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.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0005515 protein binding | IPI PMID:25036637 A quantitative chaperone interaction network reveals the arc... | KEEP AS NON CORE | Summary: Quantitative chaperone interaction network (Taipale et al.) capturing an FKBPL-ANKRD49 (Q8WVL7) interaction. Bare protein binding is uninformative. Reason: A recurrent interaction partner (ANKRD49), but recorded as bare protein binding; not the characterized core HSP90/p21 co-chaperone function. Supporting Evidence: file:human/FKBPL/FKBPL-goa.tsv GO:0005515 protein binding IPI PMID:25036637 UniProtKB:Q8WVL7 |
| GO:0005515 protein binding | IPI PMID:25416956 A proteome-scale map of the human interactome network. | KEEP AS NON CORE | Summary: Yeast two-hybrid human interactome screen capturing an FKBPL-CALCOCO2/NDP52 (Q13137) interaction. Bare protein binding is uninformative. Reason: A documented interaction (CALCOCO2), but recorded as bare protein binding; not the characterized core function. Supporting Evidence: file:human/FKBPL/FKBPL-goa.tsv GO:0005515 protein binding IPI PMID:25416956 UniProtKB:Q13137 |
| GO:0005515 protein binding | IPI PMID:28514442 Architecture of the human interactome defines protein commun... | KEEP AS NON CORE | Summary: IntAct interaction with ANKRD49 (Q8WVL7). Bare protein binding is uninformative; a recurrent partner. Reason: A recurrent interaction (ANKRD49) recorded as bare protein binding; not the characterized core function. Supporting Evidence: file:human/FKBPL/FKBPL-goa.tsv GO:0005515 protein binding IPI PMID:28514442 UniProtKB:Q8WVL7 |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | KEEP AS NON CORE | Summary: High-throughput interactome screen capturing an FKBPL-ANKRD49 (Q8WVL7) interaction. Bare protein binding is uninformative. Reason: Bare protein binding from a high-throughput screen; uninformative and not reflective of the characterized core function. Supporting Evidence: file:human/FKBPL/FKBPL-goa.tsv GO:0005515 protein binding IPI PMID:32296183 UniProtKB:Q8WVL7 |
| GO:0005515 protein binding | IPI PMID:33961781 Dual proteome-scale networks reveal cell-specific remodeling... | KEEP AS NON CORE | Summary: BioPlex affinity-purification interactome capturing an FKBPL-ANKRD49 (Q8WVL7) interaction. Bare protein binding is uninformative. Reason: A recurrent interaction (ANKRD49) recorded as bare protein binding; not the characterized core function. Supporting Evidence: file:human/FKBPL/FKBPL-goa.tsv GO:0005515 protein binding IPI PMID:33961781 UniProtKB:Q8WVL7 |
| GO:0005515 protein binding | IPI PMID:40205054 Multimodal cell maps as a foundation for structural and func... | KEEP AS NON CORE | Summary: Multimodal cell-maps interactome capturing an FKBPL-ANKRD49 (Q8WVL7) interaction. Bare protein binding is uninformative. Reason: A recurrent interaction (ANKRD49) recorded as bare protein binding; not the characterized core function. Supporting Evidence: file:human/FKBPL/FKBPL-goa.tsv GO:0005515 protein binding IPI PMID:40205054 UniProtKB:Q8WVL7 |
| GO:0005576 extracellular region | IDA PMID:25767277 FKBPL is a critical antiangiogenic regulator of developmenta... | KEEP AS NON CORE | 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. 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. Supporting Evidence: file:human/FKBPL/FKBPL-goa.tsv GO:0005576 extracellular region IDA PMID:25767277 file:human/FKBPL/FKBPL-deep-research-falcon.md FKBPL is also secreted by fibroblasts and endothelial cells, functioning as an extracellular anti-angiogenic protein |
| GO:0005829 cytosol | TAS Reactome:R-HSA-8852362 | ACCEPT | 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. Reason: The cytosol is where FKBPL acts as an HSP90/p21 co-chaperone; a reasonable localization. Supporting Evidence: file:human/FKBPL/FKBPL-uniprot.txt Regulates p21 protein stability by binding to Hsp90 and p21. file:human/FKBPL/FKBPL-deep-research-falcon.md Within cells, FKBPL is primarily localized to the cytosol where it participates in Hsp90-mediated chaperone complexes |
| GO:0009314 response to radiation | NAS PMID:10521921 A novel human stress response-related gene with a potential ... | KEEP AS NON CORE | 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. 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. Supporting Evidence: PMID:10521921 A novel human stress response-related gene with a potential role in induced radioresistance. file:human/FKBPL/FKBPL-uniprot.txt May be involved in response to X-ray. |
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Download this section (compressed HTML)Q: 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?
Q: How is the intracellular HSP90/p21 co-chaperone pool of FKBPL functionally related to the secreted, extracellular anti-angiogenic pool?
Q: Does FKBPL have any residual peptidyl-prolyl isomerase activity given its degenerate FKBP domain, or is it catalytically inert?
Experiment: 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.
Experiment: Compare intracellular versus recombinant secreted FKBPL for p21 stabilization, HSP90 binding, and anti-angiogenic activity to define the two functional pools.
Experiment: Affinity purification-mass spectrometry of FKBPL to determine whether HSP90 and p21 are the principal functional partners versus the recurrent ANKRD49/CALCOCO2 interactome hits.
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