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.
| 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. |
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Download this section (compressed HTML)Q: 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?
Q: Is FKBP4's PPIase catalytic activity required for its positive regulation of steroid receptors, or is the TPR/adaptor/dynein-recruitment function sufficient?
Q: What is the physiological significance of the mitochondria-to-nucleus translocation of FKBP4 under oxidative stress, and how is it triggered?
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.
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