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.