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.