly avoided.
  • Evidence alignment: PN row 3 cites "FKBP5/FKBP51 enhances autophagy to synergize with antidepressant action" (tandfonline); this PMID is absent from the review. Review PI3K/AKT evidence (PMID:28147277, PMID:28363942) is FKBP5-specific and not in PN. Partial divergence on the autophagy paper.
  • Verdict: Consistent on core; PN's autophagy role is documented but intentionally non-propagating, so no required edit. Recommended edits: none required; optionally note the FKBP5-autophagy/BECN1 paper in notes/references for completeness [REF]. Do not propagate GO:0035032/GO:0016236 (regulator, too broad) [MAP].

Full Consistency Review

  • UniProt: Q13451 (FKBP51) · batch: proteostasis-batch-2026-06-07b · review status: COMPLETE
  • PN placement: Cytonuclear|Chaperone|HSP90 system|HSP90 cochaperone|CC-TPR and PPIase domain; Cytonuclear|Folding enzyme|Peptidyl-prolyl isomerases|FKBP type; ALP|Autophagophore initiation|Class 3 PI3K complex 1|Modulator of BECN1 availability ; PN-node mapping: mapped → GO:0051879 (Hsp90 binding, more_specific_than_existing_goa), GO:0003755 (PPIase, already_in_goa_exact); ALP node = context_only/too_broad_to_propagate (projects nothing)
  • Consistency: Good on the chaperone/enzyme core. Review, notes and PN agree: active FKBP PPIase (FK506/rapamycin-inhibited) + HSP90 co-chaperone in steroid-receptor heterocomplexes (negative regulator, FKBP4 antagonist) + AKT1-PHLPP1 scaffold (neg reg PI3K/AKT, GO:0051898 IDA). Core MFs GO:0003755, GO:0031072, GO:0030674 — catalytic vs scaffold both captured. One gap: PN row 3 documents an autophagy-enhancing/BECN1 role that has NO counterpart in the review (autophagy appears only as a reference title).
  • PN story / NEW pressure: Two MF projections (GO:0003755, GO:0051879) are already in the review (GO:0051879 present ×14) → already captured. The autophagy/BECN1 story (FKBP5 enhances autophagy via BECN1) is real PN content but its node is deliberately context_only / too_broad_to_propagate (GO:0035032 PI3K-III complex, GO:0016236 macroautophagy) → PN projects no GO term, matching the TRAPP/overpropagation precedent. So no NEW GO term is asserted; over-reach correctly avoided.
  • Mapping strategy: Correct. Modulator-of-BECN1 node withheld from CC/BP propagation (regulator, not complex component); HSP-binding projection uses the narrower GO:0051879 (child of GO:0031072, OLS-verified) consistent with the review. No mapping change.
  • Evidence alignment: PN row 3 cites "FKBP5/FKBP51 enhances autophagy to synergize with antidepressant action" (tandfonline); this PMID is absent from the review. Review PI3K/AKT evidence (PMID:28147277, PMID:28363942) is FKBP5-specific and not in PN. Partial divergence on the autophagy paper.
  • Verdict: Consistent on core; PN's autophagy role is documented but intentionally non-propagating, so no required edit. Recommended edits: none required; optionally note the FKBP5-autophagy/BECN1 paper in notes/references for completeness [REF]. Do not propagate GO:0035032/GO:0016236 (regulator, too broad) [MAP].

PN Dossier Context

  • review_batch: proteostasis-batch-2026-06-07b
  • review_yaml: genes/human/FKBP5/FKBP5-ai-review.yaml
  • PN workbook rows: 3

PN row 1: Cytonuclear proteostasis | Chaperone | HSP90 system | HSP90 cochaperone | CC-TPR and PPIase domain containing

  • UniProt: Q13451
  • In branches: CY, ALP
  • PN-node mapping records (path + ancestors):
    • [subtype] Cytonuclear proteostasis|Chaperone|HSP90 system|HSP90 cochaperone|CC-TPR and PPIase domain containing
      status=no_mapping scope= GO=[]
      rationale: Reviewed as a mixed HSP90 cochaperone subtype with FKBP/PPIase-like members. The parent HSP90-cochaperone mapping captures the shared HSP90-binding role; a subtype-level PPIase mapping would overstate the activity for all members.
    • [type] Cytonuclear proteostasis|Chaperone|HSP90 system|HSP90 cochaperone
      status=mapped scope=ok_for_propagation_to_go GO=[GO:0051879 Hsp90 protein binding]
      rationale: This PN type groups HSP90 cochaperones. Hsp90 protein binding is the most defensible shared GO molecular-function target for propagation.
    • [group] Cytonuclear proteostasis|Chaperone|HSP90 system
      status=no_mapping scope= GO=[]
      rationale: Reviewed as a broad PN category rather than a specific GO class. The member genes span multiple activities, complexes, or contexts, so propagation from this node would overstate the shared biology; use narrower child or gene-level curations.
    • [class] Cytonuclear proteostasis|Chaperone
      status=no_mapping scope= GO=[]
      rationale: Reviewed as a broad PN category rather than a specific GO class. The member genes span multiple activities, complexes, or contexts, so propagation from this node would overstate the shared biology; use narrower child or gene-level curations.
    • [branch] Cytonuclear proteostasis
      status=no_mapping scope= GO=[]
      rationale: Reviewed as a top-level PN branch. This is a systems/taxonomy umbrella, not a direct GO assertion; narrower child curations carry any propagating GO mappings.

PN row 2: Cytonuclear proteostasis | Folding enzyme | Peptidyl-prolyl isomerases | FKBP type

  • UniProt: Q13451
  • In branches: CY, ALP
  • PN-node mapping records (path + ancestors):
    • [type] Cytonuclear proteostasis|Folding enzyme|Peptidyl-prolyl isomerases|FKBP type
      status=mapped scope=ok_for_propagation_to_go GO=[GO:0003755 peptidyl-prolyl cis-trans isomerase activity]
      rationale: This PN type denotes FKBP-family peptidyl-prolyl isomerases. The matching GO molecular-function term is appropriate for propagation.
    • [group] Cytonuclear proteostasis|Folding enzyme|Peptidyl-prolyl isomerases
      status=mapped scope=ok_for_propagation_to_go GO=[GO:0003755 peptidyl-prolyl cis-trans isomerase activity]
      rationale: This PN group is the cytonuclear peptidyl-prolyl isomerase branch. The matching GO molecular-function term is appropriate for propagation.
    • [class] Cytonuclear proteostasis|Folding enzyme
      status=no_mapping scope= GO=[]
      rationale: Reviewed as a broad PN category rather than a specific GO class. The member genes span multiple activities, complexes, or contexts, so propagation from this node would overstate the shared biology; use narrower child or gene-level curations.
    • [branch] Cytonuclear proteostasis
      status=no_mapping scope= GO=[]
      rationale: Reviewed as a top-level PN branch. This is a systems/taxonomy umbrella, not a direct GO assertion; narrower child curations carry any propagating GO mappings.

PN row 3: Autophagy-Lysosome Pathway | Autophagophore initiation and elongation | Class 3 PI3K complex 1, direct | Modulator of class 3 PI3K complex 1 activity | Modulator of BECN1 availability

  • UniProt: Q13451
  • In branches: CY, ALP
  • Notes: Enhances autophagy. Associates with BECN1 and influences its phosphorylation.
  • PN references (titles):
    • Full article: FKBP5/FKBP51 enhances autophagy to synergize with antidepressant action (tandfonline.com)
  • PN-node mapping records (path + ancestors):
    • [subtype] Autophagy-Lysosome Pathway|Autophagophore initiation and elongation|Class 3 PI3K complex 1, direct|Modulator of class 3 PI3K complex 1 activity|Modulator of BECN1 availability
      status=context_only scope=too_broad_to_propagate GO=[GO:0035032 phosphatidylinositol 3-kinase complex, class III]
      rationale: Reviewed as a class-III PI3K complex context or regulator bucket. This node is useful for curator interpretation, but it should not project cellular-component membership; only explicit complex-component leaves propagate to GO complex terms.
    • [type] Autophagy-Lysosome Pathway|Autophagophore initiation and elongation|Class 3 PI3K complex 1, direct|Modulator of class 3 PI3K complex 1 activity
      status=context_only scope=too_broad_to_propagate GO=[GO:0035032 phosphatidylinositol 3-kinase complex, class III]
      rationale: Reviewed as a class-III PI3K complex context or regulator bucket. This node is useful for curator interpretation, but it should not project cellular-component membership; only explicit complex-component leaves propagate to GO complex terms.
    • [group] Autophagy-Lysosome Pathway|Autophagophore initiation and elongation|Class 3 PI3K complex 1, direct
      status=context_only scope=too_broad_to_propagate GO=[GO:0035032 phosphatidylinositol 3-kinase complex, class III]
      rationale: Reviewed as a class-III PI3K complex context or regulator bucket. This node is useful for curator interpretation, but it should not project cellular-component membership; only explicit complex-component leaves propagate to GO complex terms.
    • [class] Autophagy-Lysosome Pathway|Autophagophore initiation and elongation
      status=context_only scope=too_broad_to_propagate GO=[GO:0016236 macroautophagy]
      rationale: This class is a real macroautophagy context, but its descendants include core factors, component buckets, upstream modulators, localization roles, and residual categories. Projecting generic macroautophagy from this ancestor creates TRAPP-like overpropagation, so candidate GO annotations must come from narrower curated nodes.
    • [branch] Autophagy-Lysosome Pathway
      status=no_mapping scope= GO=[]
      rationale: Reviewed as the top-level PN branch. It is a project taxonomy umbrella rather than a direct GO assertion; all propagation must come from manually curated child nodes.

Projected GO annotations (3)

  • GO:0051879 Hsp90 protein binding | scope=ok_for_propagation_to_go | goa_status=more_specific_than_existing_goa | from=Cytonuclear proteostasis|Chaperone|HSP90 system|HSP90 cochaperone
  • GO:0003755 peptidyl-prolyl cis-trans isomerase activity | scope=ok_for_propagation_to_go | goa_status=already_in_goa_exact | from=Cytonuclear proteostasis|Folding enzyme|Peptidyl-prolyl isomerases
  • GO:0003755 peptidyl-prolyl cis-trans isomerase activity | scope=ok_for_propagation_to_go | goa_status=already_in_goa_exact | from=Cytonuclear proteostasis|Folding enzyme|Peptidyl-prolyl isomerases|FKBP type

Note

This file is generated from the current PROTEOSTASIS phase-1 dossier and local gene-review artifacts. Edit the source review, PN mapping, or dossier rather than this generated note when correcting the underlying curation.

📄 View Raw YAML

 
id: Q13451
gene_symbol: FKBP5
product_type: PROTEIN
status: COMPLETE
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: 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.
existing_annotations:
- term:
    id: GO:0006457
    label: protein folding
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    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.
    action: KEEP_AS_NON_CORE
    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.
    supported_by:
    - reference_id: file:human/FKBP5/FKBP5-uniprot.txt
      supporting_text: Immunophilin protein with PPIase and co-chaperone activities
- term:
    id: GO:0003755
    label: peptidyl-prolyl cis-trans isomerase activity
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: enables
  review:
    summary: FKBP5 is a peptidyl-prolyl cis-trans isomerase (rotamase, EC 5.2.1.8) inhibited by FK506/rapamycin. A defining core molecular function.
    action: ACCEPT
    reason: PPIase activity is directly demonstrated (IDA PMID:11350175; EC 5.2.1.8) and is core; IBA transfer is consistent with experimental evidence.
    supported_by:
    - reference_id: file:human/FKBP5/FKBP5-uniprot.txt
      supporting_text: 'RecName: Full=Peptidyl-prolyl cis-trans isomerase FKBP5'
- term:
    id: GO:0003755
    label: peptidyl-prolyl cis-trans isomerase activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: enables
  review:
    summary: Electronic (InterPro/EC-based) annotation of PPIase activity, consistent with the experimentally and phylogenetically supported core catalytic function.
    action: ACCEPT
    reason: Agrees with stronger IDA/IBA evidence; the FKBP-type domain signature reliably predicts this activity.
    supported_by:
    - reference_id: file:human/FKBP5/FKBP5-uniprot.txt
      supporting_text: 'RecName: Full=Peptidyl-prolyl cis-trans isomerase FKBP5'
- term:
    id: GO:0005528
    label: FK506 binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  qualifier: enables
  review:
    summary: FKBP5 binds FK506 (and rapamycin), which inhibits its PPIase activity; the defining property of the FKBP family.
    action: ACCEPT
    reason: FK506 binding is documented (activity inhibited by FK506 and rapamycin; TAS PMID:9001212) and is a characteristic molecular function.
    supported_by:
    - reference_id: file:human/FKBP5/FKBP5-uniprot.txt
      supporting_text: 'ACTIVITY REGULATION: Inhibited by both FK506 and rapamycin.'
- term:
    id: GO:0005634
    label: nucleus
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  qualifier: located_in
  review:
    summary: A nuclear pool of FKBP5 is documented (by similarity to mouse Q64378), consistent with its role in steroid receptor regulation.
    action: KEEP_AS_NON_CORE
    reason: Nuclear localization is real but secondary to the principal cytoplasmic site of co-chaperone action; retained as non-core.
    supported_by:
    - reference_id: file:human/FKBP5/FKBP5-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Cytoplasm'
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  qualifier: located_in
  review:
    summary: Electronic annotation of cytoplasmic localization (UniProt subcellular-location), the principal site of FKBP5 action.
    action: ACCEPT
    reason: Correct primary localization; agrees with IDA/HPA cytosol and IC evidence.
    supported_by:
    - reference_id: file:human/FKBP5/FKBP5-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Cytoplasm'
- term:
    id: GO:0006457
    label: protein folding
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  qualifier: involved_in
  review:
    summary: Electronic annotation of protein folding, duplicating the IBA/IDA/TAS folding annotations. The informative function is the PPIase/co-chaperone activity.
    action: KEEP_AS_NON_CORE
    reason: A downstream/contributory process rather than the core molecular function.
    supported_by:
    - reference_id: file:human/FKBP5/FKBP5-uniprot.txt
      supporting_text: Immunophilin protein with PPIase and co-chaperone activities
- term:
    id: GO:0031072
    label: heat shock protein binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  qualifier: enables
  review:
    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.
    action: ACCEPT
    reason: HSP90 binding is directly documented (IPI PMID:9660753) and central to FKBP5's co-chaperone role.
    supported_by:
    - reference_id: file:human/FKBP5/FKBP5-uniprot.txt
      supporting_text: Part of a heteromultimeric cytoplasmic complex with HSP90AA1, HSPA1A/HSPA1B and steroid receptors.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:14676191
  qualifier: enables
  review:
    summary: IntAct interaction with STK11/LKB1 (Q15831), a kinase HSP90 client. Bare protein binding is uninformative.
    action: KEEP_AS_NON_CORE
    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.
    supported_by:
    - reference_id: file:human/FKBP5/FKBP5-goa.tsv
      supporting_text: GO:0005515 protein binding IPI PMID:14676191 UniProtKB:Q15831
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:14743216
  qualifier: enables
  review:
    summary: IntAct interaction with CHUK/IKK-alpha (O15111). Bare protein binding is uninformative; FKBP5 engages the IKK machinery.
    action: KEEP_AS_NON_CORE
    reason: A real interaction (IKK component) recorded as bare protein binding; relevant to FKBP5's NF-kB role but not a core MF annotation.
    supported_by:
    - reference_id: file:human/FKBP5/FKBP5-goa.tsv
      supporting_text: GO:0005515 protein binding IPI PMID:14743216 UniProtKB:O15111
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:19615732
  qualifier: enables
  review:
    summary: IntAct interaction with USP49 (Q70CQ1). Bare protein binding is uninformative; an isolated interactome hit.
    action: KEEP_AS_NON_CORE
    reason: An isolated interaction recorded as bare protein binding; uninformative and not core.
    supported_by:
    - reference_id: file:human/FKBP5/FKBP5-goa.tsv
      supporting_text: GO:0005515 protein binding IPI PMID:19615732 UniProtKB:Q70CQ1
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:19875381
  qualifier: enables
  review:
    summary: IntAct interaction with HSP90AA1 (P07900). Bare protein binding is uninformative; the partner is HSP90, the core co-chaperone interaction.
    action: MODIFY
    reason: Bare protein binding is uninformative; the WITH partner is HSP90AA1, so Hsp90 protein binding (GO:0051879) is the precise function.
    proposed_replacement_terms:
    - id: GO:0051879
      label: Hsp90 protein binding
    supported_by:
    - reference_id: file:human/FKBP5/FKBP5-goa.tsv
      supporting_text: GO:0005515 protein binding IPI PMID:19875381 UniProtKB:P07900
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:20562859
  qualifier: enables
  review:
    summary: IntAct interaction with STK11/LKB1 (Q15831), a kinase HSP90 client. Bare protein binding is uninformative.
    action: KEEP_AS_NON_CORE
    reason: A real kinase-client interaction recorded as bare protein binding; consistent with the co-chaperone role but not individually core.
    supported_by:
    - reference_id: file:human/FKBP5/FKBP5-goa.tsv
      supporting_text: GO:0005515 protein binding IPI PMID:20562859 UniProtKB:Q15831
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:21170051
  qualifier: enables
  review:
    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.
    action: MODIFY
    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_replacement_terms:
    - id: GO:0051879
      label: Hsp90 protein binding
    supported_by:
    - reference_id: PMID:21170051
      supporting_text: Mixed Hsp90-cochaperone complexes are important for the progression of the reaction cycle.
    - reference_id: file:human/FKBP5/FKBP5-goa.tsv
      supporting_text: GO:0005515 protein binding IPI PMID:21170051 UniProtKB:P08238
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:21360678
  qualifier: enables
  review:
    summary: IntAct interaction with HSP90AA1 (P07900). Bare protein binding is uninformative; the partner is HSP90.
    action: MODIFY
    reason: Bare protein binding is uninformative; the WITH partner is HSP90AA1, so Hsp90 protein binding (GO:0051879) is the precise function.
    proposed_replacement_terms:
    - id: GO:0051879
      label: Hsp90 protein binding
    supported_by:
    - reference_id: file:human/FKBP5/FKBP5-goa.tsv
      supporting_text: GO:0005515 protein binding IPI PMID:21360678 UniProtKB:P07900
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:23455922
  qualifier: enables
  review:
    summary: IntAct interaction with CDK9 (P50750), a kinase HSP90 client. Bare protein binding is uninformative.
    action: KEEP_AS_NON_CORE
    reason: A real kinase-client interaction recorded as bare protein binding; consistent with the co-chaperone role but not individually core.
    supported_by:
    - reference_id: file:human/FKBP5/FKBP5-goa.tsv
      supporting_text: GO:0005515 protein binding IPI PMID:23455922 UniProtKB:P50750
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:23602568
  qualifier: enables
  review:
    summary: IntAct interactions with CDK9 (P50750) and CDK15 (Q96Q40), kinase HSP90 clients. Bare protein binding is uninformative.
    action: KEEP_AS_NON_CORE
    reason: Real kinase-client interactions recorded as bare protein binding; consistent with the co-chaperone role but not individually core.
    supported_by:
    - reference_id: file:human/FKBP5/FKBP5-goa.tsv
      supporting_text: GO:0005515 protein binding IPI PMID:23602568 UniProtKB:P50750
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:24169621
  qualifier: enables
  review:
    summary: IntAct interaction with a viral protein (Q9WMX2 processed chain). Bare protein binding is uninformative; a cross-species interactome hit.
    action: KEEP_AS_NON_CORE
    reason: An isolated cross-species interaction recorded as bare protein binding; uninformative and not core.
    supported_by:
    - reference_id: file:human/FKBP5/FKBP5-goa.tsv
      supporting_text: GO:0005515 protein binding IPI PMID:24169621 UniProtKB:Q9WMX2-PRO_0000037552
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:24981860
  qualifier: enables
  review:
    summary: IntAct interaction with CDK9 (P50750), a kinase HSP90 client. Bare protein binding is uninformative.
    action: KEEP_AS_NON_CORE
    reason: A real kinase-client interaction recorded as bare protein binding; not individually core.
    supported_by:
    - reference_id: file:human/FKBP5/FKBP5-goa.tsv
      supporting_text: GO:0005515 protein binding IPI PMID:24981860 UniProtKB:P50750
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:25036637
  qualifier: enables
  review:
    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.
    action: MODIFY
    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_replacement_terms:
    - id: GO:0051879
      label: Hsp90 protein binding
    supported_by:
    - reference_id: file:human/FKBP5/FKBP5-goa.tsv
      supporting_text: GO:0005515 protein binding IPI PMID:25036637 UniProtKB:P08238
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:25852190
  qualifier: enables
  review:
    summary: IntAct interaction with STK11/LKB1 (Q15831), a kinase HSP90 client. Bare protein binding is uninformative.
    action: KEEP_AS_NON_CORE
    reason: A real kinase-client interaction recorded as bare protein binding; not individually core.
    supported_by:
    - reference_id: file:human/FKBP5/FKBP5-goa.tsv
      supporting_text: GO:0005515 protein binding IPI PMID:25852190 UniProtKB:Q15831
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:27086506
  qualifier: enables
  review:
    summary: IntAct interaction with KSR2 (Q6VAB6), a kinase scaffold/HSP90 client. Bare protein binding is uninformative.
    action: KEEP_AS_NON_CORE
    reason: A real kinase-client interaction recorded as bare protein binding; not individually core.
    supported_by:
    - reference_id: file:human/FKBP5/FKBP5-goa.tsv
      supporting_text: GO:0005515 protein binding IPI PMID:27086506 UniProtKB:Q6VAB6
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:28514442
  qualifier: enables
  review:
    summary: IntAct interactions with SGK1 (O00141), MOS (P00540) and STK11 (Q15831), kinase HSP90 clients. Bare protein binding is uninformative.
    action: KEEP_AS_NON_CORE
    reason: Real kinase-client interactions recorded as bare protein binding; consistent with the co-chaperone role but not individually core.
    supported_by:
    - reference_id: file:human/FKBP5/FKBP5-goa.tsv
      supporting_text: GO:0005515 protein binding IPI PMID:28514442 UniProtKB:O00141
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:29079741
  qualifier: enables
  review:
    summary: IntAct interaction with HSP90AA1 (P07900). Bare protein binding is uninformative; the partner is HSP90.
    action: MODIFY
    reason: Bare protein binding is uninformative; the WITH partner is HSP90AA1, so Hsp90 protein binding (GO:0051879) is the precise function.
    proposed_replacement_terms:
    - id: GO:0051879
      label: Hsp90 protein binding
    supported_by:
    - reference_id: file:human/FKBP5/FKBP5-goa.tsv
      supporting_text: GO:0005515 protein binding IPI PMID:29079741 UniProtKB:P07900
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:30021884
  qualifier: enables
  review:
    summary: IntAct interaction with PYGB (P11216). Bare protein binding is uninformative; an isolated interactome hit.
    action: KEEP_AS_NON_CORE
    reason: An isolated interaction recorded as bare protein binding; uninformative and not core.
    supported_by:
    - reference_id: file:human/FKBP5/FKBP5-goa.tsv
      supporting_text: GO:0005515 protein binding IPI PMID:30021884 UniProtKB:P11216
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:30382094
  qualifier: enables
  review:
    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.
    action: MODIFY
    reason: Bare protein binding is uninformative; the principal WITH partner is HSP90AB1, so Hsp90 protein binding (GO:0051879) is the appropriate specific term.
    proposed_replacement_terms:
    - id: GO:0051879
      label: Hsp90 protein binding
    supported_by:
    - reference_id: file:human/FKBP5/FKBP5-goa.tsv
      supporting_text: GO:0005515 protein binding IPI PMID:30382094 UniProtKB:P08238
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:32707033
  qualifier: enables
  review:
    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.
    action: KEEP_AS_NON_CORE
    reason: Bare protein binding from one high-throughput screen with many kinase partners not independently validated; uninformative and not individually core.
    supported_by:
    - reference_id: file:human/FKBP5/FKBP5-goa.tsv
      supporting_text: GO:0005515 protein binding IPI PMID:32707033 UniProtKB:P50750
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:33961781
  qualifier: enables
  review:
    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.
    action: KEEP_AS_NON_CORE
    reason: Bare protein binding from one high-throughput interactome with many partners not independently validated; uninformative and not individually core.
    supported_by:
    - reference_id: file:human/FKBP5/FKBP5-goa.tsv
      supporting_text: GO:0005515 protein binding IPI PMID:33961781 UniProtKB:P50750
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:34591612
  qualifier: enables
  review:
    summary: IntAct interactions with EGFR (P00533) and STK11 (Q15831), kinase HSP90 clients. Bare protein binding is uninformative.
    action: KEEP_AS_NON_CORE
    reason: Real kinase-client interactions recorded as bare protein binding; not individually core.
    supported_by:
    - reference_id: file:human/FKBP5/FKBP5-goa.tsv
      supporting_text: GO:0005515 protein binding IPI PMID:34591612 UniProtKB:P00533
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:35271311
  qualifier: enables
  review:
    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.
    action: MODIFY
    reason: Bare protein binding is uninformative; the principal partners include HSP90AA1/AB1, so Hsp90 protein binding (GO:0051879) is appropriate.
    proposed_replacement_terms:
    - id: GO:0051879
      label: Hsp90 protein binding
    supported_by:
    - reference_id: file:human/FKBP5/FKBP5-goa.tsv
      supporting_text: GO:0005515 protein binding IPI PMID:35271311 UniProtKB:P07900
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:40205054
  qualifier: enables
  review:
    summary: Multimodal cell-maps interactome capturing FKBP5 with CDK9 (P50750) and STK11 (Q15831), kinase HSP90 clients. Bare protein binding is uninformative.
    action: KEEP_AS_NON_CORE
    reason: Real kinase-client interactions recorded as bare protein binding; not individually core.
    supported_by:
    - reference_id: file:human/FKBP5/FKBP5-goa.tsv
      supporting_text: GO:0005515 protein binding IPI PMID:40205054 UniProtKB:P50750
- term:
    id: GO:0005634
    label: nucleus
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: located_in
  review:
    summary: Nuclear localization inferred by sequence similarity from the mouse ortholog (Q64378).
    action: KEEP_AS_NON_CORE
    reason: A real but secondary localization relative to the principal cytoplasmic site of action; retained as non-core.
    supported_by:
    - reference_id: file:human/FKBP5/FKBP5-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Cytoplasm'
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: located_in
  review:
    summary: Cytoplasmic localization inferred by sequence similarity from the mouse ortholog, consistent with the principal site of FKBP5 action.
    action: ACCEPT
    reason: Correct primary localization, corroborated by IC, IDA/HPA and IEA evidence.
    supported_by:
    - reference_id: file:human/FKBP5/FKBP5-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Cytoplasm'
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: IC
  original_reference_id: PMID:28147277
  qualifier: is_active_in
  review:
    summary: Curator-inferred (IC) cytoplasmic site of action from the study showing FKBP5 scaffolds the AKT1-PHLPP1 interaction. The cytoplasm is where FKBP5 acts.
    action: ACCEPT
    reason: The cytoplasm is the principal site where FKBP5 acts as a co-chaperone and AKT1-PHLPP1 scaffold; well supported.
    supported_by:
    - reference_id: file:human/FKBP5/FKBP5-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Cytoplasm'
- term:
    id: GO:0030674
    label: protein-macromolecule adaptor activity
  evidence_type: IDA
  original_reference_id: PMID:28147277
  qualifier: enables
  review:
    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).
    action: ACCEPT
    reason: Directly demonstrated (IDA) scaffolding of the AKT1-PHLPP1 interaction; FKBP5 also acts as an adaptor bridging steroid receptors to HSP90.
    supported_by:
    - reference_id: file:human/FKBP5/FKBP5-uniprot.txt
      supporting_text: Acts as a regulator of Akt/AKT1 activity by promoting the interaction between Akt/AKT1 and PHLPP1
- term:
    id: GO:0051898
    label: negative regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction
  evidence_type: IDA
  original_reference_id: PMID:28363942
  qualifier: involved_in
  review:
    summary: By scaffolding AKT1-PHLPP1, FKBP5 enhances AKT1 dephosphorylation and thereby negatively regulates PI3K/AKT signaling. A directly demonstrated biological process.
    action: ACCEPT
    reason: Directly demonstrated (IDA); a genuine FKBP5 biological process linked to its scaffold/adaptor activity.
    supported_by:
    - reference_id: file:human/FKBP5/FKBP5-uniprot.txt
      supporting_text: enhancing dephosphorylation and subsequent activation of Akt/AKT1
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-5618073
  qualifier: located_in
  review:
    summary: Reactome pathway annotation placing FKBP5 in the cytosol, consistent with its primary localization.
    action: ACCEPT
    reason: Curated cytosolic localization consistent with the principal site of FKBP5 action.
    supported_by:
    - reference_id: file:human/FKBP5/FKBP5-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Cytoplasm'
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-5618098
  qualifier: located_in
  review:
    summary: Reactome pathway annotation placing FKBP5 in the cytosol; redundant with the primary localization.
    action: KEEP_AS_NON_CORE
    reason: Redundant curated cytosol annotation; consistent but duplicative.
    supported_by:
    - reference_id: file:human/FKBP5/FKBP5-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Cytoplasm'
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-5618105
  qualifier: located_in
  review:
    summary: Reactome pathway annotation placing FKBP5 in the cytosol; redundant with the primary localization.
    action: KEEP_AS_NON_CORE
    reason: Redundant curated cytosol annotation; consistent but duplicative.
    supported_by:
    - reference_id: file:human/FKBP5/FKBP5-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Cytoplasm'
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9909510
  qualifier: located_in
  review:
    summary: Reactome pathway annotation placing FKBP5 in the cytosol; redundant with the primary localization.
    action: KEEP_AS_NON_CORE
    reason: Redundant curated cytosol annotation; consistent but duplicative.
    supported_by:
    - reference_id: file:human/FKBP5/FKBP5-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Cytoplasm'
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9909519
  qualifier: located_in
  review:
    summary: Reactome pathway annotation placing FKBP5 in the cytosol; redundant with the primary localization.
    action: KEEP_AS_NON_CORE
    reason: Redundant curated cytosol annotation; consistent but duplicative.
    supported_by:
    - reference_id: file:human/FKBP5/FKBP5-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Cytoplasm'
- term:
    id: GO:0016020
    label: membrane
  evidence_type: HDA
  original_reference_id: PMID:19946888
  qualifier: located_in
  review:
    summary: High-throughput proteomic detection of FKBP5 in a membrane fraction. FKBP5 is a soluble cytoplasmic protein; this is not a characterized membrane localization.
    action: KEEP_AS_NON_CORE
    reason: A high-throughput proteomic detection; plausible co-fractionation but peripheral to the gene's core cytoplasmic function.
    supported_by:
    - reference_id: file:human/FKBP5/FKBP5-goa.tsv
      supporting_text: GO:0016020 membrane HDA PMID:19946888
- term:
    id: GO:0070062
    label: extracellular exosome
  evidence_type: HDA
  original_reference_id: PMID:19056867
  qualifier: located_in
  review:
    summary: Detection of FKBP5 in extracellular exosome proteomics. As an abundant cytoplasmic protein, FKBP5 is frequently detected in exosome preparations.
    action: KEEP_AS_NON_CORE
    reason: A high-throughput proteomic detection; peripheral to the gene's core cytoplasmic function.
    supported_by:
    - reference_id: file:human/FKBP5/FKBP5-goa.tsv
      supporting_text: GO:0070062 extracellular exosome HDA PMID:19056867
- term:
    id: GO:0003755
    label: peptidyl-prolyl cis-trans isomerase activity
  evidence_type: IDA
  original_reference_id: PMID:11350175
  qualifier: enables
  review:
    summary: Direct experimental demonstration of FKBP5 peptidyl-prolyl cis-trans isomerase activity. The core catalytic function.
    action: ACCEPT
    reason: IDA evidence directly supports PPIase activity (EC 5.2.1.8), a defining core molecular function of FKBP5.
    supported_by:
    - reference_id: file:human/FKBP5/FKBP5-uniprot.txt
      supporting_text: 'RecName: Full=Peptidyl-prolyl cis-trans isomerase FKBP5'
- term:
    id: GO:0006457
    label: protein folding
  evidence_type: IDA
  original_reference_id: PMID:11350175
  qualifier: involved_in
  review:
    summary: Direct experimental evidence linking FKBP5 to protein folding via its rotamase/PPIase activity. The molecular function (PPIase) is the more informative annotation.
    action: KEEP_AS_NON_CORE
    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.
    supported_by:
    - reference_id: file:human/FKBP5/FKBP5-uniprot.txt
      supporting_text: Immunophilin protein with PPIase and co-chaperone activities
- term:
    id: GO:0031072
    label: heat shock protein binding
  evidence_type: IPI
  original_reference_id: PMID:9660753
  qualifier: enables
  review:
    summary: Direct interaction (IPI) with HSP90AA1 (P07900), the principal heat shock protein partner of FKBP5. A core co-chaperone molecular function.
    action: ACCEPT
    reason: Experimentally documented HSP90 binding (the basis of FKBP5's TPR-mediated co-chaperone role) supports heat shock protein binding as a core function.
    supported_by:
    - reference_id: file:human/FKBP5/FKBP5-goa.tsv
      supporting_text: GO:0031072 heat shock protein binding IPI PMID:9660753 UniProtKB:P07900
- term:
    id: GO:0005528
    label: FK506 binding
  evidence_type: TAS
  original_reference_id: PMID:9001212
  qualifier: enables
  review:
    summary: Author-stated FK506 binding. FK506 binding is the defining property of the FKBP family and inhibits FKBP5's PPIase activity.
    action: ACCEPT
    reason: FK506 binding is documented and characteristic of the FKBP family.
    supported_by:
    - reference_id: file:human/FKBP5/FKBP5-uniprot.txt
      supporting_text: 'ACTIVITY REGULATION: Inhibited by both FK506 and rapamycin.'
- term:
    id: GO:0006457
    label: protein folding
  evidence_type: TAS
  original_reference_id: PMID:9001212
  qualifier: involved_in
  review:
    summary: Author-stated (TAS) involvement of FKBP5 in protein folding. The informative function is its PPIase/co-chaperone activity.
    action: KEEP_AS_NON_CORE
    reason: A contributory process downstream of FKBP5's PPIase/co-chaperone activity; the catalytic and binding MFs are the core.
    supported_by:
    - reference_id: file:human/FKBP5/FKBP5-uniprot.txt
      supporting_text: Immunophilin protein with PPIase and co-chaperone activities
references:
- id: GO_REF:0000024
  title: Manual transfer of experimentally-verified manual GO annotation data to orthologs by curator judgment of sequence similarity
  findings: []
- id: GO_REF:0000033
  title: Annotation inferences using phylogenetic trees
  findings: []
- id: GO_REF:0000044
  title: Gene Ontology annotation through association of InterPro records with GO terms
  findings: []
- id: GO_REF:0000117
  title: Electronic Gene Ontology annotations created by ARBA machine learning models
  findings: []
- id: GO_REF:0000120
  title: Combined Automated Annotation using Multiple IEA Methods
  findings: []
- id: PMID:11350175
  title: 'Functional analysis of the Hsp90-associated human peptidyl prolyl cis/trans isomerases FKBP51, FKBP52 and Cyp40.'
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: "Not cached, but anchored to GOA: this PMID is the IDA source for GO:0003755 (peptidyl-prolyl cis-trans isomerase activity) in FKBP5-goa.tsv, directly establishing the core PPIase molecular function."
  findings:
  - statement: Direct demonstration of FKBP5/FKBP51 peptidyl-prolyl cis-trans isomerase (rotamase) activity.
    reference_section_type: RESULTS
- id: PMID:14676191
  title: Comprehensive proteomic analysis of human Par protein complexes reveals an interconnected protein network.
  findings: []
- id: PMID:14743216
  title: A physical and functional map of the human TNF-alpha/NF-kappa B signal transduction pathway.
  findings: []
- id: PMID:19056867
  title: Large-scale proteomics and phosphoproteomics of urinary exosomes.
  findings: []
- id: PMID:19615732
  title: Defining the human deubiquitinating enzyme interaction landscape.
  findings: []
- id: PMID:19875381
  title: A proteomic investigation of ligand-dependent HSP90 complexes reveals CHORDC1 as a novel ADP-dependent HSP90-interacting protein.
  findings: []
- id: PMID:19946888
  title: Defining the membrane proteome of NK cells.
  findings: []
- id: PMID:20562859
  title: Network organization of the human autophagy system.
  findings: []
- id: PMID:21170051
  title: Mixed Hsp90-cochaperone complexes are important for the progression of the reaction cycle.
  findings:
  - statement: PPIase co-chaperones such as FKBP5 are incorporated into asymmetric mixed Hsp90-cochaperone complexes during the chaperone reaction cycle.
    reference_section_type: RESULTS
- id: PMID:21360678
  title: Label-free quantitative proteomics and SAINT analysis enable interactome mapping for the human Ser/Thr protein phosphatase 5.
  findings: []
- id: PMID:23455922
  title: Interlaboratory reproducibility of large-scale human protein-complex analysis by standardized AP-MS.
  findings: []
- id: PMID:23602568
  title: The protein interaction landscape of the human CMGC kinase group.
  findings: []
- id: PMID:24169621
  title: Elucidating novel hepatitis C virus-host interactions using combined mass spectrometry and functional genomics approaches.
  findings: []
- id: PMID:24981860
  title: Human-chromatin-related protein interactions identify a demethylase complex required for chromosome segregation.
  findings: []
- id: PMID:25036637
  title: A quantitative chaperone interaction network reveals the architecture of cellular protein homeostasis pathways.
  findings:
  - statement: FKBP5 is part of the Hsp90 co-chaperone module, interacting with HSP90 and numerous protein kinase clients.
    reference_section_type: RESULTS
- id: PMID:25852190
  title: Integrative analysis of kinase networks in TRAIL-induced apoptosis provides a source of potential targets for combination therapy.
  findings: []
- id: PMID:27086506
  title: 'HiQuant: Rapid Postquantification Analysis of Large-Scale MS-Generated Proteomics Data.'
  findings: []
- id: PMID:28147277
  title: 'Regulation of Serine-Threonine Kinase Akt Activation by NAD(+)-Dependent Deacetylase SIRT7.'
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: "Not cached, but anchored to GOA: this PMID is the IDA source for GO:0030674 (protein-macromolecule adaptor activity) in FKBP5-goa.tsv, supporting the core scaffold/adaptor function (FKBP51 bridging AKT1-PHLPP1)."
  findings:
  - statement: FKBP5 (FKBP51) promotes the interaction between AKT1 and PHLPP1, acting as a scaffold/adaptor to enhance AKT1 dephosphorylation; acetylation regulates this scaffolding.
    reference_section_type: RESULTS
- id: PMID:28363942
  title: 'USP49 negatively regulates tumorigenesis and chemoresistance through FKBP51-AKT signaling.'
  findings:
  - statement: FKBP5 negatively regulates PI3K/AKT signal transduction by enhancing PHLPP1-mediated AKT1 dephosphorylation.
    reference_section_type: RESULTS
- id: PMID:28514442
  title: Architecture of the human interactome defines protein communities and disease networks.
  findings: []
- id: PMID:29079741
  title: Combined x-ray crystallography and computational modeling approach to investigate the Hsp90 C-terminal peptide binding to FKBP51.
  findings: []
- id: PMID:30021884
  title: Histone Interaction Landscapes Visualized by Crosslinking Mass Spectrometry in Intact Cell Nuclei.
  findings: []
- id: PMID:30382094
  title: Structure and pro-toxic mechanism of the human Hsp90/PPIase/Tau complex.
  findings: []
- id: PMID:32707033
  title: Kinase Interaction Network Expands Functional and Disease Roles of Human Kinases.
  findings: []
- id: PMID:33961781
  title: Dual proteome-scale networks reveal cell-specific remodeling of the human interactome.
  findings:
  - statement: BioPlex affinity-purification interactome capturing FKBP5 interactions with numerous protein kinase clients.
    reference_section_type: RESULTS
- id: PMID:34591612
  title: A protein interaction landscape of breast cancer.
  findings: []
- id: PMID:35271311
  title: 'OpenCell: Endogenous tagging for the cartography of human cellular organization.'
  findings: []
- id: PMID:40205054
  title: Multimodal cell maps as a foundation for structural and functional genomics.
  findings:
  - statement: Multimodal cell-maps interactome capturing FKBP5 interactions with kinase clients.
    reference_section_type: RESULTS
- id: PMID:9001212
  title: 'Molecular cloning of human FKBP51 and comparisons of immunophilin interactions with Hsp90 and progesterone receptor.'
  findings:
  - statement: FKBP5 (FKBP51) is an FK506-binding immunophilin with rotamase/PPIase activity.
    reference_section_type: RESULTS
- id: PMID:9660753
  title: Specific binding of tetratricopeptide repeat proteins to the C-terminal 12-kDa domain of Hsp90.
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: "GOA IPI source for GO:0031072 (heat shock protein binding; HSP90AA1) in FKBP5-goa.tsv, supporting the HSP90-binding function. Title corrected to verbatim PubMed."
  findings:
  - statement: FKBP5 directly binds HSP90AA1.
    reference_section_type: RESULTS
- id: Reactome:R-HSA-5618073
  title: 'Reactome: FKBP5 in cytosol.'
  findings: []
- id: Reactome:R-HSA-5618098
  title: 'Reactome: FKBP5 in cytosol.'
  findings: []
- id: Reactome:R-HSA-5618105
  title: 'Reactome: FKBP5 in cytosol.'
  findings: []
- id: Reactome:R-HSA-9909510
  title: 'Reactome: FKBP5 in cytosol.'
  findings: []
- id: Reactome:R-HSA-9909519
  title: 'Reactome: FKBP5 in cytosol.'
  findings: []
- id: file:human/FKBP5/FKBP5-uniprot.txt
  title: UniProt entry Q13451 (FKBP5_HUMAN), Peptidyl-prolyl cis-trans isomerase FKBP5 / FKBP51
  findings:
  - statement: Immunophilin with PPIase and co-chaperone activities; component of unligated steroid receptor heterocomplexes via HSP90 (negative regulator, displaced by FKBP4 on ligand binding); scaffolds AKT1-PHLPP1 to negatively regulate PI3K/AKT; engages IKBKB/IKBKE; cytoplasmic and nuclear localization.
    reference_section_type: OTHER
core_functions:
- description: Peptidyl-prolyl cis-trans isomerase (rotamase, EC 5.2.1.8), the catalytic activity of the FKBP domain, inhibited by FK506 and rapamycin.
  molecular_function:
    id: GO:0003755
    label: peptidyl-prolyl cis-trans isomerase activity
  locations:
  - id: GO:0005737
    label: cytoplasm
  supported_by:
  - reference_id: file:human/FKBP5/FKBP5-uniprot.txt
    supporting_text: 'RecName: Full=Peptidyl-prolyl cis-trans isomerase FKBP5'
- description: HSP90 co-chaperone that binds HSP90 via its TPR domain and is part of unligated steroid hormone receptor heterocomplexes; negative regulator of glucocorticoid and progesterone receptor signaling (antagonist of FKBP4).
  molecular_function:
    id: GO:0031072
    label: heat shock protein binding
  locations:
  - id: GO:0005737
    label: cytoplasm
  supported_by:
  - reference_id: file:human/FKBP5/FKBP5-uniprot.txt
    supporting_text: Part of a heteromultimeric cytoplasmic complex with HSP90AA1, HSPA1A/HSPA1B and steroid receptors.
  - reference_id: file:human/FKBP5/FKBP5-goa.tsv
    supporting_text: GO:0031072 heat shock protein binding IPI PMID:9660753 UniProtKB:P07900
- description: Scaffold/adaptor that promotes the AKT1-PHLPP1 interaction, enhancing PHLPP1-mediated AKT1 dephosphorylation and thereby negatively regulating PI3K/AKT signaling.
  molecular_function:
    id: GO:0030674
    label: protein-macromolecule adaptor activity
  locations:
  - id: GO:0005737
    label: cytoplasm
  supported_by:
  - reference_id: file:human/FKBP5/FKBP5-uniprot.txt
    supporting_text: Acts as a regulator of Akt/AKT1 activity by promoting the interaction between Akt/AKT1 and PHLPP1
proposed_new_terms: []
suggested_questions:
- question: How do FKBP5 and FKBP4 produce opposite effects on glucocorticoid receptor activity despite sharing the same TPR-HSP90 binding mode and overall domain architecture?
- question: 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?
- question: How does glucocorticoid-induced FKBP5 expression quantitatively tune the HPA-axis negative feedback loop, and how do disease-associated FKBP5 variants alter this?
suggested_experiments:
- description: 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.
- description: 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.
- description: Use FKBP5 knockout/knockdown with AKT phosphorylation readouts (and PHLPP1 co-depletion) to confirm the scaffold mechanism for negative regulation of PI3K/AKT signaling.