id: Q9UIM3 gene_symbol: FKBPL product_type: PROTEIN status: COMPLETE taxon: id: NCBITaxon:9606 label: Homo sapiens description: FKBPL (FK506-binding protein-like, also known as WISp39) is a divergent member of the FKBP family that retains tetratricopeptide (TPR) repeats but lacks a canonical catalytically active FKBP-type peptidyl-prolyl isomerase domain, so it has no established rotamase activity. It acts as an HSP90 co-chaperone that, through its TPR region, binds HSP90 and, together with the cyclin-dependent kinase inhibitor p21 (CDKN1A), forms a ternary complex that controls p21 protein stability, thereby linking FKBPL to cell-cycle and DNA-damage/radiation responses (it was originally identified as a stress-response gene implicated in induced radioresistance). FKBPL also exists as a secreted, extracellular protein with potent anti-angiogenic activity, a property exploited by FKBPL-derived therapeutic peptides. It is ubiquitously expressed with higher levels in testis. existing_annotations: - 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 an FKBPL-ANKRD49 (Q8WVL7) interaction. Bare protein binding is uninformative. action: KEEP_AS_NON_CORE reason: A recurrent interaction partner (ANKRD49), but recorded as bare protein binding; not the characterized core HSP90/p21 co-chaperone function. supported_by: - reference_id: file:human/FKBPL/FKBPL-goa.tsv supporting_text: GO:0005515 protein binding IPI PMID:25036637 UniProtKB:Q8WVL7 - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:25416956 qualifier: enables review: summary: Yeast two-hybrid human interactome screen capturing an FKBPL-CALCOCO2/NDP52 (Q13137) interaction. Bare protein binding is uninformative. action: KEEP_AS_NON_CORE reason: A documented interaction (CALCOCO2), but recorded as bare protein binding; not the characterized core function. supported_by: - reference_id: file:human/FKBPL/FKBPL-goa.tsv supporting_text: GO:0005515 protein binding IPI PMID:25416956 UniProtKB:Q13137 - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:28514442 qualifier: enables review: summary: IntAct interaction with ANKRD49 (Q8WVL7). Bare protein binding is uninformative; a recurrent partner. action: KEEP_AS_NON_CORE reason: A recurrent interaction (ANKRD49) recorded as bare protein binding; not the characterized core function. supported_by: - reference_id: file:human/FKBPL/FKBPL-goa.tsv supporting_text: GO:0005515 protein binding IPI PMID:28514442 UniProtKB:Q8WVL7 - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:32296183 qualifier: enables review: summary: High-throughput interactome screen capturing an FKBPL-ANKRD49 (Q8WVL7) interaction. Bare protein binding is uninformative. action: KEEP_AS_NON_CORE reason: Bare protein binding from a high-throughput screen; uninformative and not reflective of the characterized core function. supported_by: - reference_id: file:human/FKBPL/FKBPL-goa.tsv supporting_text: GO:0005515 protein binding IPI PMID:32296183 UniProtKB:Q8WVL7 - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:33961781 qualifier: enables review: summary: BioPlex affinity-purification interactome capturing an FKBPL-ANKRD49 (Q8WVL7) interaction. Bare protein binding is uninformative. action: KEEP_AS_NON_CORE reason: A recurrent interaction (ANKRD49) recorded as bare protein binding; not the characterized core function. supported_by: - reference_id: file:human/FKBPL/FKBPL-goa.tsv supporting_text: GO:0005515 protein binding IPI PMID:33961781 UniProtKB:Q8WVL7 - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:40205054 qualifier: enables review: summary: Multimodal cell-maps interactome capturing an FKBPL-ANKRD49 (Q8WVL7) interaction. Bare protein binding is uninformative. action: KEEP_AS_NON_CORE reason: A recurrent interaction (ANKRD49) recorded as bare protein binding; not the characterized core function. supported_by: - reference_id: file:human/FKBPL/FKBPL-goa.tsv supporting_text: GO:0005515 protein binding IPI PMID:40205054 UniProtKB:Q8WVL7 - term: id: GO:0005576 label: extracellular region evidence_type: IDA original_reference_id: PMID:25767277 qualifier: located_in review: summary: Direct evidence that FKBPL is a secreted, extracellular protein, consistent with its characterized anti-angiogenic activity as a secreted factor. Falcon deep research corroborates that FKBPL is secreted by fibroblasts and endothelial cells and acts at the cell surface as an anti-angiogenic factor targeting CD44. action: KEEP_AS_NON_CORE reason: A genuine secreted/extracellular pool with anti-angiogenic function, but distinct from FKBPL's intracellular HSP90/p21 co-chaperone role; retained as non-core. supported_by: - reference_id: file:human/FKBPL/FKBPL-goa.tsv supporting_text: GO:0005576 extracellular region IDA PMID:25767277 - reference_id: file:human/FKBPL/FKBPL-deep-research-falcon.md supporting_text: FKBPL is also secreted by fibroblasts and endothelial cells, functioning as an extracellular anti-angiogenic protein - term: id: GO:0005829 label: cytosol evidence_type: TAS original_reference_id: Reactome:R-HSA-8852362 qualifier: located_in review: summary: Reactome annotation placing FKBPL in the cytosol, consistent with its intracellular HSP90/p21 co-chaperone function. Falcon deep research independently describes FKBPL as primarily cytosolic, participating in Hsp90-mediated chaperone complexes. action: ACCEPT reason: The cytosol is where FKBPL acts as an HSP90/p21 co-chaperone; a reasonable localization. supported_by: - reference_id: file:human/FKBPL/FKBPL-uniprot.txt supporting_text: Regulates p21 protein stability by binding to Hsp90 and p21. - reference_id: file:human/FKBPL/FKBPL-deep-research-falcon.md supporting_text: Within cells, FKBPL is primarily localized to the cytosol where it participates in Hsp90-mediated chaperone complexes - term: id: GO:0009314 label: response to radiation evidence_type: NAS original_reference_id: PMID:10521921 qualifier: involved_in review: summary: FKBPL was identified as a stress-response gene with a potential role in induced radioresistance; it may be involved in the response to X-ray. A plausible biological process. action: KEEP_AS_NON_CORE reason: A documented (NAS) stress/radiation-response role consistent with its regulation of p21 stability, but a non-core process relative to the molecular co-chaperone function. supported_by: - reference_id: PMID:10521921 supporting_text: A novel human stress response-related gene with a potential role in induced radioresistance. - reference_id: file:human/FKBPL/FKBPL-uniprot.txt supporting_text: May be involved in response to X-ray. references: - id: PMID:10521921 title: A novel human stress response-related gene with a potential role in induced radioresistance. findings: - statement: FKBPL is a stress-response-related gene with a potential role in induced radioresistance. reference_section_type: RESULTS - id: PMID:25036637 title: A quantitative chaperone interaction network reveals the architecture of cellular protein homeostasis pathways. reference_review: relevance: MEDIUM correctness: VERIFIED review_notes: "Cached publications/PMID_25036637.md title matches YAML; a global chaperone-interaction-network study (GOA: GO:0005515 IPI). Places FKBPL in the cellular chaperone/proteostasis network but does not by itself establish the specific Hsp90/p21 core function; supporting/contextual rather than primary." findings: - statement: FKBPL appears in the chaperone interaction network (interacting with ANKRD49). reference_section_type: RESULTS - id: PMID:25416956 title: A proteome-scale map of the human interactome network. findings: - statement: Yeast two-hybrid human interactome map capturing an FKBPL-CALCOCO2 interaction. reference_section_type: RESULTS - id: PMID:25767277 title: 'FKBPL is a critical antiangiogenic regulator of developmental and pathological angiogenesis.' reference_review: relevance: HIGH correctness: VERIFIED review_notes: "Not cached, but anchored to GOA: this PMID is the IDA source for GO:0005576 (extracellular region) in FKBPL-goa.tsv, supporting FKBPL's secreted anti-angiogenic role." findings: - statement: FKBPL is detected in the extracellular region and acts as a secreted anti-angiogenic factor. reference_section_type: RESULTS - id: PMID:28514442 title: Architecture of the human interactome defines protein communities and disease networks. findings: [] - id: PMID:32296183 title: A reference map of the human binary protein interactome. findings: [] - id: PMID:33961781 title: Dual proteome-scale networks reveal cell-specific remodeling of the human interactome. findings: - statement: BioPlex affinity-purification interactome capturing an FKBPL-ANKRD49 interaction. reference_section_type: RESULTS - id: PMID:40205054 title: Multimodal cell maps as a foundation for structural and functional genomics. findings: - statement: Multimodal cell-maps interactome capturing an FKBPL-ANKRD49 interaction. reference_section_type: RESULTS - id: Reactome:R-HSA-8852362 title: 'Reactome: FKBPL in cytosol.' findings: [] - id: file:human/FKBPL/FKBPL-uniprot.txt title: UniProt entry Q9UIM3 (FKBPL_HUMAN), FK506-binding protein-like / WISp39 findings: - statement: TPR-containing FKBP-like protein lacking a catalytic PPIase domain; regulates p21 (CDKN1A) protein stability by binding HSP90 and p21 and forming a ternary HSP90AB1/p21 complex; may be involved in the response to X-ray; ubiquitously expressed (highest in testis). reference_section_type: OTHER - id: file:human/FKBPL/FKBPL-deep-research-falcon.md title: Falcon deep research report for FKBPL reference_review: relevance: HIGH correctness: UNVERIFIED review_notes: "LLM-synthesized (Edison/Falcon) report; not independently verified against primary full text. Correctly frames FKBPL as a divergent FKBP-family immunophilin that LACKS significant PPIase activity and acts as a non-enzymatic co-chaperone/scaffold (Hsp90-associated p21 stabilization) and secreted CD44-targeting anti-angiogenic factor; it does NOT over-attribute canonical FK506-binding/catalytic rotamase activity to FKBPL (it explicitly notes only a degenerate PPIase-like domain). Useful new leads beyond the current review: a 2024 ER-phagy/secretion role via CKAP4 and LC3/GABARAP LIR motifs (Li et al., Nat Commun PMID:39256376/doi:10.1038/s41467-024-52188-7), Hsp90-associated steroid-receptor (ER/AR/GR) co-chaperone involvement, NF-kB/vascular-integrity regulation, and HIF-1a/hypoxia endothelial roles. These leads are plausible and consistent with domain architecture but are taken from an unverified secondary synthesis; treat the specific pathway/partner claims as MEDIUM-confidence pending primary-source confirmation." findings: - statement: FKBPL is a divergent FKBP-family immunophilin that lacks significant peptidyl-prolyl cis-trans isomerase activity and acts as a non-enzymatic scaffold/co-chaperone; intracellularly it is Hsp90-associated and stabilizes p21 (CDKN1A), while a secreted pool acts extracellularly as an anti-angiogenic factor targeting CD44. reference_section_type: RESULTS - statement: A 2024 study reports a novel cytosolic FKBPL function in ER-phagy and protein secretion, in which FKBPL interacts with the ER-resident transmembrane protein CKAP4 and bridges it to LC3/GABARAP autophagy machinery via LIR motifs. reference_section_type: RESULTS core_functions: - description: HSP90 co-chaperone / TPR-mediated chaperone-binding adaptor that binds HSP90 and forms a ternary complex with HSP90 and the CDK inhibitor p21 (CDKN1A) to regulate p21 protein stability. FKBPL lacks catalytic PPIase activity; its function is adaptor/co-chaperone binding. molecular_function: id: GO:0051879 label: Hsp90 protein binding locations: - id: GO:0005829 label: cytosol supported_by: - reference_id: file:human/FKBPL/FKBPL-uniprot.txt supporting_text: Regulates p21 protein stability by binding to Hsp90 and p21. - reference_id: file:human/FKBPL/FKBPL-uniprot.txt supporting_text: Forms a ternary complex with CDKN1A/p21 and HSP90AB1/Hsp90. - reference_id: file:human/FKBPL/FKBPL-deep-research-falcon.md supporting_text: FKBPL is a divergent member of the FK506-binding protein family that notably lacks significant peptidyl-prolyl cis-trans isomerase (PPIase) enzymatic activity - reference_id: file:human/FKBPL/FKBPL-deep-research-falcon.md supporting_text: The primary intracellular function of FKBPL involves its role as an Hsp90-associated co-chaperone. proposed_new_terms: [] suggested_questions: - question: Does FKBPL act as a bona fide HSP90 co-chaperone in the classical sense, or primarily as a TPR adaptor that recruits HSP90 to specific clients such as p21? - question: How is the intracellular HSP90/p21 co-chaperone pool of FKBPL functionally related to the secreted, extracellular anti-angiogenic pool? - question: Does FKBPL have any residual peptidyl-prolyl isomerase activity given its degenerate FKBP domain, or is it catalytically inert? suggested_experiments: - description: Use the HSP90-binding-deficient FKBPL mutant (K287A/R291A) to test whether HSP90 binding is required for FKBPL-dependent p21 stabilization and for radioresistance phenotypes. - description: Compare intracellular versus recombinant secreted FKBPL for p21 stabilization, HSP90 binding, and anti-angiogenic activity to define the two functional pools. - description: Affinity purification-mass spectrometry of FKBPL to determine whether HSP90 and p21 are the principal functional partners versus the recurrent ANKRD49/CALCOCO2 interactome hits.