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. FKBP4 has rotamase (PPIase) activity that can catalyze proline isomerization, a rate-limiting step in folding, and it acts as an HSP90 co-chaperone. The molecular activity (PPIase / co-chaperone binding) is the more informative annotation; the folding process is a downstream/contributory outcome rather than autonomous foldase activity. Reason: FKBP4 contributes to folding through its PPIase activity and HSP90 co-chaperone role, but the precise molecular functions (peptidyl-prolyl isomerase activity, HSP90 binding, adaptor activity) capture the core function better; protein folding is retained as a plausible non-core process. Supporting Evidence: file:human/FKBP4/FKBP4-uniprot.txt Immunophilin protein with PPIase and co-chaperone activities.
GO:0003755 peptidyl-prolyl cis-trans isomerase activity	IBA GO_REF:0000033	ACCEPT	Summary: FKBP4 is a bona fide peptidyl-prolyl cis-trans isomerase (rotamase, EC 5.2.1.8), with the activity residing in the N-terminal FKBP domain and inhibited by FK506. This is a defining, well-supported core molecular function. Reason: PPIase activity is directly demonstrated (EC 5.2.1.8; FK506-inhibitable) and is a core catalytic function of FKBP4; IBA transfer is consistent with experimental evidence. Supporting Evidence: file:human/FKBP4/FKBP4-uniprot.txt RecName: Full=Peptidyl-prolyl cis-trans isomerase FKBP4 file:human/FKBP4/FKBP4-uniprot.txt The PPIase activity is mainly due to the first PPIase FKBP-type domain
GO:0005829 cytosol	IBA GO_REF:0000033	ACCEPT	Summary: FKBP4 acts in the cytosol, where it assembles steroid receptor-HSP90 heterocomplexes. Cytosolic localization is well supported experimentally and by phylogenetic inference. Reason: The cytosol is the principal site where FKBP4 acts as an HSP90 co-chaperone; this IBA is corroborated by direct experimental localization (HPA IDA) and the UniProt subcellular-location section. Supporting Evidence: file:human/FKBP4/FKBP4-uniprot.txt SUBCELLULAR LOCATION: Cytoplasm, cytosol
GO:0003755 peptidyl-prolyl cis-trans isomerase activity	IEA GO_REF:0000120	ACCEPT	Summary: Electronic (InterPro/EC-based) annotation of PPIase activity, redundant with and consistent with the experimentally and phylogenetically supported core catalytic function. Reason: Agrees with stronger IDA/IBA evidence for PPIase activity; the FKBP-type domain signature reliably predicts this activity. Supporting Evidence: file:human/FKBP4/FKBP4-uniprot.txt RecName: Full=Peptidyl-prolyl cis-trans isomerase FKBP4
GO:0005528 FK506 binding	IEA GO_REF:0000117	ACCEPT	Summary: FKBP4 binds the immunosuppressant FK506, which inhibits its PPIase activity; this is the defining property of the FK506-binding protein (FKBP) family. Reason: FK506 binding is directly documented (activity inhibited by FK506; TAS PMID:1376003) and is a characteristic molecular function; the IEA agrees with experimental evidence. Supporting Evidence: file:human/FKBP4/FKBP4-uniprot.txt ACTIVITY REGULATION: Inhibited by FK506.
GO:0005634 nucleus	IEA GO_REF:0000120	KEEP AS NON CORE	Summary: FKBP4 is found in the nucleus, consistent with its role in shuttling steroid hormone receptors from cytoplasm to nucleus and a reported mitochondria-to-nucleus translocation under oxidative stress. Reason: Nuclear localization is real but reflects the trafficking/shuttling endpoint rather than the principal cytosolic site of co-chaperone action; retained as non-core. Supporting Evidence: file:human/FKBP4/FKBP4-uniprot.txt Shuttles from mitochondria to nucleus
GO:0005739 mitochondrion	IEA GO_REF:0000044	KEEP AS NON CORE	Summary: A mitochondrial pool of FKBP4 has been documented experimentally; the TPR repeats mediate mitochondrial localization, and FKBP4 may protect against mitochondrial oxidative stress. Reason: Mitochondrial localization is experimentally supported (EXP PMID:21730050) but is a secondary/context-specific compartment relative to the cytosolic co-chaperone function. Supporting Evidence: file:human/FKBP4/FKBP4-uniprot.txt The TPR repeats mediate mitochondrial localization.
GO:0005829 cytosol	IEA GO_REF:0000044	ACCEPT	Summary: Electronic annotation of cytosolic localization (UniProt subcellular-location), redundant with the IDA/IBA cytosol annotations. Reason: Correct primary localization for this cytosolic co-chaperone; agrees with stronger experimental evidence. Supporting Evidence: file:human/FKBP4/FKBP4-uniprot.txt SUBCELLULAR LOCATION: Cytoplasm, cytosol
GO:0005856 cytoskeleton	IEA GO_REF:0000044	KEEP AS NON CORE	Summary: FKBP4 associates with the cytoskeleton, consistent with its tubulin/microtubule and MAPT/tau regulatory activities and growth-cone localization. Reason: Cytoskeletal association underlies the microtubule/tau regulatory role; retained as a real but non-core localization for the principal co-chaperone function. Supporting Evidence: file:human/FKBP4/FKBP4-uniprot.txt Cytoplasm, cytoskeleton
GO:0006457 protein folding	IEA GO_REF:0000117	KEEP AS NON CORE	Summary: Electronic annotation of the protein folding process, duplicating the IBA/IDA/TAS protein-folding annotations. The informative function is the PPIase/co-chaperone activity. Reason: Same rationale as the IBA protein-folding annotation; a downstream/contributory process rather than the core molecular function. Supporting Evidence: file:human/FKBP4/FKBP4-uniprot.txt Immunophilin protein with PPIase and co-chaperone activities.
GO:0030424 axon	IEA GO_REF:0000044	KEEP AS NON CORE	Summary: FKBP4 localizes to axons / the distal parts of neurons, consistent with its role in growth-cone guidance via TRPC1 and tau regulation. Reason: Axonal localization is supported (by similarity to mouse Q9QVC8) and relevant to the neuronal growth-cone role, but is a specialized, non-core localization. Supporting Evidence: file:human/FKBP4/FKBP4-uniprot.txt Cell projection, axon
GO:0005515 protein binding	IPI PMID:14638689 S100A1 is a novel molecular chaperone and a member of the Hs...	KEEP AS NON CORE	Summary: IntAct interaction with S100A1 (P35467). The bare protein binding term is uninformative; the S100A1 interaction (TPR-mediated, Ca2+-dependent) modulates the FKBP4-HSP90 association. Reason: A real, specific physical interaction, but bare protein binding is uninformative and this S100 interaction is regulatory rather than the core function. Supporting Evidence: file:human/FKBP4/FKBP4-goa.tsv GO:0005515 protein binding IPI PMID:14638689 UniProtKB:P35467
GO:0005515 protein binding	IPI PMID:19875381 A proteomic investigation of ligand-dependent HSP90 complexe...	MODIFY	Summary: IntAct interaction with HSP90AA1 (P07900). The bare protein binding term is uninformative; the partner is HSP90, so this is better captured as Hsp90 protein binding, the core co-chaperone function. Reason: Bare protein binding is uninformative; the WITH partner is HSP90AA1, so Hsp90 protein binding (GO:0051879) is the precise molecular function. Proposed replacements: Hsp90 protein binding Supporting Evidence: file:human/FKBP4/FKBP4-goa.tsv GO:0005515 protein binding IPI PMID:19875381 UniProtKB:P07900
GO:0005515 protein binding	IPI PMID:20133804 A role for FKBP52 in Tau protein function.	MODIFY	Summary: IntAct interaction with MAPT/tau (P10636-8). The bare protein binding term is uninformative; the tau interaction underlies FKBP4's regulation of microtubule dynamics. Reason: Bare protein binding is uninformative; the WITH partner is MAPT/tau, so tau protein binding (GO:0048156) captures the specific, biologically meaningful interaction. Proposed replacements: tau protein binding Supporting Evidence: file:human/FKBP4/FKBP4-goa.tsv GO:0005515 protein binding IPI PMID:20133804 UniProtKB:P10636-8
GO:0005515 protein binding	IPI PMID:20188096 S100 proteins regulate the interaction of Hsp90 with cycloph...	KEEP AS NON CORE	Summary: IntAct interactions with S100 proteins (S100A1/A2/A6) and HSP90AA1; S100 binding via the TPR domain is Ca2+-dependent and regulates FKBP4-HSP90 association. Bare protein binding is uninformative. Reason: Real, specific interactions documented (S100A1/A2/A6, HSP90), but recorded as bare protein binding; the S100 component is a Ca2+-dependent regulatory interaction, kept non-core. Supporting Evidence: file:human/FKBP4/FKBP4-uniprot.txt Interacts (via TPR domain) with S100A1, S100A2 and S100A6; the interaction is Ca(2+) dependent.
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, so Hsp90 protein binding is the precise function. 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/FKBP4/FKBP4-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). The bare protein binding term 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/FKBP4/FKBP4-goa.tsv GO:0005515 protein binding IPI PMID:21360678 UniProtKB:P07900
GO:0005515 protein binding	IPI PMID:21730179 Targeting the regulation of androgen receptor signaling by t...	KEEP AS NON CORE	Summary: IntAct interactions with HSP90AB1 (P08238) and the androgen receptor AR (P10275). AR is a key FKBP4 client; FKBP4 is a positive regulator of AR signaling. Bare protein binding is uninformative. Reason: Real, biologically meaningful interactions (HSP90 and AR client), but recorded as bare protein binding; the AR client interaction is captured better in the androgen receptor pathway, kept non-core here. Supporting Evidence: file:human/FKBP4/FKBP4-goa.tsv GO:0005515 protein binding IPI PMID:21730179 UniProtKB:P10275
GO:0005515 protein binding	IPI PMID:23741051 Hsp90 cochaperones p23 and FKBP4 physically interact with hA...	KEEP AS NON CORE	Summary: FKBP4 (with p23/PTGES3) physically interacts with hAgo2 (AGO2, Q9UKV8) and is required for efficient RNA interference. Bare protein binding is uninformative; this captures a specific Hsp90-cochaperone role in RISC loading. Reason: A specific, experimentally supported interaction (FKBP4-hAgo2) relevant to RNAi, but recorded as bare protein binding and peripheral to the core steroid-receptor co-chaperone function. Supporting Evidence: PMID:23741051 Whereas FKBP4 and p23 form a stable file:human/FKBP4/FKBP4-goa.tsv GO:0005515 protein binding IPI PMID:23741051 UniProtKB:Q9UKV8
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 FKBP4 interactions with HSP90AB1 (P08238), CDC37 (Q16543) and GLMN (Q92990), placing it in the Hsp90 co-chaperone module. Bare protein binding is uninformative; 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 the appropriate specific term. Proposed replacements: Hsp90 protein binding Supporting Evidence: file:human/FKBP4/FKBP4-goa.tsv GO:0005515 protein binding IPI PMID:25036637 UniProtKB:P08238
GO:0005515 protein binding	IPI PMID:25277244 The functional landscape of Hsp27 reveals new cellular proce...	KEEP AS NON CORE	Summary: IntAct interaction with HSPB1/HSP27 (P04792). The bare protein binding term is uninformative; this is a single chaperone-network interaction. Reason: A real interaction with the small heat-shock protein HSPB1, but recorded as bare protein binding and not part of the core steroid-receptor function. Supporting Evidence: file:human/FKBP4/FKBP4-goa.tsv GO:0005515 protein binding IPI PMID:25277244 UniProtKB:P04792
GO:0005515 protein binding	IPI PMID:28514442 Architecture of the human interactome defines protein commun...	MODIFY	Summary: IntAct interaction with HSP90AB1 (P08238). The bare protein binding term is uninformative; the partner is HSP90. Reason: Bare protein binding is uninformative; the WITH partner is HSP90AB1, so Hsp90 protein binding (GO:0051879) is the precise function. Proposed replacements: Hsp90 protein binding Supporting Evidence: file:human/FKBP4/FKBP4-goa.tsv GO:0005515 protein binding IPI PMID:28514442 UniProtKB:P08238
GO:0005515 protein binding	IPI PMID:32296183 A reference map of the human binary protein interactome.	KEEP AS NON CORE	Summary: IntAct interaction with GLMN (Q92990, the FKBP-associated protein FAP48). The bare protein binding term is uninformative. Reason: A real, specific interaction (GLMN/FAP48), documented also in UniProt, but recorded as bare protein binding and not the core function. Supporting Evidence: file:human/FKBP4/FKBP4-uniprot.txt Interacts with GLMN
GO:0005515 protein binding	IPI PMID:32707033 Kinase Interaction Network Expands Functional and Disease Ro...	KEEP AS NON CORE	Summary: IntAct interaction (P53671) from a high-throughput screen. The bare protein binding term is uninformative and represents an isolated high-throughput interaction. Reason: An isolated high-throughput interaction recorded as bare protein binding; uninformative and not part of the established core function. Supporting Evidence: file:human/FKBP4/FKBP4-goa.tsv GO:0005515 protein binding IPI PMID:32707033 UniProtKB:P53671
GO:0005515 protein binding	IPI PMID:33961781 Dual proteome-scale networks reveal cell-specific remodeling...	MODIFY	Summary: BioPlex affinity-purification interactome capturing FKBP4 interactions with HSP90AA1 (P07900) and GLMN (Q92990). Bare protein binding is uninformative; the central interaction is with HSP90. Reason: Bare protein binding is uninformative; the principal WITH partner is HSP90AA1, so Hsp90 protein binding (GO:0051879) is the appropriate specific term. Proposed replacements: Hsp90 protein binding Supporting Evidence: file:human/FKBP4/FKBP4-goa.tsv GO:0005515 protein binding IPI PMID:33961781 UniProtKB:P07900
GO:0005515 protein binding	IPI PMID:35063084 Tau interactome maps synaptic and mitochondrial processes as...	MODIFY	Summary: IntAct interaction with MAPT/tau (P10636-8). The bare protein binding term is uninformative; the tau interaction underlies FKBP4's microtubule-regulatory role. Reason: Bare protein binding is uninformative; the WITH partner is MAPT/tau, so tau protein binding (GO:0048156) is the precise function. Proposed replacements: tau protein binding Supporting Evidence: file:human/FKBP4/FKBP4-goa.tsv GO:0005515 protein binding IPI PMID:35063084 UniProtKB:P10636-8
GO:0005515 protein binding	IPI PMID:36115835 Quantitative fragmentomics allow affinity mapping of interac...	KEEP AS NON CORE	Summary: A large high-throughput interactome screen reporting many FKBP4 partners (mostly cytoskeletal/coiled-coil proteins). Bare protein binding from a single broad screen is uninformative and does not individually inform FKBP4's core function. Reason: Bare protein binding from one high-throughput screen with many partners not independently validated; uninformative and not reflective of the core co-chaperone function. Supporting Evidence: file:human/FKBP4/FKBP4-goa.tsv GO:0005515 protein binding IPI PMID:36115835 UniProtKB:O75970
GO:0005524 ATP binding	IEA GO_REF:0000107	MARK AS OVER ANNOTATED	Summary: Electronic annotation of ATP binding transferred from the mouse ortholog (P30416) via Ensembl. FKBP4 is a PPIase/co-chaperone with no established ATPase activity or characterized ATP-binding site; HSP90/HSP70 (its partners), not FKBP4, are the ATP-dependent chaperones. Reason: No experimental evidence that FKBP4 binds or hydrolyzes ATP; this looks like an erroneous electronic transfer. PPIase activity is ATP-independent. Supporting Evidence: file:human/FKBP4/FKBP4-goa.tsv GO:0005524 ATP binding IEA GO_REF:0000107 UniProtKB:P30416
GO:0005525 GTP binding	IEA GO_REF:0000107	MARK AS OVER ANNOTATED	Summary: Electronic annotation of GTP binding transferred from the mouse ortholog via Ensembl. FKBP4 has no established GTPase or GTP-binding function. Reason: No experimental evidence FKBP4 binds GTP; an unsupported electronic transfer for a PPIase/co-chaperone. Supporting Evidence: file:human/FKBP4/FKBP4-goa.tsv GO:0005525 GTP binding IEA GO_REF:0000107 UniProtKB:P30416
GO:0031072 heat shock protein binding	IEA GO_REF:0000120	ACCEPT	Summary: FKBP4 binds heat shock proteins, principally HSP90 (via its TPR domain) and associates with HSP70 in steroid receptor complexes. This is a core molecular function of FKBP4 as an HSP90 co-chaperone. Reason: Direct, experimentally documented binding to HSP90 (IPI PMID:9660753) and HSP70 association supports this molecular function; central to FKBP4's co-chaperone role. Supporting Evidence: file:human/FKBP4/FKBP4-uniprot.txt Associates with HSP90AA1 and HSP70 in steroid hormone receptor complexes.
GO:0035259 nuclear glucocorticoid receptor binding	IEA GO_REF:0000107	ACCEPT	Summary: FKBP4 binds the glucocorticoid receptor (NR3C1) in the HSP90 heterocomplex and promotes its function; the electronic transfer from mouse is consistent with documented human GR interaction. Reason: GR (NR3C1) binding is documented experimentally (interaction with glucocorticoid receptor, PubMed:21730050) and underlies FKBP4's positive regulation of GR signaling. Supporting Evidence: file:human/FKBP4/FKBP4-uniprot.txt Interacts with NR3C1 and dynein.
GO:0051219 phosphoprotein binding	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: Electronic annotation of phosphoprotein binding transferred from the mouse ortholog. This is generic and not independently informative for FKBP4's characterized function. Reason: A generic, electronically-inferred binding term without specific human evidence; retained as non-core rather than removed. Supporting Evidence: file:human/FKBP4/FKBP4-goa.tsv GO:0051219 phosphoprotein binding IEA GO_REF:0000107
GO:0005829 cytosol	IDA GO_REF:0000052	ACCEPT	Summary: Direct immunofluorescence (HPA) evidence for cytosolic localization, the principal site of FKBP4 action. Reason: IDA-supported cytosolic localization agrees with the documented primary site of FKBP4 and is a precise cellular-component annotation. Supporting Evidence: file:human/FKBP4/FKBP4-goa.tsv GO:0005829 cytosol IDA GO_REF:0000052 HPA
GO:0005739 mitochondrion	EXP PMID:21730050 The 90-kDa heat-shock protein (Hsp90)-binding immunophilin F...	KEEP AS NON CORE	Summary: Experimental evidence that FKBP4 is a mitochondrial protein that translocates to the nucleus to protect cells against oxidative stress. Reason: Experimentally supported mitochondrial localization, but a secondary/context-specific compartment relative to the cytosolic co-chaperone function. Supporting Evidence: file:human/FKBP4/FKBP4-uniprot.txt Shuttles from mitochondria to nucleus
GO:0005515 protein binding	IPI PMID:11583998 Evidence for a mechanism of repression of heat shock factor ...	KEEP AS NON CORE	Summary: Interaction with HSF1 (heat shock factor 1, Q00613) in the HSP90 multichaperone complex that represses HSF1 transcriptional activity. Bare protein binding is uninformative; the interaction occurs within the HSP90 chaperone complex. Reason: A real, specific interaction (FKBP4-HSF1 in the HSP90 complex), documented in UniProt, but recorded as bare protein binding and peripheral to the core steroid-receptor function. Supporting Evidence: file:human/FKBP4/FKBP4-uniprot.txt Interacts with HSF1 in the HSP90 complex.
GO:0005829 cytosol	TAS Reactome:R-HSA-5618073	ACCEPT	Summary: Reactome pathway annotation placing FKBP4 in the cytosol, consistent with its primary localization. Reason: Curated cytosolic localization consistent with the principal site of FKBP4 action. Supporting Evidence: file:human/FKBP4/FKBP4-uniprot.txt SUBCELLULAR LOCATION: Cytoplasm, cytosol
GO:0005829 cytosol	TAS Reactome:R-HSA-5618080	KEEP AS NON CORE	Summary: Reactome pathway annotation placing FKBP4 in the cytosol, redundant with the primary cytosolic localization. Reason: Redundant curated cytosol annotation from a Reactome pathway; consistent but duplicative. Supporting Evidence: file:human/FKBP4/FKBP4-uniprot.txt SUBCELLULAR LOCATION: Cytoplasm, cytosol
GO:0005829 cytosol	TAS Reactome:R-HSA-5618085	KEEP AS NON CORE	Summary: Reactome pathway annotation placing FKBP4 in the cytosol; redundant with the primary localization. Reason: Redundant curated cytosol annotation; consistent but duplicative. Supporting Evidence: file:human/FKBP4/FKBP4-uniprot.txt SUBCELLULAR LOCATION: Cytoplasm, cytosol
GO:0005829 cytosol	TAS Reactome:R-HSA-5618099	KEEP AS NON CORE	Summary: Reactome pathway annotation placing FKBP4 in the cytosol; redundant with the primary localization. Reason: Redundant curated cytosol annotation; consistent but duplicative. Supporting Evidence: file:human/FKBP4/FKBP4-uniprot.txt SUBCELLULAR LOCATION: Cytoplasm, cytosol
GO:0005829 cytosol	TAS Reactome:R-HSA-5618110	KEEP AS NON CORE	Summary: Reactome pathway annotation placing FKBP4 in the cytosol; redundant with the primary localization. Reason: Redundant curated cytosol annotation; consistent but duplicative. Supporting Evidence: file:human/FKBP4/FKBP4-uniprot.txt SUBCELLULAR LOCATION: Cytoplasm, cytosol
GO:0005829 cytosol	TAS Reactome:R-HSA-9678925	KEEP AS NON CORE	Summary: Reactome pathway annotation placing FKBP4 in the cytosol; redundant with the primary localization. Reason: Redundant curated cytosol annotation; consistent but duplicative. Supporting Evidence: file:human/FKBP4/FKBP4-uniprot.txt SUBCELLULAR LOCATION: Cytoplasm, cytosol
GO:0005829 cytosol	TAS Reactome:R-HSA-9690534	KEEP AS NON CORE	Summary: Reactome pathway annotation placing FKBP4 in the cytosol; redundant with the primary localization. Reason: Redundant curated cytosol annotation; consistent but duplicative. Supporting Evidence: file:human/FKBP4/FKBP4-uniprot.txt SUBCELLULAR LOCATION: Cytoplasm, cytosol
GO:0005829 cytosol	TAS Reactome:R-HSA-9705925	KEEP AS NON CORE	Summary: Reactome pathway annotation placing FKBP4 in the cytosol; redundant with the primary localization. Reason: Redundant curated cytosol annotation; consistent but duplicative. Supporting Evidence: file:human/FKBP4/FKBP4-uniprot.txt SUBCELLULAR LOCATION: Cytoplasm, cytosol
GO:0005829 cytosol	TAS Reactome:R-HSA-9705926	KEEP AS NON CORE	Summary: Reactome pathway annotation placing FKBP4 in the cytosol; redundant with the primary localization. Reason: Redundant curated cytosol annotation; consistent but duplicative. Supporting Evidence: file:human/FKBP4/FKBP4-uniprot.txt SUBCELLULAR LOCATION: Cytoplasm, cytosol
GO:0005829 cytosol	TAS Reactome:R-HSA-9706837	KEEP AS NON CORE	Summary: Reactome pathway annotation placing FKBP4 in the cytosol; redundant with the primary localization. Reason: Redundant curated cytosol annotation; consistent but duplicative. Supporting Evidence: file:human/FKBP4/FKBP4-uniprot.txt SUBCELLULAR LOCATION: Cytoplasm, cytosol
GO:0005829 cytosol	TAS Reactome:R-HSA-9725855	KEEP AS NON CORE	Summary: Reactome pathway annotation placing FKBP4 in the cytosol; redundant with the primary localization. Reason: Redundant curated cytosol annotation; consistent but duplicative. Supporting Evidence: file:human/FKBP4/FKBP4-uniprot.txt SUBCELLULAR LOCATION: Cytoplasm, cytosol
GO:0005829 cytosol	TAS Reactome:R-HSA-9725885	KEEP AS NON CORE	Summary: Reactome pathway annotation placing FKBP4 in the cytosol; redundant with the primary localization. Reason: Redundant curated cytosol annotation; consistent but duplicative. Supporting Evidence: file:human/FKBP4/FKBP4-uniprot.txt SUBCELLULAR LOCATION: Cytoplasm, cytosol
GO:0005829 cytosol	TAS Reactome:R-HSA-9726509	KEEP AS NON CORE	Summary: Reactome pathway annotation placing FKBP4 in the cytosol; redundant with the primary localization. Reason: Redundant curated cytosol annotation; consistent but duplicative. Supporting Evidence: file:human/FKBP4/FKBP4-uniprot.txt SUBCELLULAR LOCATION: Cytoplasm, cytosol
GO:0005829 cytosol	TAS Reactome:R-HSA-9726580	KEEP AS NON CORE	Summary: Reactome pathway annotation placing FKBP4 in the cytosol; redundant with the primary localization. Reason: Redundant curated cytosol annotation; consistent but duplicative. Supporting Evidence: file:human/FKBP4/FKBP4-uniprot.txt SUBCELLULAR LOCATION: Cytoplasm, cytosol
GO:0005829 cytosol	TAS Reactome:R-HSA-9726621	KEEP AS NON CORE	Summary: Reactome pathway annotation placing FKBP4 in the cytosol; redundant with the primary localization. Reason: Redundant curated cytosol annotation; consistent but duplicative. Supporting Evidence: file:human/FKBP4/FKBP4-uniprot.txt SUBCELLULAR LOCATION: Cytoplasm, cytosol
GO:0005654 nucleoplasm	TAS Reactome:R-HSA-5324617	KEEP AS NON CORE	Summary: Reactome annotation placing FKBP4 in the nucleoplasm, consistent with its nuclear pool and role in steroid receptor nuclear translocation. Reason: Nuclear/nucleoplasm localization reflects the receptor-trafficking endpoint rather than the principal cytosolic co-chaperone site; retained as non-core. Supporting Evidence: file:human/FKBP4/FKBP4-uniprot.txt Shuttles from mitochondria to nucleus
GO:0005654 nucleoplasm	TAS Reactome:R-HSA-5618080	KEEP AS NON CORE	Summary: Reactome annotation placing FKBP4 in the nucleoplasm; redundant with the nuclear pool annotation. Reason: Redundant curated nucleoplasm annotation; consistent with the nuclear trafficking endpoint. Supporting Evidence: file:human/FKBP4/FKBP4-uniprot.txt Shuttles from mitochondria to nucleus
GO:0005654 nucleoplasm	TAS Reactome:R-HSA-5618093	KEEP AS NON CORE	Summary: Reactome annotation placing FKBP4 in the nucleoplasm; redundant with the nuclear pool annotation. Reason: Redundant curated nucleoplasm annotation; consistent with the nuclear trafficking endpoint. Supporting Evidence: file:human/FKBP4/FKBP4-uniprot.txt Shuttles from mitochondria to nucleus
GO:0005654 nucleoplasm	TAS Reactome:R-HSA-9038161	KEEP AS NON CORE	Summary: Reactome annotation placing FKBP4 in the nucleoplasm; redundant with the nuclear pool annotation. Reason: Redundant curated nucleoplasm annotation; consistent with the nuclear trafficking endpoint. Supporting Evidence: file:human/FKBP4/FKBP4-uniprot.txt Shuttles from mitochondria to nucleus
GO:0003723 RNA binding	HDA PMID:22658674 Insights into RNA biology from an atlas of mammalian mRNA-bi...	KEEP AS NON CORE	Summary: High-throughput RNA-interactome capture detected FKBP4 as an RNA-bound protein. This is a proteome-wide screen result; FKBP4 has no characterized sequence-specific RNA-binding function, though it does participate (via hAgo2) in RNAi. Reason: A high-throughput RNA-interactome capture hit without a defined RNA-binding mechanism for FKBP4; retained as non-core rather than a core molecular function. Supporting Evidence: file:human/FKBP4/FKBP4-goa.tsv GO:0003723 RNA binding HDA PMID:22658674
GO:0070062 extracellular exosome	HDA PMID:19056867 Large-scale proteomics and phosphoproteomics of urinary exos...	KEEP AS NON CORE	Summary: Detection of FKBP4 in extracellular exosome proteomics. As an abundant cytosolic protein, FKBP4 is frequently detected in exosome preparations; this is not its principal functional location. Reason: A high-throughput proteomic detection in exosomes; plausible passive presence but peripheral to the gene's core cytosolic function. Supporting Evidence: file:human/FKBP4/FKBP4-goa.tsv GO:0070062 extracellular exosome HDA PMID:19056867
GO:0070062 extracellular exosome	HDA PMID:20458337 MHC class II-associated proteins in B-cell exosomes and pote...	KEEP AS NON CORE	Summary: Second exosome proteomics dataset detecting FKBP4, redundant with the first. Reason: A high-throughput proteomic detection in exosomes; peripheral to the gene's core function. Supporting Evidence: file:human/FKBP4/FKBP4-goa.tsv GO:0070062 extracellular exosome HDA PMID:20458337
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 FKBP4 peptidyl-prolyl cis-trans isomerase activity. This is the core catalytic function. Reason: IDA evidence directly supports PPIase activity, a defining core molecular function of FKBP4 (EC 5.2.1.8). Supporting Evidence: file:human/FKBP4/FKBP4-uniprot.txt RecName: Full=Peptidyl-prolyl cis-trans isomerase FKBP4
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 FKBP4 to protein folding via its rotamase/PPIase activity. The molecular function (PPIase) is the more informative annotation; folding is a contributory process. Reason: FKBP4 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/FKBP4/FKBP4-uniprot.txt Immunophilin protein with PPIase and co-chaperone activities.
GO:0010977 negative regulation of neuron projection development	ISS GO_REF:0000024	KEEP AS NON CORE	Summary: FKBP4 negatively regulates neuron projection development, inferred by sequence similarity. FKBP4 controls neuronal growth-cone guidance via TRPC1 and antagonizes tau-promoted microtubule assembly. Reason: A plausible neuronal process consistent with the documented growth-cone/TRPC1 and tau/microtubule roles, but inferred (ISS) and a specialized, non-core process. Supporting Evidence: file:human/FKBP4/FKBP4-uniprot.txt The isomerase activity controls neuronal growth cones via regulation of TRPC1 channel opening.
GO:0031111 negative regulation of microtubule polymerization or depolymerization	ISS GO_REF:0000024	KEEP AS NON CORE	Summary: FKBP4 regulates microtubule dynamics by inhibiting MAPT/tau's ability to promote microtubule assembly; its C-terminal region prevents tubulin polymerization. Inferred by sequence similarity. Reason: Consistent with the documented tau/tubulin regulatory role, but inferred (ISS) and a specialized, non-core process relative to the core co-chaperone function. Supporting Evidence: file:human/FKBP4/FKBP4-uniprot.txt Also acts as a regulator of microtubule dynamics by inhibiting MAPT/TAU ability to promote microtubule assembly.
GO:0044295 axonal growth cone	ISS GO_REF:0000024	KEEP AS NON CORE	Summary: FKBP4 localizes to the axonal growth cone, consistent with its TRPC1-mediated control of growth-cone chemotropic guidance. Inferred by sequence similarity from mouse. Reason: A specialized neuronal localization supporting the growth-cone guidance role; inferred (ISS) and non-core relative to the principal cytosolic function. Supporting Evidence: file:human/FKBP4/FKBP4-uniprot.txt The isomerase activity controls neuronal growth cones via regulation of TRPC1 channel opening.
GO:0005829 cytosol	ISS GO_REF:0000024	ACCEPT	Summary: Cytosolic localization inferred by sequence similarity from the mouse ortholog, consistent with the principal site of FKBP4 action. Reason: Correct primary localization, corroborated by direct experimental (IDA/HPA) and IBA evidence. Supporting Evidence: file:human/FKBP4/FKBP4-uniprot.txt SUBCELLULAR LOCATION: Cytoplasm, cytosol
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 FKBP4. This is a core co-chaperone molecular function. Reason: Experimentally documented HSP90 binding (the basis of FKBP4's TPR-mediated co-chaperone role) supports heat shock protein binding as a core function. Supporting Evidence: file:human/FKBP4/FKBP4-goa.tsv GO:0031072 heat shock protein binding IPI PMID:9660753 UniProtKB:P07900
GO:0005515 protein binding	IPI PMID:12604780 The FKBP-associated protein FAP48 is an antiproliferative mo...	KEEP AS NON CORE	Summary: Interaction with GLMN (FAP48, Q92990). The bare protein binding term is uninformative; this is a documented FKBP-associated protein interaction. Reason: A real, specific interaction (GLMN/FAP48) recorded in UniProt, but bare protein binding is uninformative and not the core function. Supporting Evidence: file:human/FKBP4/FKBP4-uniprot.txt Interacts with GLMN
GO:0030674 protein-macromolecule adaptor activity	TAS PMID:2378870 The 56-59-kilodalton protein identified in untransformed ste...	ACCEPT	Summary: FKBP4 acts as an adaptor that bridges steroid hormone receptors to the HSP90/HSP70 chaperone machine and to dynein, captured by the classic identification of the 56-59 kDa immunophilin in untransformed steroid receptor complexes. This adaptor role is a genuine core molecular function. Reason: FKBP4 functions as a co-chaperone adaptor linking receptors to HSP90/HSP70 and recruiting dynein; the TAS adaptor-activity annotation captures this bridging role. Supporting Evidence: file:human/FKBP4/FKBP4-uniprot.txt Component of steroid receptors heterocomplexes through interaction with heat-shock protein 90 (HSP90). file:human/FKBP4/FKBP4-uniprot.txt Interacts with NR3C1 and dynein.
GO:0005737 cytoplasm	TAS PMID:2378870 The 56-59-kilodalton protein identified in untransformed ste...	ACCEPT	Summary: Classic identification of FKBP4 in cytosolic steroid receptor complexes, supporting cytoplasmic localization. Reason: Cytoplasmic localization is the principal site of FKBP4 action and is well supported. Supporting Evidence: file:human/FKBP4/FKBP4-uniprot.txt SUBCELLULAR LOCATION: Cytoplasm, cytosol
GO:0006457 protein folding	TAS PMID:1279700 Expression and characterization of human FKBP52, an immunoph...	KEEP AS NON CORE	Summary: Author-stated (TAS) involvement of FKBP4 in protein folding, from the original characterization of human FKBP52 as an HSP90-associated immunophilin. The informative function is its PPIase/co-chaperone activity. Reason: Protein folding is a contributory process downstream of FKBP4's PPIase/co-chaperone activity; the catalytic and binding MFs are the core. Supporting Evidence: file:human/FKBP4/FKBP4-uniprot.txt Immunophilin protein with PPIase and co-chaperone activities.
GO:0005528 FK506 binding	TAS PMID:1376003 Association of a 59-kilodalton immunophilin with the glucoco...	ACCEPT	Summary: Author-stated FK506 binding, from the identification of the 59 kDa immunophilin in the glucocorticoid receptor complex. FK506 binding is the defining property of the FKBP family. Reason: FK506 binding is directly documented and inhibits FKBP4's PPIase activity; a characteristic molecular function. Supporting Evidence: file:human/FKBP4/FKBP4-uniprot.txt ACTIVITY REGULATION: Inhibited by FK506.

Core Functions

Peptidyl-prolyl cis-trans isomerase (rotamase, EC 5.2.1.8), the catalytic activity of the N-terminal FKBP domain, inhibited by FK506; this activity controls clients such as the TRPC1 channel and contributes to protein maturation.

Molecular Function:

peptidyl-prolyl cis-trans isomerase activity

Cellular Locations:

cytosol

Supporting Evidence:

file:human/FKBP4/FKBP4-uniprot.txt
RecName: Full=Peptidyl-prolyl cis-trans isomerase FKBP4
file:human/FKBP4/FKBP4-uniprot.txt
The PPIase activity is mainly due to the first PPIase FKBP-type domain

HSP90 co-chaperone that binds HSP90 (and associates with HSP70) via its TPR domain and is incorporated into steroid hormone receptor maturation heterocomplexes; positive regulator of glucocorticoid, androgen and progesterone receptor signaling.

Molecular Function:

heat shock protein binding

Cellular Locations:

cytosol

Supporting Evidence:

file:human/FKBP4/FKBP4-uniprot.txt
Associates with HSP90AA1 and HSP70 in steroid hormone receptor complexes.
file:human/FKBP4/FKBP4-goa.tsv
GO:0031072 heat shock protein binding IPI PMID:9660753 UniProtKB:P07900

Co-chaperone adaptor that bridges steroid hormone receptors to the HSP90/HSP70 machine and recruits cytoplasmic dynein, promoting retrograde transport and nuclear translocation of activated receptors.

Molecular Function:

protein-macromolecule adaptor activity

Cellular Locations:

cytosol

Supporting Evidence:

file:human/FKBP4/FKBP4-uniprot.txt
Component of steroid receptors heterocomplexes through interaction with heat-shock protein 90 (HSP90).
file:human/FKBP4/FKBP4-uniprot.txt
Interacts with NR3C1 and dynein.

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:0000052

Gene Ontology annotation based on curation of immunofluorescence data

GO_REF:0000107

Automatic transfer of experimentally verified manual GO annotation data to orthologs using Ensembl Compara

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 FKBP4/FKBP52 peptidyl-prolyl cis-trans isomerase (rotamase) activity.

PMID:11583998

Evidence for a mechanism of repression of heat shock factor 1 transcriptional activity by a multichaperone complex.

FKBP4 interacts with HSF1 within an HSP90 multichaperone complex that represses HSF1 transcriptional activity.

PMID:12604780

The FKBP-associated protein FAP48 is an antiproliferative molecule and a player in T cell activation that increases IL2 synthesis.

FKBP4 interacts with GLMN (FAP48), an FKBP-associated antiproliferative protein.

PMID:1279700

Expression and characterization of human FKBP52, an immunophilin that associates with the 90-kDa heat shock protein and is a component of steroid receptor complexes.

Human FKBP52 is an immunophilin that associates with HSP90 and is a component of steroid receptor complexes.

PMID:1376003

Association of a 59-kilodalton immunophilin with the glucocorticoid receptor complex.

A 59 kDa FK506-binding immunophilin (FKBP4/FKBP52) associates with the glucocorticoid receptor complex.

PMID:14638689

S100A1 is a novel molecular chaperone and a member of the Hsp70/Hsp90 multichaperone complex.

PMID:19056867

Large-scale proteomics and phosphoproteomics of urinary exosomes.

PMID:19875381

A proteomic investigation of ligand-dependent HSP90 complexes reveals CHORDC1 as a novel ADP-dependent HSP90-interacting protein.

PMID:20133804

A role for FKBP52 in Tau protein function.

PMID:20188096

S100 proteins regulate the interaction of Hsp90 with cyclophilin 40 and FKBP52 through their tetratricopeptide repeats.

S100A1/A2/A6 bind FKBP4 via its TPR domain in a Ca2+-dependent manner and modulate the FKBP4-HSP90 interaction.

PMID:20458337

MHC class II-associated proteins in B-cell exosomes and potential functional implications for exosome biogenesis.

PMID:21170051

Mixed Hsp90-cochaperone complexes are important for the progression of the reaction cycle.

PPIase co-chaperones such as FKBP4 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:21730050

The 90-kDa heat-shock protein (Hsp90)-binding immunophilin FKBP51 is a mitochondrial protein that translocates to the nucleus to protect cells against oxidative stress.

FKBP4 (FKBP52) localizes to mitochondria, interacts with the glucocorticoid receptor, and translocates to the nucleus to protect cells against oxidative stress.

PMID:21730179

Targeting the regulation of androgen receptor signaling by the heat shock protein 90 cochaperone FKBP52 in prostate cancer cells.

PMID:22658674

Insights into RNA biology from an atlas of mammalian mRNA-binding proteins.

PMID:23741051

Hsp90 cochaperones p23 and FKBP4 physically interact with hAgo2 and activate RNA interference-mediated silencing in mammalian cells.

FKBP4 (with p23) physically interacts with hAgo2 and is required for efficient RNA interference-mediated silencing.

PMID:25036637

A quantitative chaperone interaction network reveals the architecture of cellular protein homeostasis pathways.

FKBP4 is part of the Hsp90 co-chaperone module, interacting with HSP90, CDC37 and GLMN.

PMID:25277244

The functional landscape of Hsp27 reveals new cellular processes such as DNA repair and alternative splicing and proposes novel anticancer targets.

PMID:28514442

Architecture of the human interactome defines protein communities and disease networks.

PMID:2378870

The 56-59-kilodalton protein identified in untransformed steroid receptor complexes is a unique protein that exists in cytosol in a complex with both the 70- and 90-kilodalton heat shock proteins.

FKBP4 exists in the cytosol in a complex with both HSP70 and HSP90 within untransformed steroid receptor complexes, acting as an adaptor.

PMID:32296183

A reference map of the human binary protein interactome.

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 FKBP4 interactions with HSP90AA1 and GLMN.

PMID:35063084

Tau interactome maps synaptic and mitochondrial processes associated with neurodegeneration.

PMID:36115835

Quantitative fragmentomics allow affinity mapping of interactomes.

PMID:9660753

Specific binding of tetratricopeptide repeat proteins to the C-terminal 12-kDa domain of Hsp90.

FKBP4 directly binds HSP90AA1.

Reactome:R-HSA-5324617

Reactome: FKBP4 in nucleoplasm.

Reactome:R-HSA-5618073

Reactome: FKBP4 in cytosol.

Reactome:R-HSA-5618080

Reactome: FKBP4 in cytosol/nucleoplasm.

Reactome:R-HSA-5618085

Reactome: FKBP4 in cytosol.

Reactome:R-HSA-5618093

Reactome: FKBP4 in nucleoplasm.

Reactome:R-HSA-5618099

Reactome: FKBP4 in cytosol.

Reactome:R-HSA-5618110

Reactome: FKBP4 in cytosol.

Reactome:R-HSA-9038161

Reactome: FKBP4 in nucleoplasm.

Reactome:R-HSA-9678925

Reactome: FKBP4 in cytosol.

Reactome:R-HSA-9690534

Reactome: FKBP4 in cytosol.

Reactome:R-HSA-9705925

Reactome: FKBP4 in cytosol.

Reactome:R-HSA-9705926

Reactome: FKBP4 in cytosol.

Reactome:R-HSA-9706837

Reactome: FKBP4 in cytosol.

Reactome:R-HSA-9725855

Reactome: FKBP4 in cytosol.

Reactome:R-HSA-9725885

Reactome: FKBP4 in cytosol.

Reactome:R-HSA-9726509

Reactome: FKBP4 in cytosol.

Reactome:R-HSA-9726580

Reactome: FKBP4 in cytosol.

Reactome:R-HSA-9726621

Reactome: FKBP4 in cytosol.

file:human/FKBP4/FKBP4-uniprot.txt

UniProt entry Q02790 (FKBP4_HUMAN), Peptidyl-prolyl cis-trans isomerase FKBP4 / FKBP52

Immunophilin with PPIase and co-chaperone activities; component of steroid receptor heterocomplexes via HSP90; promotes intracellular trafficking of steroid hormone receptors; controls neuronal growth cones via TRPC1; regulates microtubule dynamics via MAPT/tau; cytosolic, mitochondrial, nuclear and cytoskeletal localization.

Suggested Experiments

Experiment: Compare FKBP4 wild-type versus PPIase-dead (active-site mutant) and TPR-deletion constructs for their ability to potentiate glucocorticoid/androgen receptor transcriptional activity in cells, to separate catalytic from adaptor contributions.

Experiment: Reconstitute steroid receptor-HSP90-FKBP4 heterocomplex assembly in vitro and measure FKBP4-dependent dynein recruitment and receptor hormone-binding affinity, contrasting FKBP4 with FKBP5.

Experiment: Use proximity-labeling (BioID/TurboID) of FKBP4 across compartments (cytosol, mitochondria, growth cone) to map context-specific client and chaperone partners and validate the oxidative-stress translocation.

📚 Additional Documentation

Notes

(FKBP4-notes.md)

FKBP4 (FKBP52) research notes

UniProt: Q02790. 459 aa. EC 5.2.1.8 (peptidyl-prolyl cis-trans isomerase / rotamase).
Domains: two FKBP-type PPIase domains (50-138 active; 167-253), three TPR repeats (270-386).

Core biology (well-established)

Immunophilin with PPIase + co-chaperone activity; component of steroid receptor
heterocomplexes via interaction with HSP90 [file:human/FKBP4/FKBP4-uniprot.txt
"Immunophilin protein with PPIase and co-chaperone activities. Component of steroid
receptors heterocomplexes through interaction with heat-shock protein 90 (HSP90)."].
Binds HSP90 via TPR domain; ternary complexes with HSP90/HSP70 and steroid receptors
(GR/NR3C1, AR, PR, MR/NR3C2). Promotes intracellular trafficking of steroid receptors
between cytoplasm and nucleus [uniprot "May play a role in the intracellular trafficking
of heterooligomeric forms of steroid hormone receptors between cytoplasm and nuclear
compartments."]. FKBP52 is a POSITIVE regulator of GR/AR/PR (contrast FKBP5/FKBP51 which
is negative).
Recruits dynein motor to receptor-HSP90 complexes, promoting NR3C1 transport to nucleus
[uniprot "Interacts with dynein; causes partially NR3C1 transport to the nucleus."].
PPIase activity controls neuronal growth cones via TRPC1 channel opening
[PMID:19945390; uniprot "The isomerase activity controls neuronal growth cones via
regulation of TRPC1 channel opening."]; F67/D68 mutation reduces catalytic activity toward TRPC1.
Regulator of microtubule dynamics by inhibiting MAPT/TAU promotion of microtubule assembly
[uniprot "Also acts as a regulator of microtubule dynamics by inhibiting MAPT/TAU ability
to promote microtubule assembly."]; C-terminal region (375-458) prevents tubulin polymerization.
May have protective role against oxidative stress in mitochondria (shuttles mito->nucleus)
[PMID:21730050; uniprot "May have a protective role against oxidative stress in mitochondria."].
Inhibited by FK506; binds immunosuppressant FK506 (FKBP = FK506-binding protein).

Interactions

HSP90AA1/HSP90AB1 (TPR-mediated), HSP70, HSF1 (in HSP90 multichaperone complex repressing HSF1),
GLMN/FAP48, S100A1/A2/A6 (Ca2+-dependent, TPR; S100A1/A2 inhibit FKBP4-HSP90), AR, MAPT/TAU,
CDC37, tubulin, PHYH, dynein.
p23 (PTGES3) + FKBP4 interact with hAgo2 and activate RNAi PMID:23741051.
Mixed Hsp90-cochaperone complexes: PPIase replaces Sti1/Hop in the cycle PMID:21170051.

Subcellular location

Cytoplasm/cytosol (primary), mitochondrion, nucleus, cytoskeleton/microtubule, axon/growth cone.
Detected in extracellular exosomes (HDA proteomics — likely passive secretion, non-core).

Interactome / proteomics PMIDs (mostly IPI bare protein binding)

14638689, 19875381, 20133804, 20188096(S100), 21170051, 21360678, 21730179(AR), 23741051(Ago2),
25036637(Taipale chaperone net), 25277244(Hsp27 net), 28514442, 32296183, 32707033, 33961781,
35063084(Tau), 36115835. 9660753 = HSP90 binding (IPI). 11583998=HSF1. 12604780=GLMN.

Action plan

PPIase activity (IDA PMID:11350175, IBA, IEA): ACCEPT core MF GO:0003755.
heat shock protein binding (IPI 9660753 HSP90; IEA): ACCEPT — core co-chaperone MF GO:0031072.
protein folding (IBA/IEA/IDA/TAS): KEEP_AS_NON_CORE (co-chaperone assists HSP90; PPIase is a
foldase-type activity but "protein folding" BP is downstream/generic).
FK506 binding GO:0005528: ACCEPT (defining property; immunophilin).
cytosol/cytoplasm (multiple): ACCEPT one IDA; redundant Reactome TAS cytosol KEEP_AS_NON_CORE.
mitochondrion (EXP PMID:21730050; IEA): ACCEPT (experimental).
nucleus / nucleoplasm: KEEP_AS_NON_CORE (shuttling; trafficking role).
cytoskeleton/microtubule/axon/growth cone: KEEP_AS_NON_CORE (tubulin/TAU regulation, ISS).
protein-macromolecule adaptor activity GO:0030674 (TAS 2378870): ACCEPT — captures co-chaperone
adaptor role bridging receptor to HSP90/dynein.
nuclear glucocorticoid receptor binding GO:0035259 (IEA): KEEP_AS_NON_CORE / accept-ish (real GR binding).
negative regulation of microtubule polymerization / neuron projection (ISS): KEEP_AS_NON_CORE.
ATP binding / GTP binding (IEA Ensembl from mouse P30416): MARK_AS_OVER_ANNOTATED — no evidence
FKBP52 is an ATPase/GTPase; these are dubious electronic transfers.
RNA binding (HDA PMID:22658674): KEEP_AS_NON_CORE (high-throughput RNA-interactome capture).
phosphoprotein binding GO:0051219 (IEA): KEEP_AS_NON_CORE.
extracellular exosome (HDA): KEEP_AS_NON_CORE.
protein binding IPI block: KEEP_AS_NON_CORE generally; MODIFY the HSP90 ones to Hsp90 protein
binding where partner is HSP90AA1/AB1; AR partner -> KEEP_AS_NON_CORE (real, informs AR pathway).

Pn Notes

(FKBP4-pn-notes.md)

FKBP4 PN Consistency Notes

Generated: 2026-06-18
Project: PROTEOSTASIS
Scope: PN consistency rereview against local AIGR review and available deep-research artifacts
UniProt: Q02790
AIGR review status: COMPLETE
Review batch: proteostasis-batch-2026-06-07b
Batch change status: added

Source Files Checked

AIGR review YAML: present - genes/human/FKBP4/FKBP4-ai-review.yaml
AIGR review HTML: present - genes/human/FKBP4/FKBP4-ai-review.html
Gene notes: present - genes/human/FKBP4/FKBP4-notes.md
GOA TSV: present - genes/human/FKBP4/FKBP4-goa.tsv
UniProt record: present - genes/human/FKBP4/FKBP4-uniprot.txt
PN dossier: projects/PROTEOSTASIS/reports/phase1_dossiers/FKBP4.md
PN consistency section: projects/PROTEOSTASIS/reports/phase1_dossiers/_sections/FKBP4.md
PN projection report: projects/PROTEOSTASIS/reports/pn_projection/pn_projected_gene_go_summary.tsv
PN mapping audit: projects/PROTEOSTASIS/reports/pn_mapping_audit/current_mapping_scrutiny.tsv

Deep Research Files

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

AIGR Review Snapshot

Description: FKBP4 (FKBP52, also called the 52 kDa FK506-binding protein, p59 or HSP-binding immunophilin) is a cytoplasmic immunophilin and HSP90 co-chaperone. It contains two FKBP-type peptidyl-prolyl cis-trans isomerase (PPIase/rotamase) domains (the N-terminal domain carries the active site and is inhibited by FK506) and three C-terminal tetratricopeptide (TPR) repeats that mediate binding to the EEVD motif of HSP90. Through its TPR domain it is incorporated, together with HSP90 and HSP70, into the mature heterocomplexes of steroid hormone receptors (glucocorticoid, androgen, progesterone and mineralocorticoid receptors), where it acts as a positive regulator of receptor hormone-binding affinity and nuclear translocation. By recruiting cytoplasmic dynein to the receptor-HSP90 complex it promotes retrograde, microtubule-dependent transport of activated receptors toward the nucleus. Beyond steroid signaling, its PPIase activity regulates TRPC1 channel opening to control neuronal growth-cone chemotropic guidance, and it modulates microtubule dynamics by antagonizing the tau (MAPT) protein. It localizes mainly to the cytosol but also to mitochondria, the nucleus, the cytoskeleton and axonal projections, and shuttles between these compartments. FKBP4 is the functional antagonist of its paralog FKBP5 (FKBP51), which is a negative regulator of the same steroid receptors.
Existing/core annotation action counts: ACCEPT: 15; KEEP_AS_NON_CORE: 44; MARK_AS_OVER_ANNOTATED: 2; MODIFY: 8

PN Consistency Summary

Consistency: Strong. Review, notes and PN agree FKBP52 is a catalytically active FKBP PPIase (N-terminal domain, FK506-inhibited) AND an HSP90 co-chaperone (TPR→EEVD) in steroid-receptor heterocomplexes, plus a dynein-recruiting adaptor. Both the catalytic (PPIase) and scaffold/co-chaperone MFs are distinguished — prompt's catalytic-vs-scaffold check satisfied. Core MFs = GO:0003755, GO:0031072, GO:0030674. No contradictions.
PN story / NEW pressure: Nothing new. PN's GO:0003755 already in review (core, ACCEPT). PN's GO:0051879 (Hsp90 binding) already present in review ×6 — so the "more_specific_than_existing_goa" projection is already captured, not a NEW pressure.
Evidence alignment: PN carries no extra reference titles; review GO:0031072/0051879 supported by GOA IPI PMID:9660753 (HSP90). Consistent.
Verdict: Fully consistent; PN adds no new defensible term (both projected terms already in review). Recommended edits: none.

Full Consistency Review

UniProt: Q02790 (FKBP52) · 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 ; PN-node mapping: mapped → GO:0051879 (Hsp90 protein binding, more_specific_than_existing_goa), GO:0003755 (PPIase activity, already_in_goa_exact)
Consistency: Strong. Review, notes and PN agree FKBP52 is a catalytically active FKBP PPIase (N-terminal domain, FK506-inhibited) AND an HSP90 co-chaperone (TPR→EEVD) in steroid-receptor heterocomplexes, plus a dynein-recruiting adaptor. Both the catalytic (PPIase) and scaffold/co-chaperone MFs are distinguished — prompt's catalytic-vs-scaffold check satisfied. Core MFs = GO:0003755, GO:0031072, GO:0030674. No contradictions.
PN story / NEW pressure: Nothing new. PN's GO:0003755 already in review (core, ACCEPT). PN's GO:0051879 (Hsp90 binding) already present in review ×6 — so the "more_specific_than_existing_goa" projection is already captured, not a NEW pressure.
Mapping strategy: PN type node maps to broad GO:0031072 at the subtype but elects GO:0051879 (the narrower, OLS-confirmed child) at the projection level, matching the review. Conservative and correct: subtype-level PPIase mapping is withheld (mixed-member node) while the gene genuinely carries PPIase. No mapping change.
Evidence alignment: PN carries no extra reference titles; review GO:0031072/0051879 supported by GOA IPI PMID:9660753 (HSP90). Consistent.
Verdict: Fully consistent; PN adds no new defensible term (both projected terms already in review). Recommended edits: none.

PN Dossier Context

review_batch: proteostasis-batch-2026-06-07b
review_yaml: genes/human/FKBP4/FKBP4-ai-review.yaml
PN workbook rows: 2

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

UniProt: Q02790
In branches: CY
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: Q02790
In branches: CY
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.

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: Q02790
gene_symbol: FKBP4
product_type: PROTEIN
status: COMPLETE
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: FKBP4 (FKBP52, also called the 52 kDa FK506-binding protein, p59 or HSP-binding immunophilin) is a cytoplasmic immunophilin and HSP90 co-chaperone. It contains two FKBP-type peptidyl-prolyl cis-trans isomerase (PPIase/rotamase) domains (the N-terminal domain carries the active site and is inhibited by FK506) and three C-terminal tetratricopeptide (TPR) repeats that mediate binding to the EEVD motif of HSP90. Through its TPR domain it is incorporated, together with HSP90 and HSP70, into the mature heterocomplexes of steroid hormone receptors (glucocorticoid, androgen, progesterone and mineralocorticoid receptors), where it acts as a positive regulator of receptor hormone-binding affinity and nuclear translocation. By recruiting cytoplasmic dynein to the receptor-HSP90 complex it promotes retrograde, microtubule-dependent transport of activated receptors toward the nucleus. Beyond steroid signaling, its PPIase activity regulates TRPC1 channel opening to control neuronal growth-cone chemotropic guidance, and it modulates microtubule dynamics by antagonizing the tau (MAPT) protein. It localizes mainly to the cytosol but also to mitochondria, the nucleus, the cytoskeleton and axonal projections, and shuttles between these compartments. FKBP4 is the functional antagonist of its paralog FKBP5 (FKBP51), which is a negative regulator of the same steroid receptors.
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. FKBP4 has rotamase (PPIase) activity that can catalyze proline isomerization, a rate-limiting step in folding, and it acts as an HSP90 co-chaperone. The molecular activity (PPIase / co-chaperone binding) is the more informative annotation; the folding process is a downstream/contributory outcome rather than autonomous foldase activity.
    action: KEEP_AS_NON_CORE
    reason: FKBP4 contributes to folding through its PPIase activity and HSP90 co-chaperone role, but the precise molecular functions (peptidyl-prolyl isomerase activity, HSP90 binding, adaptor activity) capture the core function better; protein folding is retained as a plausible non-core process.
    supported_by:
    - reference_id: file:human/FKBP4/FKBP4-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: FKBP4 is a bona fide peptidyl-prolyl cis-trans isomerase (rotamase, EC 5.2.1.8), with the activity residing in the N-terminal FKBP domain and inhibited by FK506. This is a defining, well-supported core molecular function.
    action: ACCEPT
    reason: PPIase activity is directly demonstrated (EC 5.2.1.8; FK506-inhibitable) and is a core catalytic function of FKBP4; IBA transfer is consistent with experimental evidence.
    supported_by:
    - reference_id: file:human/FKBP4/FKBP4-uniprot.txt
      supporting_text: 'RecName: Full=Peptidyl-prolyl cis-trans isomerase FKBP4'
    - reference_id: file:human/FKBP4/FKBP4-uniprot.txt
      supporting_text: The PPIase activity is mainly due to the first PPIase FKBP-type domain
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: is_active_in
  review:
    summary: FKBP4 acts in the cytosol, where it assembles steroid receptor-HSP90 heterocomplexes. Cytosolic localization is well supported experimentally and by phylogenetic inference.
    action: ACCEPT
    reason: The cytosol is the principal site where FKBP4 acts as an HSP90 co-chaperone; this IBA is corroborated by direct experimental localization (HPA IDA) and the UniProt subcellular-location section.
    supported_by:
    - reference_id: file:human/FKBP4/FKBP4-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Cytoplasm, cytosol'
- 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, redundant with and consistent with the experimentally and phylogenetically supported core catalytic function.
    action: ACCEPT
    reason: Agrees with stronger IDA/IBA evidence for PPIase activity; the FKBP-type domain signature reliably predicts this activity.
    supported_by:
    - reference_id: file:human/FKBP4/FKBP4-uniprot.txt
      supporting_text: 'RecName: Full=Peptidyl-prolyl cis-trans isomerase FKBP4'
- term:
    id: GO:0005528
    label: FK506 binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  qualifier: enables
  review:
    summary: FKBP4 binds the immunosuppressant FK506, which inhibits its PPIase activity; this is the defining property of the FK506-binding protein (FKBP) family.
    action: ACCEPT
    reason: FK506 binding is directly documented (activity inhibited by FK506; TAS PMID:1376003) and is a characteristic molecular function; the IEA agrees with experimental evidence.
    supported_by:
    - reference_id: file:human/FKBP4/FKBP4-uniprot.txt
      supporting_text: 'ACTIVITY REGULATION: Inhibited by FK506.'
- term:
    id: GO:0005634
    label: nucleus
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: located_in
  review:
    summary: FKBP4 is found in the nucleus, consistent with its role in shuttling steroid hormone receptors from cytoplasm to nucleus and a reported mitochondria-to-nucleus translocation under oxidative stress.
    action: KEEP_AS_NON_CORE
    reason: Nuclear localization is real but reflects the trafficking/shuttling endpoint rather than the principal cytosolic site of co-chaperone action; retained as non-core.
    supported_by:
    - reference_id: file:human/FKBP4/FKBP4-uniprot.txt
      supporting_text: Shuttles from mitochondria to nucleus
- term:
    id: GO:0005739
    label: mitochondrion
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  qualifier: located_in
  review:
    summary: A mitochondrial pool of FKBP4 has been documented experimentally; the TPR repeats mediate mitochondrial localization, and FKBP4 may protect against mitochondrial oxidative stress.
    action: KEEP_AS_NON_CORE
    reason: Mitochondrial localization is experimentally supported (EXP PMID:21730050) but is a secondary/context-specific compartment relative to the cytosolic co-chaperone function.
    supported_by:
    - reference_id: file:human/FKBP4/FKBP4-uniprot.txt
      supporting_text: The TPR repeats mediate mitochondrial localization.
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  qualifier: located_in
  review:
    summary: Electronic annotation of cytosolic localization (UniProt subcellular-location), redundant with the IDA/IBA cytosol annotations.
    action: ACCEPT
    reason: Correct primary localization for this cytosolic co-chaperone; agrees with stronger experimental evidence.
    supported_by:
    - reference_id: file:human/FKBP4/FKBP4-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Cytoplasm, cytosol'
- term:
    id: GO:0005856
    label: cytoskeleton
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  qualifier: located_in
  review:
    summary: FKBP4 associates with the cytoskeleton, consistent with its tubulin/microtubule and MAPT/tau regulatory activities and growth-cone localization.
    action: KEEP_AS_NON_CORE
    reason: Cytoskeletal association underlies the microtubule/tau regulatory role; retained as a real but non-core localization for the principal co-chaperone function.
    supported_by:
    - reference_id: file:human/FKBP4/FKBP4-uniprot.txt
      supporting_text: Cytoplasm, cytoskeleton
- term:
    id: GO:0006457
    label: protein folding
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  qualifier: involved_in
  review:
    summary: Electronic annotation of the protein folding process, duplicating the IBA/IDA/TAS protein-folding annotations. The informative function is the PPIase/co-chaperone activity.
    action: KEEP_AS_NON_CORE
    reason: Same rationale as the IBA protein-folding annotation; a downstream/contributory process rather than the core molecular function.
    supported_by:
    - reference_id: file:human/FKBP4/FKBP4-uniprot.txt
      supporting_text: Immunophilin protein with PPIase and co-chaperone activities.
- term:
    id: GO:0030424
    label: axon
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  qualifier: located_in
  review:
    summary: FKBP4 localizes to axons / the distal parts of neurons, consistent with its role in growth-cone guidance via TRPC1 and tau regulation.
    action: KEEP_AS_NON_CORE
    reason: Axonal localization is supported (by similarity to mouse Q9QVC8) and relevant to the neuronal growth-cone role, but is a specialized, non-core localization.
    supported_by:
    - reference_id: file:human/FKBP4/FKBP4-uniprot.txt
      supporting_text: Cell projection, axon
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:14638689
  qualifier: enables
  review:
    summary: IntAct interaction with S100A1 (P35467). The bare protein binding term is uninformative; the S100A1 interaction (TPR-mediated, Ca2+-dependent) modulates the FKBP4-HSP90 association.
    action: KEEP_AS_NON_CORE
    reason: A real, specific physical interaction, but bare protein binding is uninformative and this S100 interaction is regulatory rather than the core function.
    supported_by:
    - reference_id: file:human/FKBP4/FKBP4-goa.tsv
      supporting_text: GO:0005515 protein binding IPI PMID:14638689 UniProtKB:P35467
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:19875381
  qualifier: enables
  review:
    summary: IntAct interaction with HSP90AA1 (P07900). The bare protein binding term is uninformative; the partner is HSP90, so this is better captured as Hsp90 protein binding, the core co-chaperone function.
    action: MODIFY
    reason: Bare protein binding is uninformative; the WITH partner is HSP90AA1, so Hsp90 protein binding (GO:0051879) is the precise molecular function.
    proposed_replacement_terms:
    - id: GO:0051879
      label: Hsp90 protein binding
    supported_by:
    - reference_id: file:human/FKBP4/FKBP4-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:20133804
  qualifier: enables
  review:
    summary: IntAct interaction with MAPT/tau (P10636-8). The bare protein binding term is uninformative; the tau interaction underlies FKBP4's regulation of microtubule dynamics.
    action: MODIFY
    reason: Bare protein binding is uninformative; the WITH partner is MAPT/tau, so tau protein binding (GO:0048156) captures the specific, biologically meaningful interaction.
    proposed_replacement_terms:
    - id: GO:0048156
      label: tau protein binding
    supported_by:
    - reference_id: file:human/FKBP4/FKBP4-goa.tsv
      supporting_text: GO:0005515 protein binding IPI PMID:20133804 UniProtKB:P10636-8
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:20188096
  qualifier: enables
  review:
    summary: IntAct interactions with S100 proteins (S100A1/A2/A6) and HSP90AA1; S100 binding via the TPR domain is Ca2+-dependent and regulates FKBP4-HSP90 association. Bare protein binding is uninformative.
    action: KEEP_AS_NON_CORE
    reason: Real, specific interactions documented (S100A1/A2/A6, HSP90), but recorded as bare protein binding; the S100 component is a Ca2+-dependent regulatory interaction, kept non-core.
    supported_by:
    - reference_id: file:human/FKBP4/FKBP4-uniprot.txt
      supporting_text: Interacts (via TPR domain) with S100A1, S100A2 and S100A6; the interaction is Ca(2+) dependent.
- 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, so Hsp90 protein binding is the precise function.
    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/FKBP4/FKBP4-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). The bare protein binding term 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/FKBP4/FKBP4-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:21730179
  qualifier: enables
  review:
    summary: IntAct interactions with HSP90AB1 (P08238) and the androgen receptor AR (P10275). AR is a key FKBP4 client; FKBP4 is a positive regulator of AR signaling. Bare protein binding is uninformative.
    action: KEEP_AS_NON_CORE
    reason: Real, biologically meaningful interactions (HSP90 and AR client), but recorded as bare protein binding; the AR client interaction is captured better in the androgen receptor pathway, kept non-core here.
    supported_by:
    - reference_id: file:human/FKBP4/FKBP4-goa.tsv
      supporting_text: GO:0005515 protein binding IPI PMID:21730179 UniProtKB:P10275
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:23741051
  qualifier: enables
  review:
    summary: FKBP4 (with p23/PTGES3) physically interacts with hAgo2 (AGO2, Q9UKV8) and is required for efficient RNA interference. Bare protein binding is uninformative; this captures a specific Hsp90-cochaperone role in RISC loading.
    action: KEEP_AS_NON_CORE
    reason: A specific, experimentally supported interaction (FKBP4-hAgo2) relevant to RNAi, but recorded as bare protein binding and peripheral to the core steroid-receptor co-chaperone function.
    supported_by:
    - reference_id: PMID:23741051
      supporting_text: Whereas FKBP4 and p23 form a stable
    - reference_id: file:human/FKBP4/FKBP4-goa.tsv
      supporting_text: GO:0005515 protein binding IPI PMID:23741051 UniProtKB:Q9UKV8
- 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 FKBP4 interactions with HSP90AB1 (P08238), CDC37 (Q16543) and GLMN (Q92990), placing it in the Hsp90 co-chaperone module. Bare protein binding is uninformative; 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 the appropriate specific term.
    proposed_replacement_terms:
    - id: GO:0051879
      label: Hsp90 protein binding
    supported_by:
    - reference_id: file:human/FKBP4/FKBP4-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:25277244
  qualifier: enables
  review:
    summary: IntAct interaction with HSPB1/HSP27 (P04792). The bare protein binding term is uninformative; this is a single chaperone-network interaction.
    action: KEEP_AS_NON_CORE
    reason: A real interaction with the small heat-shock protein HSPB1, but recorded as bare protein binding and not part of the core steroid-receptor function.
    supported_by:
    - reference_id: file:human/FKBP4/FKBP4-goa.tsv
      supporting_text: GO:0005515 protein binding IPI PMID:25277244 UniProtKB:P04792
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:28514442
  qualifier: enables
  review:
    summary: IntAct interaction with HSP90AB1 (P08238). The bare protein binding term is uninformative; the partner is HSP90.
    action: MODIFY
    reason: Bare protein binding is uninformative; the WITH partner is HSP90AB1, 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/FKBP4/FKBP4-goa.tsv
      supporting_text: GO:0005515 protein binding IPI PMID:28514442 UniProtKB:P08238
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:32296183
  qualifier: enables
  review:
    summary: IntAct interaction with GLMN (Q92990, the FKBP-associated protein FAP48). The bare protein binding term is uninformative.
    action: KEEP_AS_NON_CORE
    reason: A real, specific interaction (GLMN/FAP48), documented also in UniProt, but recorded as bare protein binding and not the core function.
    supported_by:
    - reference_id: file:human/FKBP4/FKBP4-uniprot.txt
      supporting_text: Interacts with GLMN
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:32707033
  qualifier: enables
  review:
    summary: IntAct interaction (P53671) from a high-throughput screen. The bare protein binding term is uninformative and represents an isolated high-throughput interaction.
    action: KEEP_AS_NON_CORE
    reason: An isolated high-throughput interaction recorded as bare protein binding; uninformative and not part of the established core function.
    supported_by:
    - reference_id: file:human/FKBP4/FKBP4-goa.tsv
      supporting_text: GO:0005515 protein binding IPI PMID:32707033 UniProtKB:P53671
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:33961781
  qualifier: enables
  review:
    summary: BioPlex affinity-purification interactome capturing FKBP4 interactions with HSP90AA1 (P07900) and GLMN (Q92990). Bare protein binding is uninformative; the central interaction is with HSP90.
    action: MODIFY
    reason: Bare protein binding is uninformative; the principal WITH partner is HSP90AA1, 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/FKBP4/FKBP4-goa.tsv
      supporting_text: GO:0005515 protein binding IPI PMID:33961781 UniProtKB:P07900
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:35063084
  qualifier: enables
  review:
    summary: IntAct interaction with MAPT/tau (P10636-8). The bare protein binding term is uninformative; the tau interaction underlies FKBP4's microtubule-regulatory role.
    action: MODIFY
    reason: Bare protein binding is uninformative; the WITH partner is MAPT/tau, so tau protein binding (GO:0048156) is the precise function.
    proposed_replacement_terms:
    - id: GO:0048156
      label: tau protein binding
    supported_by:
    - reference_id: file:human/FKBP4/FKBP4-goa.tsv
      supporting_text: GO:0005515 protein binding IPI PMID:35063084 UniProtKB:P10636-8
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:36115835
  qualifier: enables
  review:
    summary: A large high-throughput interactome screen reporting many FKBP4 partners (mostly cytoskeletal/coiled-coil proteins). Bare protein binding from a single broad screen is uninformative and does not individually inform FKBP4's core function.
    action: KEEP_AS_NON_CORE
    reason: Bare protein binding from one high-throughput screen with many partners not independently validated; uninformative and not reflective of the core co-chaperone function.
    supported_by:
    - reference_id: file:human/FKBP4/FKBP4-goa.tsv
      supporting_text: GO:0005515 protein binding IPI PMID:36115835 UniProtKB:O75970
- term:
    id: GO:0005524
    label: ATP binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: enables
  review:
    summary: Electronic annotation of ATP binding transferred from the mouse ortholog (P30416) via Ensembl. FKBP4 is a PPIase/co-chaperone with no established ATPase activity or characterized ATP-binding site; HSP90/HSP70 (its partners), not FKBP4, are the ATP-dependent chaperones.
    action: MARK_AS_OVER_ANNOTATED
    reason: No experimental evidence that FKBP4 binds or hydrolyzes ATP; this looks like an erroneous electronic transfer. PPIase activity is ATP-independent.
    supported_by:
    - reference_id: file:human/FKBP4/FKBP4-goa.tsv
      supporting_text: GO:0005524 ATP binding IEA GO_REF:0000107 UniProtKB:P30416
- term:
    id: GO:0005525
    label: GTP binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: enables
  review:
    summary: Electronic annotation of GTP binding transferred from the mouse ortholog via Ensembl. FKBP4 has no established GTPase or GTP-binding function.
    action: MARK_AS_OVER_ANNOTATED
    reason: No experimental evidence FKBP4 binds GTP; an unsupported electronic transfer for a PPIase/co-chaperone.
    supported_by:
    - reference_id: file:human/FKBP4/FKBP4-goa.tsv
      supporting_text: GO:0005525 GTP binding IEA GO_REF:0000107 UniProtKB:P30416
- term:
    id: GO:0031072
    label: heat shock protein binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: enables
  review:
    summary: FKBP4 binds heat shock proteins, principally HSP90 (via its TPR domain) and associates with HSP70 in steroid receptor complexes. This is a core molecular function of FKBP4 as an HSP90 co-chaperone.
    action: ACCEPT
    reason: Direct, experimentally documented binding to HSP90 (IPI PMID:9660753) and HSP70 association supports this molecular function; central to FKBP4's co-chaperone role.
    supported_by:
    - reference_id: file:human/FKBP4/FKBP4-uniprot.txt
      supporting_text: Associates with HSP90AA1 and HSP70 in steroid hormone receptor complexes.
- term:
    id: GO:0035259
    label: nuclear glucocorticoid receptor binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: enables
  review:
    summary: FKBP4 binds the glucocorticoid receptor (NR3C1) in the HSP90 heterocomplex and promotes its function; the electronic transfer from mouse is consistent with documented human GR interaction.
    action: ACCEPT
    reason: GR (NR3C1) binding is documented experimentally (interaction with glucocorticoid receptor, PubMed:21730050) and underlies FKBP4's positive regulation of GR signaling.
    supported_by:
    - reference_id: file:human/FKBP4/FKBP4-uniprot.txt
      supporting_text: Interacts with NR3C1 and dynein.
- term:
    id: GO:0051219
    label: phosphoprotein binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: enables
  review:
    summary: Electronic annotation of phosphoprotein binding transferred from the mouse ortholog. This is generic and not independently informative for FKBP4's characterized function.
    action: KEEP_AS_NON_CORE
    reason: A generic, electronically-inferred binding term without specific human evidence; retained as non-core rather than removed.
    supported_by:
    - reference_id: file:human/FKBP4/FKBP4-goa.tsv
      supporting_text: GO:0051219 phosphoprotein binding IEA GO_REF:0000107
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: IDA
  original_reference_id: GO_REF:0000052
  qualifier: located_in
  review:
    summary: Direct immunofluorescence (HPA) evidence for cytosolic localization, the principal site of FKBP4 action.
    action: ACCEPT
    reason: IDA-supported cytosolic localization agrees with the documented primary site of FKBP4 and is a precise cellular-component annotation.
    supported_by:
    - reference_id: file:human/FKBP4/FKBP4-goa.tsv
      supporting_text: GO:0005829 cytosol IDA GO_REF:0000052 HPA
- term:
    id: GO:0005739
    label: mitochondrion
  evidence_type: EXP
  original_reference_id: PMID:21730050
  qualifier: located_in
  review:
    summary: Experimental evidence that FKBP4 is a mitochondrial protein that translocates to the nucleus to protect cells against oxidative stress.
    action: KEEP_AS_NON_CORE
    reason: Experimentally supported mitochondrial localization, but a secondary/context-specific compartment relative to the cytosolic co-chaperone function.
    supported_by:
    - reference_id: file:human/FKBP4/FKBP4-uniprot.txt
      supporting_text: Shuttles from mitochondria to nucleus
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:11583998
  qualifier: enables
  review:
    summary: Interaction with HSF1 (heat shock factor 1, Q00613) in the HSP90 multichaperone complex that represses HSF1 transcriptional activity. Bare protein binding is uninformative; the interaction occurs within the HSP90 chaperone complex.
    action: KEEP_AS_NON_CORE
    reason: A real, specific interaction (FKBP4-HSF1 in the HSP90 complex), documented in UniProt, but recorded as bare protein binding and peripheral to the core steroid-receptor function.
    supported_by:
    - reference_id: file:human/FKBP4/FKBP4-uniprot.txt
      supporting_text: Interacts with HSF1 in the HSP90 complex.
- 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 FKBP4 in the cytosol, consistent with its primary localization.
    action: ACCEPT
    reason: Curated cytosolic localization consistent with the principal site of FKBP4 action.
    supported_by:
    - reference_id: file:human/FKBP4/FKBP4-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Cytoplasm, cytosol'
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-5618080
  qualifier: located_in
  review:
    summary: Reactome pathway annotation placing FKBP4 in the cytosol, redundant with the primary cytosolic localization.
    action: KEEP_AS_NON_CORE
    reason: Redundant curated cytosol annotation from a Reactome pathway; consistent but duplicative.
    supported_by:
    - reference_id: file:human/FKBP4/FKBP4-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Cytoplasm, cytosol'
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-5618085
  qualifier: located_in
  review:
    summary: Reactome pathway annotation placing FKBP4 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/FKBP4/FKBP4-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Cytoplasm, cytosol'
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-5618099
  qualifier: located_in
  review:
    summary: Reactome pathway annotation placing FKBP4 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/FKBP4/FKBP4-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Cytoplasm, cytosol'
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-5618110
  qualifier: located_in
  review:
    summary: Reactome pathway annotation placing FKBP4 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/FKBP4/FKBP4-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Cytoplasm, cytosol'
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9678925
  qualifier: located_in
  review:
    summary: Reactome pathway annotation placing FKBP4 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/FKBP4/FKBP4-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Cytoplasm, cytosol'
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9690534
  qualifier: located_in
  review:
    summary: Reactome pathway annotation placing FKBP4 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/FKBP4/FKBP4-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Cytoplasm, cytosol'
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9705925
  qualifier: located_in
  review:
    summary: Reactome pathway annotation placing FKBP4 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/FKBP4/FKBP4-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Cytoplasm, cytosol'
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9705926
  qualifier: located_in
  review:
    summary: Reactome pathway annotation placing FKBP4 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/FKBP4/FKBP4-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Cytoplasm, cytosol'
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9706837
  qualifier: located_in
  review:
    summary: Reactome pathway annotation placing FKBP4 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/FKBP4/FKBP4-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Cytoplasm, cytosol'
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9725855
  qualifier: located_in
  review:
    summary: Reactome pathway annotation placing FKBP4 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/FKBP4/FKBP4-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Cytoplasm, cytosol'
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9725885
  qualifier: located_in
  review:
    summary: Reactome pathway annotation placing FKBP4 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/FKBP4/FKBP4-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Cytoplasm, cytosol'
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9726509
  qualifier: located_in
  review:
    summary: Reactome pathway annotation placing FKBP4 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/FKBP4/FKBP4-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Cytoplasm, cytosol'
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9726580
  qualifier: located_in
  review:
    summary: Reactome pathway annotation placing FKBP4 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/FKBP4/FKBP4-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Cytoplasm, cytosol'
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9726621
  qualifier: located_in
  review:
    summary: Reactome pathway annotation placing FKBP4 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/FKBP4/FKBP4-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Cytoplasm, cytosol'
- term:
    id: GO:0005654
    label: nucleoplasm
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-5324617
  qualifier: located_in
  review:
    summary: Reactome annotation placing FKBP4 in the nucleoplasm, consistent with its nuclear pool and role in steroid receptor nuclear translocation.
    action: KEEP_AS_NON_CORE
    reason: Nuclear/nucleoplasm localization reflects the receptor-trafficking endpoint rather than the principal cytosolic co-chaperone site; retained as non-core.
    supported_by:
    - reference_id: file:human/FKBP4/FKBP4-uniprot.txt
      supporting_text: Shuttles from mitochondria to nucleus
- term:
    id: GO:0005654
    label: nucleoplasm
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-5618080
  qualifier: located_in
  review:
    summary: Reactome annotation placing FKBP4 in the nucleoplasm; redundant with the nuclear pool annotation.
    action: KEEP_AS_NON_CORE
    reason: Redundant curated nucleoplasm annotation; consistent with the nuclear trafficking endpoint.
    supported_by:
    - reference_id: file:human/FKBP4/FKBP4-uniprot.txt
      supporting_text: Shuttles from mitochondria to nucleus
- term:
    id: GO:0005654
    label: nucleoplasm
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-5618093
  qualifier: located_in
  review:
    summary: Reactome annotation placing FKBP4 in the nucleoplasm; redundant with the nuclear pool annotation.
    action: KEEP_AS_NON_CORE
    reason: Redundant curated nucleoplasm annotation; consistent with the nuclear trafficking endpoint.
    supported_by:
    - reference_id: file:human/FKBP4/FKBP4-uniprot.txt
      supporting_text: Shuttles from mitochondria to nucleus
- term:
    id: GO:0005654
    label: nucleoplasm
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9038161
  qualifier: located_in
  review:
    summary: Reactome annotation placing FKBP4 in the nucleoplasm; redundant with the nuclear pool annotation.
    action: KEEP_AS_NON_CORE
    reason: Redundant curated nucleoplasm annotation; consistent with the nuclear trafficking endpoint.
    supported_by:
    - reference_id: file:human/FKBP4/FKBP4-uniprot.txt
      supporting_text: Shuttles from mitochondria to nucleus
- term:
    id: GO:0003723
    label: RNA binding
  evidence_type: HDA
  original_reference_id: PMID:22658674
  qualifier: enables
  review:
    summary: High-throughput RNA-interactome capture detected FKBP4 as an RNA-bound protein. This is a proteome-wide screen result; FKBP4 has no characterized sequence-specific RNA-binding function, though it does participate (via hAgo2) in RNAi.
    action: KEEP_AS_NON_CORE
    reason: A high-throughput RNA-interactome capture hit without a defined RNA-binding mechanism for FKBP4; retained as non-core rather than a core molecular function.
    supported_by:
    - reference_id: file:human/FKBP4/FKBP4-goa.tsv
      supporting_text: GO:0003723 RNA binding HDA PMID:22658674
- term:
    id: GO:0070062
    label: extracellular exosome
  evidence_type: HDA
  original_reference_id: PMID:19056867
  qualifier: located_in
  review:
    summary: Detection of FKBP4 in extracellular exosome proteomics. As an abundant cytosolic protein, FKBP4 is frequently detected in exosome preparations; this is not its principal functional location.
    action: KEEP_AS_NON_CORE
    reason: A high-throughput proteomic detection in exosomes; plausible passive presence but peripheral to the gene's core cytosolic function.
    supported_by:
    - reference_id: file:human/FKBP4/FKBP4-goa.tsv
      supporting_text: GO:0070062 extracellular exosome HDA PMID:19056867
- term:
    id: GO:0070062
    label: extracellular exosome
  evidence_type: HDA
  original_reference_id: PMID:20458337
  qualifier: located_in
  review:
    summary: Second exosome proteomics dataset detecting FKBP4, redundant with the first.
    action: KEEP_AS_NON_CORE
    reason: A high-throughput proteomic detection in exosomes; peripheral to the gene's core function.
    supported_by:
    - reference_id: file:human/FKBP4/FKBP4-goa.tsv
      supporting_text: GO:0070062 extracellular exosome HDA PMID:20458337
- 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 FKBP4 peptidyl-prolyl cis-trans isomerase activity. This is the core catalytic function.
    action: ACCEPT
    reason: IDA evidence directly supports PPIase activity, a defining core molecular function of FKBP4 (EC 5.2.1.8).
    supported_by:
    - reference_id: file:human/FKBP4/FKBP4-uniprot.txt
      supporting_text: 'RecName: Full=Peptidyl-prolyl cis-trans isomerase FKBP4'
- term:
    id: GO:0006457
    label: protein folding
  evidence_type: IDA
  original_reference_id: PMID:11350175
  qualifier: involved_in
  review:
    summary: Direct experimental evidence linking FKBP4 to protein folding via its rotamase/PPIase activity. The molecular function (PPIase) is the more informative annotation; folding is a contributory process.
    action: KEEP_AS_NON_CORE
    reason: FKBP4 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/FKBP4/FKBP4-uniprot.txt
      supporting_text: Immunophilin protein with PPIase and co-chaperone activities.
- term:
    id: GO:0010977
    label: negative regulation of neuron projection development
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: involved_in
  review:
    summary: FKBP4 negatively regulates neuron projection development, inferred by sequence similarity. FKBP4 controls neuronal growth-cone guidance via TRPC1 and antagonizes tau-promoted microtubule assembly.
    action: KEEP_AS_NON_CORE
    reason: A plausible neuronal process consistent with the documented growth-cone/TRPC1 and tau/microtubule roles, but inferred (ISS) and a specialized, non-core process.
    supported_by:
    - reference_id: file:human/FKBP4/FKBP4-uniprot.txt
      supporting_text: The isomerase activity controls neuronal growth cones via regulation of TRPC1 channel opening.
- term:
    id: GO:0031111
    label: negative regulation of microtubule polymerization or depolymerization
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: involved_in
  review:
    summary: FKBP4 regulates microtubule dynamics by inhibiting MAPT/tau's ability to promote microtubule assembly; its C-terminal region prevents tubulin polymerization. Inferred by sequence similarity.
    action: KEEP_AS_NON_CORE
    reason: Consistent with the documented tau/tubulin regulatory role, but inferred (ISS) and a specialized, non-core process relative to the core co-chaperone function.
    supported_by:
    - reference_id: file:human/FKBP4/FKBP4-uniprot.txt
      supporting_text: Also acts as a regulator of microtubule dynamics by inhibiting MAPT/TAU ability to promote microtubule assembly.
- term:
    id: GO:0044295
    label: axonal growth cone
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: located_in
  review:
    summary: FKBP4 localizes to the axonal growth cone, consistent with its TRPC1-mediated control of growth-cone chemotropic guidance. Inferred by sequence similarity from mouse.
    action: KEEP_AS_NON_CORE
    reason: A specialized neuronal localization supporting the growth-cone guidance role; inferred (ISS) and non-core relative to the principal cytosolic function.
    supported_by:
    - reference_id: file:human/FKBP4/FKBP4-uniprot.txt
      supporting_text: The isomerase activity controls neuronal growth cones via regulation of TRPC1 channel opening.
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: located_in
  review:
    summary: Cytosolic localization inferred by sequence similarity from the mouse ortholog, consistent with the principal site of FKBP4 action.
    action: ACCEPT
    reason: Correct primary localization, corroborated by direct experimental (IDA/HPA) and IBA evidence.
    supported_by:
    - reference_id: file:human/FKBP4/FKBP4-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Cytoplasm, cytosol'
- 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 FKBP4. This is a core co-chaperone molecular function.
    action: ACCEPT
    reason: Experimentally documented HSP90 binding (the basis of FKBP4's TPR-mediated co-chaperone role) supports heat shock protein binding as a core function.
    supported_by:
    - reference_id: file:human/FKBP4/FKBP4-goa.tsv
      supporting_text: GO:0031072 heat shock protein binding IPI PMID:9660753 UniProtKB:P07900
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:12604780
  qualifier: enables
  review:
    summary: Interaction with GLMN (FAP48, Q92990). The bare protein binding term is uninformative; this is a documented FKBP-associated protein interaction.
    action: KEEP_AS_NON_CORE
    reason: A real, specific interaction (GLMN/FAP48) recorded in UniProt, but bare protein binding is uninformative and not the core function.
    supported_by:
    - reference_id: file:human/FKBP4/FKBP4-uniprot.txt
      supporting_text: Interacts with GLMN
- term:
    id: GO:0030674
    label: protein-macromolecule adaptor activity
  evidence_type: TAS
  original_reference_id: PMID:2378870
  qualifier: enables
  review:
    summary: FKBP4 acts as an adaptor that bridges steroid hormone receptors to the HSP90/HSP70 chaperone machine and to dynein, captured by the classic identification of the 56-59 kDa immunophilin in untransformed steroid receptor complexes. This adaptor role is a genuine core molecular function.
    action: ACCEPT
    reason: FKBP4 functions as a co-chaperone adaptor linking receptors to HSP90/HSP70 and recruiting dynein; the TAS adaptor-activity annotation captures this bridging role.
    supported_by:
    - reference_id: file:human/FKBP4/FKBP4-uniprot.txt
      supporting_text: Component of steroid receptors heterocomplexes through interaction with heat-shock protein 90 (HSP90).
    - reference_id: file:human/FKBP4/FKBP4-uniprot.txt
      supporting_text: Interacts with NR3C1 and dynein.
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: TAS
  original_reference_id: PMID:2378870
  qualifier: located_in
  review:
    summary: Classic identification of FKBP4 in cytosolic steroid receptor complexes, supporting cytoplasmic localization.
    action: ACCEPT
    reason: Cytoplasmic localization is the principal site of FKBP4 action and is well supported.
    supported_by:
    - reference_id: file:human/FKBP4/FKBP4-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Cytoplasm, cytosol'
- term:
    id: GO:0006457
    label: protein folding
  evidence_type: TAS
  original_reference_id: PMID:1279700
  qualifier: involved_in
  review:
    summary: Author-stated (TAS) involvement of FKBP4 in protein folding, from the original characterization of human FKBP52 as an HSP90-associated immunophilin. The informative function is its PPIase/co-chaperone activity.
    action: KEEP_AS_NON_CORE
    reason: Protein folding is a contributory process downstream of FKBP4's PPIase/co-chaperone activity; the catalytic and binding MFs are the core.
    supported_by:
    - reference_id: file:human/FKBP4/FKBP4-uniprot.txt
      supporting_text: Immunophilin protein with PPIase and co-chaperone activities.
- term:
    id: GO:0005528
    label: FK506 binding
  evidence_type: TAS
  original_reference_id: PMID:1376003
  qualifier: enables
  review:
    summary: Author-stated FK506 binding, from the identification of the 59 kDa immunophilin in the glucocorticoid receptor complex. FK506 binding is the defining property of the FKBP family.
    action: ACCEPT
    reason: FK506 binding is directly documented and inhibits FKBP4's PPIase activity; a characteristic molecular function.
    supported_by:
    - reference_id: file:human/FKBP4/FKBP4-uniprot.txt
      supporting_text: 'ACTIVITY REGULATION: Inhibited by FK506.'
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:0000052
  title: Gene Ontology annotation based on curation of immunofluorescence data
  findings: []
- id: GO_REF:0000107
  title: Automatic transfer of experimentally verified manual GO annotation data to orthologs using Ensembl Compara
  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 FKBP4-goa.tsv, directly establishing the core PPIase molecular function."
  findings:
  - statement: Direct demonstration of FKBP4/FKBP52 peptidyl-prolyl cis-trans isomerase (rotamase) activity.
    reference_section_type: RESULTS
- id: PMID:11583998
  title: Evidence for a mechanism of repression of heat shock factor 1 transcriptional activity by a multichaperone complex.
  findings:
  - statement: FKBP4 interacts with HSF1 within an HSP90 multichaperone complex that represses HSF1 transcriptional activity.
    reference_section_type: RESULTS
- id: PMID:12604780
  title: The FKBP-associated protein FAP48 is an antiproliferative molecule and a player in T cell activation that increases IL2 synthesis.
  findings:
  - statement: FKBP4 interacts with GLMN (FAP48), an FKBP-associated antiproliferative protein.
    reference_section_type: RESULTS
- id: PMID:1279700
  title: Expression and characterization of human FKBP52, an immunophilin that associates with the 90-kDa heat shock protein and is a component of steroid receptor complexes.
  findings:
  - statement: Human FKBP52 is an immunophilin that associates with HSP90 and is a component of steroid receptor complexes.
    reference_section_type: RESULTS
- id: PMID:1376003
  title: Association of a 59-kilodalton immunophilin with the glucocorticoid receptor complex.
  findings:
  - statement: A 59 kDa FK506-binding immunophilin (FKBP4/FKBP52) associates with the glucocorticoid receptor complex.
    reference_section_type: RESULTS
- id: PMID:14638689
  title: 'S100A1 is a novel molecular chaperone and a member of the Hsp70/Hsp90 multichaperone complex.'
  findings: []
- id: PMID:19056867
  title: Large-scale proteomics and phosphoproteomics of urinary exosomes.
  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:20133804
  title: A role for FKBP52 in Tau protein function.
  findings: []
- id: PMID:20188096
  title: S100 proteins regulate the interaction of Hsp90 with cyclophilin 40 and FKBP52 through their tetratricopeptide repeats.
  findings:
  - statement: S100A1/A2/A6 bind FKBP4 via its TPR domain in a Ca2+-dependent manner and modulate the FKBP4-HSP90 interaction.
    reference_section_type: RESULTS
- id: PMID:20458337
  title: MHC class II-associated proteins in B-cell exosomes and potential functional implications for exosome biogenesis.
  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 FKBP4 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:21730050
  title: 'The 90-kDa heat-shock protein (Hsp90)-binding immunophilin FKBP51 is a mitochondrial protein that translocates to the nucleus to protect cells against oxidative stress.'
  findings:
  - statement: FKBP4 (FKBP52) localizes to mitochondria, interacts with the glucocorticoid receptor, and translocates to the nucleus to protect cells against oxidative stress.
    reference_section_type: RESULTS
- id: PMID:21730179
  title: 'Targeting the regulation of androgen receptor signaling by the heat shock protein 90 cochaperone FKBP52 in prostate cancer cells.'
  findings: []
- id: PMID:22658674
  title: Insights into RNA biology from an atlas of mammalian mRNA-binding proteins.
  findings: []
- id: PMID:23741051
  title: Hsp90 cochaperones p23 and FKBP4 physically interact with hAgo2 and activate RNA interference-mediated silencing in mammalian cells.
  findings:
  - statement: FKBP4 (with p23) physically interacts with hAgo2 and is required for efficient RNA interference-mediated silencing.
    reference_section_type: RESULTS
- id: PMID:25036637
  title: A quantitative chaperone interaction network reveals the architecture of cellular protein homeostasis pathways.
  findings:
  - statement: FKBP4 is part of the Hsp90 co-chaperone module, interacting with HSP90, CDC37 and GLMN.
    reference_section_type: RESULTS
- id: PMID:25277244
  title: The functional landscape of Hsp27 reveals new cellular processes such as DNA repair and alternative splicing and proposes novel anticancer targets.
  findings: []
- id: PMID:28514442
  title: Architecture of the human interactome defines protein communities and disease networks.
  findings: []
- id: PMID:2378870
  title: The 56-59-kilodalton protein identified in untransformed steroid receptor complexes is a unique protein that exists in cytosol in a complex with both the 70- and 90-kilodalton heat shock proteins.
  findings:
  - statement: FKBP4 exists in the cytosol in a complex with both HSP70 and HSP90 within untransformed steroid receptor complexes, acting as an adaptor.
    reference_section_type: RESULTS
- id: PMID:32296183
  title: A reference map of the human binary protein interactome.
  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 FKBP4 interactions with HSP90AA1 and GLMN.
    reference_section_type: RESULTS
- id: PMID:35063084
  title: Tau interactome maps synaptic and mitochondrial processes associated with neurodegeneration.
  findings: []
- id: PMID:36115835
  title: Quantitative fragmentomics allow affinity mapping of interactomes.
  findings: []
- 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 FKBP4-goa.tsv, supporting the HSP90-binding co-chaperone function. Title corrected to verbatim PubMed."
  findings:
  - statement: FKBP4 directly binds HSP90AA1.
    reference_section_type: RESULTS
- id: Reactome:R-HSA-5324617
  title: 'Reactome: FKBP4 in nucleoplasm.'
  findings: []
- id: Reactome:R-HSA-5618073
  title: 'Reactome: FKBP4 in cytosol.'
  findings: []
- id: Reactome:R-HSA-5618080
  title: 'Reactome: FKBP4 in cytosol/nucleoplasm.'
  findings: []
- id: Reactome:R-HSA-5618085
  title: 'Reactome: FKBP4 in cytosol.'
  findings: []
- id: Reactome:R-HSA-5618093
  title: 'Reactome: FKBP4 in nucleoplasm.'
  findings: []
- id: Reactome:R-HSA-5618099
  title: 'Reactome: FKBP4 in cytosol.'
  findings: []
- id: Reactome:R-HSA-5618110
  title: 'Reactome: FKBP4 in cytosol.'
  findings: []
- id: Reactome:R-HSA-9038161
  title: 'Reactome: FKBP4 in nucleoplasm.'
  findings: []
- id: Reactome:R-HSA-9678925
  title: 'Reactome: FKBP4 in cytosol.'
  findings: []
- id: Reactome:R-HSA-9690534
  title: 'Reactome: FKBP4 in cytosol.'
  findings: []
- id: Reactome:R-HSA-9705925
  title: 'Reactome: FKBP4 in cytosol.'
  findings: []
- id: Reactome:R-HSA-9705926
  title: 'Reactome: FKBP4 in cytosol.'
  findings: []
- id: Reactome:R-HSA-9706837
  title: 'Reactome: FKBP4 in cytosol.'
  findings: []
- id: Reactome:R-HSA-9725855
  title: 'Reactome: FKBP4 in cytosol.'
  findings: []
- id: Reactome:R-HSA-9725885
  title: 'Reactome: FKBP4 in cytosol.'
  findings: []
- id: Reactome:R-HSA-9726509
  title: 'Reactome: FKBP4 in cytosol.'
  findings: []
- id: Reactome:R-HSA-9726580
  title: 'Reactome: FKBP4 in cytosol.'
  findings: []
- id: Reactome:R-HSA-9726621
  title: 'Reactome: FKBP4 in cytosol.'
  findings: []
- id: file:human/FKBP4/FKBP4-uniprot.txt
  title: UniProt entry Q02790 (FKBP4_HUMAN), Peptidyl-prolyl cis-trans isomerase FKBP4 / FKBP52
  findings:
  - statement: Immunophilin with PPIase and co-chaperone activities; component of steroid receptor heterocomplexes via HSP90; promotes intracellular trafficking of steroid hormone receptors; controls neuronal growth cones via TRPC1; regulates microtubule dynamics via MAPT/tau; cytosolic, mitochondrial, nuclear and cytoskeletal localization.
    reference_section_type: OTHER
core_functions:
- description: Peptidyl-prolyl cis-trans isomerase (rotamase, EC 5.2.1.8), the catalytic activity of the N-terminal FKBP domain, inhibited by FK506; this activity controls clients such as the TRPC1 channel and contributes to protein maturation.
  molecular_function:
    id: GO:0003755
    label: peptidyl-prolyl cis-trans isomerase activity
  locations:
  - id: GO:0005829
    label: cytosol
  supported_by:
  - reference_id: file:human/FKBP4/FKBP4-uniprot.txt
    supporting_text: 'RecName: Full=Peptidyl-prolyl cis-trans isomerase FKBP4'
  - reference_id: file:human/FKBP4/FKBP4-uniprot.txt
    supporting_text: The PPIase activity is mainly due to the first PPIase FKBP-type domain
- description: HSP90 co-chaperone that binds HSP90 (and associates with HSP70) via its TPR domain and is incorporated into steroid hormone receptor maturation heterocomplexes; positive regulator of glucocorticoid, androgen and progesterone receptor signaling.
  molecular_function:
    id: GO:0031072
    label: heat shock protein binding
  locations:
  - id: GO:0005829
    label: cytosol
  supported_by:
  - reference_id: file:human/FKBP4/FKBP4-uniprot.txt
    supporting_text: Associates with HSP90AA1 and HSP70 in steroid hormone receptor complexes.
  - reference_id: file:human/FKBP4/FKBP4-goa.tsv
    supporting_text: GO:0031072 heat shock protein binding IPI PMID:9660753 UniProtKB:P07900
- description: Co-chaperone adaptor that bridges steroid hormone receptors to the HSP90/HSP70 machine and recruits cytoplasmic dynein, promoting retrograde transport and nuclear translocation of activated receptors.
  molecular_function:
    id: GO:0030674
    label: protein-macromolecule adaptor activity
  locations:
  - id: GO:0005829
    label: cytosol
  supported_by:
  - reference_id: file:human/FKBP4/FKBP4-uniprot.txt
    supporting_text: Component of steroid receptors heterocomplexes through interaction with heat-shock protein 90 (HSP90).
  - reference_id: file:human/FKBP4/FKBP4-uniprot.txt
    supporting_text: Interacts with NR3C1 and dynein.
proposed_new_terms: []
suggested_questions:
- question: How is the directionality of steroid-receptor regulation determined between FKBP4 (positive) and FKBP5 (negative) when both share the same TPR-HSP90 binding mode and PPIase fold?
- question: Is FKBP4's PPIase catalytic activity required for its positive regulation of steroid receptors, or is the TPR/adaptor/dynein-recruitment function sufficient?
- question: What is the physiological significance of the mitochondria-to-nucleus translocation of FKBP4 under oxidative stress, and how is it triggered?
suggested_experiments:
- description: Compare FKBP4 wild-type versus PPIase-dead (active-site mutant) and TPR-deletion constructs for their ability to potentiate glucocorticoid/androgen receptor transcriptional activity in cells, to separate catalytic from adaptor contributions.
- description: Reconstitute steroid receptor-HSP90-FKBP4 heterocomplex assembly in vitro and measure FKBP4-dependent dynein recruitment and receptor hormone-binding affinity, contrasting FKBP4 with FKBP5.
- description: Use proximity-labeling (BioID/TurboID) of FKBP4 across compartments (cytosol, mitochondria, growth cone) to map context-specific client and chaperone partners and validate the oxidative-stress translocation.

FKBP4

Gene Description

Existing Annotations Review

Core Functions

Peptidyl-prolyl cis-trans isomerase (rotamase, EC 5.2.1.8), the catalytic activity of the N-terminal FKBP domain, inhibited by FK506; this activity controls clients such as the TRPC1 channel and contributes to protein maturation.

HSP90 co-chaperone that binds HSP90 (and associates with HSP70) via its TPR domain and is incorporated into steroid hormone receptor maturation heterocomplexes; positive regulator of glucocorticoid, androgen and progesterone receptor signaling.

Co-chaperone adaptor that bridges steroid hormone receptors to the HSP90/HSP70 machine and recruits cytoplasmic dynein, promoting retrograde transport and nuclear translocation of activated receptors.

References

Suggested Questions for Experts

Suggested Experiments

📚 Additional Documentation

Notes

FKBP4 (FKBP52) research notes

Core biology (well-established)

Interactions

Subcellular location

Interactome / proteomics PMIDs (mostly IPI bare protein binding)

Action plan

Pn Notes

FKBP4 PN Consistency Notes

Source Files Checked

Deep Research Files

AIGR Review Snapshot

PN Consistency Summary

Full Consistency Review

PN Dossier Context

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

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

Projected GO annotations (3)

Note

📄 View Raw YAML