Affinage

FKBP5

Peptidyl-prolyl cis-trans isomerase FKBP5 · UniProt Q13451

Length
457 aa
Mass
51.2 kDa
Annotated
2026-04-28
100 papers in source corpus 30 papers cited in narrative 30 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

FKBP51 (encoded by FKBP5) is an Hsp90 co-chaperone and peptidyl-prolyl cis-trans isomerase that functions as a multifunctional scaffolding protein regulating steroid hormone receptor signaling, AKT-dependent metabolic pathways, NF-κB-mediated innate immunity, and autophagy. FKBP51 inhibits glucocorticoid, progesterone, and estrogen receptor function by forming receptor–Hsp90 complexes that reduce receptor phosphorylation and nuclear translocation, while enhancing androgen receptor transcriptional activity; it also modulates HIF-1α stability through competitive Hsp90 interaction (PMID:31929189, PMID:33836562, PMID:35394865, PMID:15821585, PMID:37154033). FKBP51 negatively regulates AKT signaling by scaffolding the phosphatase PHLPP to AKT for Ser473 dephosphorylation—a function regulated by USP49/USP53-mediated deubiquitination of FKBP51—and separately associates with AS160 to control GLUT4-mediated glucose uptake, with GSK3β/PP2A/CDK5 to regulate Wnt and tau signaling, and with LKB1/AMPK/WIPI complexes to balance autophagy and mTOR signaling in metabolic homeostasis (PMID:28363942, PMID:29170369, PMID:25849320, PMID:35263141). FKBP5 expression is regulated by an ultrashort glucocorticoid-driven feedback loop involving allele-specific (rs1360780), childhood-trauma-dependent DNA demethylation at intronic glucocorticoid response elements, with basal hippocampal expression further controlled by mineralocorticoid receptor binding at the Fkbp5 locus (PMID:23201972, PMID:34077736).

Mechanistic history

Synthesis pass · year-by-year structured walk · 20 steps
  1. 2002 Medium

    Establishing that FKBP51 directly binds calcineurin independently of FK506 and through its C-terminal domain—not the FK1 PPIase domain—expanded its interaction repertoire beyond Hsp90-steroid receptor complexes.

    Evidence GST pulldown with purified calcineurin, Co-IP from T cells, deletion mutagenesis

    PMID:11813252

    Open questions at the time
    • Functional consequence of calcineurin–FKBP51 interaction on NFAT or calcineurin phosphatase activity not defined
    • No in vivo validation
  2. 2010 High

    Demonstrating that FKBP51 uses its PPIase activity to regulate tau phosphorylation, prevent tau clearance via Hsp90, and stabilize microtubules established FKBP51 as a neurodegenerative disease-relevant chaperone beyond steroid receptor biology.

    Evidence Co-IP, in vitro microtubule stabilization, PPIase domain mutant analysis, tau phosphorylation assays

    PMID:20071522

    Open questions at the time
    • In vivo tauopathy phenotype of FKBP5 manipulation not yet shown in this study
    • Structural basis of tau recognition by the PPIase pocket unknown
  3. 2011 Medium

    Showing that FKBP51 physically interacts with androgen receptor and enhances AR transcriptional activity revealed that FKBP51 co-chaperone function extends to steroid receptors beyond GR, with implications for prostate cancer.

    Evidence Co-IP, AR reporter assay, stable overexpression in LNCaP cells

    PMID:15821585

    Open questions at the time
    • Domain requirements for AR interaction not mapped
    • No reciprocal Co-IP or in vivo confirmation
  4. 2012 High

    Revealing that the FKBP5 risk allele rs1360780 creates allele-specific, childhood-trauma-dependent DNA demethylation at intronic GREs—altering chromatin looping and stress-dependent transcription—established a gene × environment epigenetic mechanism for HPA axis dysregulation.

    Evidence Bisulfite sequencing, chromatin interaction assays, allele-specific methylation in human cohorts and cell lines

    PMID:23201972

    Open questions at the time
    • Whether demethylation is reversible in adulthood not established
    • Causal chain from demethylation to psychiatric disease phenotype not fully delineated
  5. 2014 High

    Identifying FKBP51 as a required regulator of adipogenesis—via reciprocal co-chaperoning of PPARγ and GRα through the Akt-p38 kinase axis—unified its metabolic and steroid receptor regulatory functions.

    Evidence FKBP51 KO MEFs, 3T3-L1 knockdown, lipid accumulation, p38 inhibitor rescue, phosphorylation analysis

    PMID:24933247 PMID:24933248

    Open questions at the time
    • Whether FKBP51 PPIase activity is required for PPARγ regulation not tested
    • In vivo adiposity phenotype in whole-body KO mice not fully reported in these studies
  6. 2015 High

    Showing that FKBP51 associates with GSK3β via its FK1 domain and assembles a heterocomplex with PP2A and CDK5 to regulate GSK3β Ser9 phosphorylation linked FKBP51 to Wnt/β-catenin signaling and psychotropic drug action.

    Evidence Co-IP with domain mapping, reporter assays, FKBP51 KO mouse behavioral studies, pharmacological lithium/paroxetine challenge

    PMID:25849320

    Open questions at the time
    • Direct versus Hsp90-scaffolded interaction with GSK3β not resolved
    • Downstream tau phosphorylation effects in tauopathy models not tested
  7. 2016 Medium

    Discovery that FKBP51 forms an Hsp90-dependent complex with hTERT and enhances telomerase activity, with stress-induced nuclear redistribution of FKBP51, expanded the functional scope of FKBP51 to telomere maintenance.

    Evidence Co-IP, TRAP telomerase activity assay, Hsp90 inhibitor disruption, confocal microscopy

    PMID:27233944

    Open questions at the time
    • Physiological relevance for telomere length maintenance in vivo not demonstrated
    • Whether PPIase activity is involved not tested
  8. 2017 High

    Demonstrating that USP49 deubiquitinates and stabilizes FKBP51, which scaffolds PHLPP-mediated AKT Ser473 dephosphorylation, defined the post-translational control of FKBP51 protein levels and established FKBP51 as a tumor suppressor through AKT pathway inhibition.

    Evidence Ubiquitination reconstitution, Co-IP, deubiquitinase assays, xenograft tumor models

    PMID:28363942

    Open questions at the time
    • Identity of the E3 ubiquitin ligase targeting FKBP51 unknown
    • Whether USP49-FKBP51 axis operates in non-cancer contexts unclear
  9. 2017 High

    Identifying FKBP51 interaction with AS160 (TBC1D4) and showing that FKBP51 loss or pharmacological inhibition (SAFit2) increases AS160 phosphorylation, GLUT4 surface expression, and glucose uptake connected FKBP51-AKT signaling to insulin-stimulated glucose metabolism.

    Evidence Co-IP, Fkbp5 KO mice, SAFit2 treatment, glucose uptake assays in skeletal myotubes

    PMID:29170369

    Open questions at the time
    • Whether FKBP51-AS160 interaction is direct or Hsp90-mediated not resolved
    • Systemic glucose homeostasis phenotype in whole-body KO not fully characterized
  10. 2017 Medium

    A Paget's disease mutation (V55L) in FKBP5 that enhances AKT phosphorylation and osteoclast hyperactivation provided genetic evidence linking FKBP51's AKT-regulatory function to human bone disease.

    Evidence Whole-exome sequencing, V55L knock-in mice, osteoclast differentiation assays, micro-CT

    PMID:28524179

    Open questions at the time
    • Structural consequence of V55L on PHLPP scaffolding not defined
    • Single pedigree; broader genetic replication lacking
  11. 2018 High

    Solution NMR structures of full-length Hsp90–FKBP51 binary and Hsp90–FKBP51–Tau ternary complexes revealed that FKBP51 stabilizes the extended Hsp90 dimer, reduces Hsp90 ATPase activity, and positions tau near the PPIase catalytic pocket in a phosphorylation-dependent manner.

    Evidence NMR solution structure, ATPase activity assays, XL-MS cross-linking

    PMID:30382094

    Open questions at the time
    • How phosphorylation of specific tau sites alters ternary complex conformation not fully mapped
    • No structure of FKBP51 with GR client bound
  12. 2018 Medium

    Demonstrating that FKBP51 exists in a complex with Hsp90, GR, and IKKα/β and facilitates IKK complex assembly for NF-κB activation extended FKBP51 scaffolding to innate immune signaling.

    Evidence Co-IP, siRNA knockdown, NF-κB nuclear translocation and cytokine assays

    PMID:30169894

    Open questions at the time
    • Whether FKBP51 binds IKK directly or through Hsp90 not resolved
    • Single Co-IP without reciprocal validation for IKK interaction
  13. 2019 Medium

    Showing that PINK1 kinase phosphorylates FKBP51 and that PINK1 loss increases FKBP51-PHLPP-AKT complex formation, reducing neuroprotective AKT signaling, linked Parkinson's disease-relevant PINK1 to FKBP51-AKT regulation.

    Evidence In vitro kinase assay, Co-IP, PINK1 KO neurons, shRNA knockdown

    PMID:30734931

    Open questions at the time
    • Exact phosphorylation site on FKBP51 not identified
    • In vivo dopaminergic neuron phenotype not characterized
  14. 2020 High

    Showing that elevated GR–FKBP51 complex in PTSD patients and fear-conditioned mice reduces GR nuclear translocation, and that a peptide disrupting this complex reverses fear-conditioned behaviors, provided translational evidence that the FKBP51–GR interaction is a druggable target in stress-related disorders.

    Evidence Co-IP from human PTSD blood and mouse brain, peptide disruption, fear-conditioning behavioral assays

    PMID:31929189

    Open questions at the time
    • Peptide pharmacokinetics and selectivity in vivo not fully characterized
    • Whether complex disruption affects other FKBP51 client interactions unknown
  15. 2021 High

    Demonstrating that FKBP51 binds progesterone receptor in decidual cells and that stress-induced FKBP51 causes functional progesterone withdrawal—with Fkbp5−/− mice completely resistant to stress-induced preterm birth—established FKBP51 as a molecular link between maternal stress and adverse pregnancy outcomes.

    Evidence Co-IP of FKBP51-PR from human decidua, Fkbp5 KO restraint-stress mouse model

    PMID:33836562

    Open questions at the time
    • Whether FKBP51 PPIase activity or TPR domain mediates PR inhibition not defined
    • Human genetic association with preterm birth not established
  16. 2021 High

    Establishing that mineralocorticoid receptor directly binds the Fkbp5 locus and controls basal hippocampal FKBP5 expression more than GR refined the transcriptional feedback model, showing that MR sets the tonic level of FKBP5 that governs GR sensitivity.

    Evidence Biotinylated-oligonucleotide IP, pharmacological MR inhibition, cell-type-specific MR/GR deletion mice

    PMID:34077736

    Open questions at the time
    • Whether MR and GR bind the same or distinct regulatory elements not resolved
    • Interaction with the epigenetic demethylation mechanism at rs1360780 not tested
  17. 2021 Medium

    Showing that FKBP51 interacts with huntingtin and that FKBP5 loss or SAFit2 treatment increases autophagic flux and reduces mutant HTT levels in human HD models and mice identified FKBP51 as a therapeutic target in Huntington's disease through autophagy regulation.

    Evidence Co-IP, siRNA, SAFit2 treatment, autophagic flux assays, HD mouse models

    PMID:34024231

    Open questions at the time
    • Whether FKBP51 directly inhibits autophagosome formation or acts through AKT/mTOR not fully dissected
    • Long-term in vivo efficacy of SAFit2 in HD not established
  18. 2022 High

    Identifying FKBP51 as a hypothalamic scaffold that recruits LKB1/AMPK to WIPI4 and TSC2 to WIPI3 to balance autophagy and mTOR—with mediobasal hypothalamus-specific deletion causing obesity and overexpression protecting against it—established FKBP51 as a central metabolic sensor integrating autophagy/mTOR in energy homeostasis.

    Evidence MS-based interactomics, Co-IP, MBH-specific viral KO/OE in mice, HFD models

    PMID:35263141

    Open questions at the time
    • Whether the LKB1/AMPK/WIPI scaffolding function operates outside hypothalamus not tested
    • Direct structural evidence for the multiprotein assembly lacking
  19. 2023 High

    Demonstrating that cardiomyocyte-specific FKBP5 knockdown increases HIF-1α (via reduced Hsp90 competition), which transcriptionally upregulates NCX1 and promotes atrial fibrillation, extended FKBP51 Hsp90-client regulation to cardiac electrophysiology and arrhythmogenesis.

    Evidence Cardiomyocyte-specific KD mice, intracardiac stimulation, Co-IP, optical mapping, 17-AAG rescue

    PMID:37154033

    Open questions at the time
    • Whether FKBP51 directly chaperones HIF-1α or acts solely through Hsp90 competition not resolved
    • Human genetic association of FKBP5 variants with atrial fibrillation not established
  20. 2023 Medium

    Identifying cannabidiol as a direct FKBP5 ligand (Tyr113-dependent) that inhibits IKK complex assembly and NF-κB activation provided a molecular target for CBD's anti-inflammatory effects.

    Evidence Protein fluorescence titration, CETSA, Y113A mutagenesis, NF-κB pathway assays, CCI mouse model

    PMID:37196785

    Open questions at the time
    • CBD selectivity for FKBP51 over FKBP52 not established
    • Whether CBD binding affects other FKBP51 functions (GR, AKT) not tested

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include the identity of the E3 ubiquitin ligase targeting FKBP51, the structural basis for FKBP51 selectivity across its diverse client proteins (GR, AR, PR, ERα, HIF-1α), and whether the multiple scaffolding functions of FKBP51 (AKT-PHLPP, IKK, LKB1-AMPK-WIPI) operate through shared or distinct Hsp90/TPR-dependent mechanisms.
  • E3 ligase for FKBP51 ubiquitination unidentified
  • No unified structural model explaining client selectivity across steroid receptors
  • Tissue-specific integration of FKBP51 scaffolding functions not mapped

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0098772 molecular function regulator activity 7 GO:0060090 molecular adaptor activity 6 GO:0044183 protein folding chaperone 5
Localization
GO:0005634 nucleus 3 GO:0005829 cytosol 3 GO:0005739 mitochondrion 1
Pathway
R-HSA-162582 Signal Transduction 9 R-HSA-1430728 Metabolism 3 R-HSA-168256 Immune System 3 R-HSA-8953897 Cellular responses to stimuli 3 R-HSA-392499 Metabolism of proteins 2 R-HSA-9612973 Autophagy 2
Partners
AKT1CHUKGSK3BHSP90AA1NR3C1PGRPHLPP1TBC1D4
Complex memberships
FKBP51-LKB1-AMPK-WIPI autophagy complexFKBP51-PHLPP-AKT scaffold complexHsp90-FKBP51-GR co-chaperone complexHsp90-FKBP51-Tau ternary complex

Evidence

Reading pass · 30 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2012 A functional FKBP5 polymorphism (rs1360780) alters chromatin interaction between the transcription start site and long-range enhancers, enabling allele-specific, childhood trauma-dependent DNA demethylation at glucocorticoid response elements (GREs) in FKBP5 introns, which increases stress-dependent gene transcription and dysregulates the HPA axis. Epigenetic analysis (bisulfite sequencing/pyrosequencing of GRE-containing intronic CpG sites), chromatin interaction assays, allele-specific methylation analysis in human cohorts Nature neuroscience High 23201972
2010 FKBP51 (FKBP5 gene product) prevents tau clearance, regulates tau phosphorylation status via its PPIase (peptidyl-prolyl cis-trans isomerase) activity, enhances tau association with Hsp90, and in vitro stabilizes microtubules in a PPIase-dependent manner. Co-immunoprecipitation, in vitro microtubule stabilization assay, PPIase activity assays with domain mutants, cell-based tau phosphorylation analysis The Journal of neuroscience High 20071522
2018 Solution structures of full-length human Hsp90 in complex with FKBP51, and of the ternary Hsp90/FKBP51/Tau complex, show that FKBP51 stabilizes the extended conformation of the Hsp90 dimer and decreases Hsp90 ATPase activity, while within the ternary complex Hsp90 scaffolds FKBP51 and nucleates multiple Tau conformations near the PPIase catalytic pocket in a phosphorylation-dependent manner. NMR solution structure determination, ATPase activity assays, mass spectrometry cross-linking Nature communications High 30382094
2017 FKBP51 forms a novel association with AS160 (TBC1D4), a substrate of AKT2 involved in glucose uptake; FKBP51 antagonism (genetic knockout or SAFit2 inhibitor) increases AS160 phosphorylation, increases GLUT4 expression at the plasma membrane, and enhances glucose uptake in skeletal myotubes. Co-immunoprecipitation, Fkbp5 knockout mice, pharmacological inhibition (SAFit2), glucose uptake assays, Western blotting Nature communications High 29170369
2017 USP49 deubiquitinates and stabilizes FKBP51, which in turn enhances PHLPP-mediated dephosphorylation of AKT at Ser473, negatively regulating AKT activation and suppressing pancreatic cancer cell proliferation. Co-immunoprecipitation, ubiquitination assays, deubiquitinase activity assays, cell proliferation assays, tumor xenograft models The EMBO journal High 28363942
2015 FKBP51 increases phosphorylation of GSK3β at Ser9, associates with GSK3β primarily through its FK1 domain, and alters GSK3β heterocomplex assembly by associating with phosphatase PP2A and kinase CDK5, acting downstream on Tau, β-catenin, and TCF/LEF targets. Deletion of FKBP51 blunts lithium- or paroxetine-induced pGSK3β(S9) increases in cells and mice. Co-immunoprecipitation, reporter gene assays, FKBP51 knockout mouse behavioral studies, pharmacological treatments Molecular psychiatry High 25849320
2014 FKBP51 acts as a co-chaperone for PPARγ and reciprocally regulates GRα and PPARγ via the Akt-p38 kinase pathway: FKBP51 loss increases Akt and p38 activity, leading to inhibitory phosphorylation of PPARγ at Ser112 and activating phosphorylation of GRα at Ser220/234, with nuclear redistribution of both receptors. FKBP51 knockout MEFs, reporter gene assays, pharmacological p38 inhibition, phosphorylation analysis by Western blot Molecular endocrinology High 24933248
2014 FKBP51 is a required regulator of adipogenesis: FKBP51 knockout MEFs show near-complete resistance to differentiation, reduced PPARγ activity at adipogenic genes, increased GRα-mediated lipolysis, and elevated p38 kinase activity targeting PPARγ Ser112 and GRα Ser212/220/234. FKBP51 knockout MEFs, stable knockdown in 3T3-L1 cells, lipid accumulation assays, fatty acid synthase activity, gene expression profiling, p38 inhibitor rescue Molecular endocrinology High 24933247
2020 FKBP51 forms a protein complex with the glucocorticoid receptor (GR) that is elevated in PTSD patients and fear-conditioned mice; elevated GR-FKBP51 complex reduces GR phosphorylation and nuclear translocation. A peptide disrupting GR-FKBP51 binding reverses fear-conditioning-induced behavioral and molecular changes, increasing GR phosphorylation, GR-FKBP52 binding, GR nuclear translocation, and 14-3-3ε expression. Co-immunoprecipitation from human PTSD blood samples and mouse brain, peptide disruption experiments, fear-conditioning mouse model, behavioral assays The Journal of clinical investigation High 31929189
2011 FKBP51 is a co-chaperone for androgen receptor (AR), physically interacts with AR, and overexpression of FKBP51 in LNCaP prostate cancer cells increases ligand-mediated AR transcriptional activation of an AR reporter and endogenous PSA expression. Co-immunoprecipitation, AR reporter gene assay, stable overexpression clones, Northern/Western blot The Journal of urology Medium 15821585
2002 FKBP51 interacts directly with calcineurin in a calcium-, calmodulin-, and FK506-independent manner; the C-terminal domain of FKBP51 (not the FK1 domain) is required for calcineurin binding, as mapped by deletion mutagenesis. GST pulldown with purified calcineurin, co-immunoprecipitation from T cell lysates, calmodulin-Sepharose precipitation, deletion mutagenesis of FKBP51 Journal of cellular biochemistry Medium 11813252
2019 Pink1 kinase directly phosphorylates FKBP51 at a serine residue in vitro and endogenously interacts with FKBP51; loss of Pink1 increases FKBP51 interaction with both AKT and PHLPP (the AKT phosphatase), reducing AKT Ser473 phosphorylation and promoting neuronal death in response to MPP+. Co-immunoprecipitation, in vitro kinase assay, AAV-FKBP5 overexpression in primary neurons, Pink1 KO mouse cortical neurons, shRNA knockdown Journal of neurochemistry Medium 30734931
2021 FKBP51 interacts with and colocalizes with HTT (huntingtin) in the striatum and cortex; decreasing FKBP5 levels or activity (siRNA or SAFit2) reduces mutant HTT levels by increasing LC3-II and autophagic flux in an mTOR-independent manner in human HD stem cell models and reduces HTT in HD mouse models in vivo. Co-immunoprecipitation, siRNA knockdown, SAFit2 pharmacological inhibition, autophagic flux assays, in vivo SAFit2 treatment of HD mouse models Autophagy Medium 34024231
2022 FKBP51 acts as a central scaffold in the mediobasal hypothalamus, recruiting the LKB1/AMPK complex to WIPI4 and TSC2 to WIPI3, thereby regulating the balance between autophagy and mTOR signaling in response to metabolic challenges. MBH-specific FKBP51 deletion induces obesity, while overexpression protects against HFD-induced obesity. Mass spectrometry-based metabolomics, Co-immunoprecipitation, MBH-specific viral vector knockout/overexpression in mice, high-fat diet models Science advances High 35263141
2023 FKBP5 negatively modulates HIF-1α protein levels by competitively interacting with Hsp90; cardiomyocyte-specific FKBP5 knockdown leads to increased HIF-1α, which transcriptionally upregulates NCX1 (Slc8a1), causing Ca2+ handling abnormalities and increased atrial fibrillation susceptibility. HSP90 inhibitor 17-AAG normalized HIF-1α and NCX1 levels and reduced AF susceptibility. Cardiomyocyte-specific knockdown mouse model, intracardiac programmed stimulation, Co-immunoprecipitation, optical mapping, cellular electrophysiology, 17-AAG rescue experiments Circulation research High 37154033
2021 FKBP51 binding to progesterone receptors (PR) in decidual cells inhibits PR function; maternal stress induces uterine FKBP51 expression and nuclear FKBP51-PR binding, leading to functional progesterone withdrawal and preterm birth. Fkbp5-/- mice completely resist maternal stress-induced preterm birth. Co-immunoprecipitation of FKBP51-PR from human decidual cells, Fkbp5 knockout mouse restraint-stress model, immunohistochemistry, gene expression analysis Proceedings of the National Academy of Sciences of the United States of America High 33836562
2021 Mineralocorticoid receptor (MR) binding to the Fkbp5 gene (demonstrated by biotinylated-oligonucleotide immunoprecipitation) regulates FKBP5 baseline expression in hippocampal neurons more than GR; MR deletion reduces hippocampal Fkbp5 levels and dampens stress-induced glucocorticoid increases, establishing MR-dependent FKBP5 as a modulator of GR sensitivity. Biotinylated-oligonucleotide immunoprecipitation, pharmacological MR inhibition, region- and cell-type-specific MR/GR deletion mouse models Cell reports High 34077736
2018 FKBP51 exists in a complex with Hsp90, GR, and members of the IKK family (IKKα/β) as confirmed by co-immunoprecipitation; FKBP51 facilitates assembly of the IκB kinase (IKK) complex for NF-κB activation. FKBP51 silencing reduces NFκB (p50/p65) nuclear translocation and decreases ICAM expression, cytokine and chemokine secretion. Co-immunoprecipitation with anti-FKBP51 antibodies, siRNA knockdown, NF-κB nuclear translocation assay, cytokine secretion assays European journal of immunology Medium 30169894
2020 FKBP5 binds IKKα and promotes RIG-I-mediated NF-κB activation; FKBP5 knockout increases IAV (influenza A virus) infection, establishing FKBP5 as a host antiviral factor acting through the RIG-I-NF-κB innate immune signaling pathway. FKBP5 knockout cells, Co-immunoprecipitation, IAV infection assays, NF-κB reporter assays Viruses Medium 32580383
2023 Cannabidiol (CBD) directly binds FKBP5 (confirmed by protein intrinsic fluorescence titration and CETSA), with Tyr113 critical for interaction; CBD inhibits FKBP5-mediated IKK complex assembly and NF-κB activation, blocking LPS-induced pro-inflammatory factor production. Y113A mutation of FKBP5 reduces CBD's anti-inflammatory effect. In vitro protein fluorescence titration, CETSA, molecular docking, site-directed mutagenesis (Y113A), NF-κB pathway assays, CCI mouse model Brain, behavior, and immunity Medium 37196785
2017 FKBP51 interacts with DLC1 and DLC2 (Rho GTPase-activating proteins), identified by immunoprecipitation and mass spectrometry. FKBP51 overexpression enhances cell motility and invasion via upregulation of RhoA and ROCK signaling, while FKBP51 depletion reduces RhoA activity, causes cortical actin redistribution, and decreases cell motility and invasion. Co-immunoprecipitation and mass spectrometry, RhoA activity assays, F-actin imaging, Boyden chamber invasion assays, siRNA knockdown and overexpression Cancer science Medium 28032931
2016 MicroRNA-511 directly binds the 3'-UTR of FKBP5 mRNA, suppressing FKBP5 mRNA and protein levels including glucocorticoid-induced upregulation; confirmed by luciferase reporter assay and RNA pulldown. miR-511 expression decreases with age in mouse brain, providing a mechanism for age-dependent increases in FKBP51. Luciferase reporter assay, RNA pulldown assay, miR-511 overexpression in cells and primary neurons, in silico target prediction The Journal of biological chemistry Medium 27334923
2016 FKBP51 forms a complex with hTERT (telomerase reverse transcriptase) via Hsp90, as shown by co-immunoprecipitation; FKBP51 overexpression significantly enhances telomerase activity. Hsp90 inhibitor radicicol disrupts the complex and partially relocalizes hTERT to the cytoplasm. Under oxidative stress, FKBP51 (but not FKBP52) redistributes from mitochondria to the nucleus, colocalizing with hTERT. Co-immunoprecipitation, telomerase activity assay (TRAP), Hsp90 inhibitor treatment, confocal microscopy Molecular oncology Medium 27233944
2021 Structure-based design of macrocyclic FKBP51 inhibitors revealed by six high-resolution crystal structures of macrocyclic ligands bound to FKBP51, confirming the selectivity-enabling binding mode in the shallow FKBP51 binding site over FKBP52. X-ray crystallography (6 crystal structures), competitive binding assays, medicinal chemistry Journal of medicinal chemistry High 33666419
2019 Loss of FKBP5 in mice reduces LTP in hippocampus, decreases excitatory glutamate receptor expression (NMDAR1, NMDAR2B, AMPAR), reduces mEPSC frequency, increases GABAergic inhibition (elevated GABA and GAD65 expression, increased mIPSC frequency), revealing a role for FKBP5 in regulating neuronal synaptic plasticity. Fkbp5 knockout mice, electrophysiology (LTP, mEPSC, mIPSC recording), Western blot for receptor expression, GABA quantification Neuroscience Medium 30685540
2023 FKBP5 regulates PPAR-γ stability in oligodendrocytes/CNS cells; loss of FKBP5 in mice slows myelin loss and regeneration in a cuprizone model, with FKBP5 promoting PINK1/Parkin-mediated mitophagy by ablating PPAR-γ in a demyelinating environment. Fkbp5 knockout mouse cuprizone demyelination model, mitophagy assays, PPAR-γ expression analysis, Co-immunoprecipitation Cell death & disease Low 37952053
2017 A FKBP5 mutation (p.Val55Leu) found in Paget's disease of bone enhances AKT phosphorylation; FKBP51V55L knock-in mice show hyperresponsive osteoclast precursors to RANKL, increased NFATC1 and osteoclast markers, elevated AKT phosphorylation in response to RANKL, and intensive trabecular bone resorption. Whole-exome sequencing, FKBP51V55L knock-in transgenic mice, osteoclast differentiation assays, AKT phosphorylation assays, micro-CT Experimental & molecular medicine Medium 28524179
2022 FKBP51 reduces estrogen receptor α (ERα) stability in breast cancer cells, while FKBP52 stabilizes ERα; these two related immunophilins act in opposite directions to regulate ERα protein levels, with FKBP51 more abundantly expressed in normal tissues than cancer cells. siRNA knockdown of FKBP51/FKBP52, Western blot for ERα protein levels, breast cancer cell proliferation assays Proceedings of the National Academy of Sciences of the United States of America Medium 35394865
2020 USP53 deubiquitinates FKBP51, which in turn dephosphorylates AKT1 (via PHLPP), promoting apoptosis and inhibiting glycolysis in lung adenocarcinoma; confirmed by co-immunoprecipitation and ubiquitination assay. Co-immunoprecipitation, ubiquitination assay, siRNA/overexpression functional assays, tumor xenograft model Molecular carcinogenesis Medium 32511815
2023 FKBP5 is a regulator of FOXO1 phosphorylation at Serine 256 in pancreatic β cells; FKBP5 inhibition promotes β-cell survival and insulin secretion under inflammatory stress, and silencing FOXO1 abrogates the protective effect of FKBP5 inhibition, establishing FOXO1 as a key downstream effector of FKBP5 in β cells. siRNA knockdown, SAFit2 pharmacological inhibition, human and mouse primary islets, FOXO1 rescue experiments, Western blotting for pFOXO1(S256) Cell death discovery Medium 37452039

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2012 Allele-specific FKBP5 DNA demethylation mediates gene-childhood trauma interactions. Nature neuroscience 1020 23201972
2015 Gene-Stress-Epigenetic Regulation of FKBP5: Clinical and Translational Implications. Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology 453 26250598
2006 Translation repression in human cells by microRNA-induced gene silencing requires RCK/p54. PLoS biology 413 16756390
2015 Holocaust Exposure Induced Intergenerational Effects on FKBP5 Methylation. Biological psychiatry 353 26410355
2002 PSF and p54(nrb)/NonO--multi-functional nuclear proteins. FEBS letters 297 12417296
2013 Gene-environment interactions at the FKBP5 locus: sensitive periods, mechanisms and pleiotropism. Genes, brain, and behavior 220 24219237
2011 FKBP51 and FKBP52 in signaling and disease. Trends in endocrinology and metabolism: TEM 217 21889356
2010 Chronic corticosterone exposure increases expression and decreases deoxyribonucleic acid methylation of Fkbp5 in mice. Endocrinology 212 20668026
2018 Understanding the Molecular Mechanisms Underpinning Gene by Environment Interactions in Psychiatric Disorders: The FKBP5 Model. Biological psychiatry 189 29573791
2010 The Hsp90 cochaperone, FKBP51, increases Tau stability and polymerizes microtubules. The Journal of neuroscience : the official journal of the Society for Neuroscience 172 20071522
2011 Steroid up-regulation of FKBP51 and its role in hormone signaling. Current opinion in pharmacology 133 21531172
2018 Hsp90 and FKBP51: complex regulators of psychiatric diseases. Philosophical transactions of the Royal Society of London. Series B, Biological sciences 114 29203717
2011 A new anti-depressive strategy for the elderly: ablation of FKBP5/FKBP51. PloS one 107 21935478
2010 The role of FKBP5 in cancer aetiology and chemoresistance. British journal of cancer 107 21119664
2013 FKBP5 and attention bias for threat: associations with hippocampal function and shape. JAMA psychiatry 105 23407841
2012 Interaction between FKBP5 and childhood trauma and risk of aggressive behavior. Archives of general psychiatry 105 22213790
2004 Identification of the polypyrimidine tract binding protein-associated splicing factor.p54(nrb) complex as a candidate DNA double-strand break rejoining factor. The Journal of biological chemistry 101 15590677
2017 Stress-responsive FKBP51 regulates AKT2-AS160 signaling and metabolic function. Nature communications 95 29170369
2019 The Many Faces of FKBP51. Biomolecules 93 30669684
1996 Functional properties of p54, a novel SR protein active in constitutive and alternative splicing. Molecular and cellular biology 89 8816452
2017 USP49 negatively regulates tumorigenesis and chemoresistance through FKBP51-AKT signaling. The EMBO journal 88 28363942
2013 Dysregulation of glucocorticoid receptor co-factors FKBP5, BAG1 and PTGES3 in prefrontal cortex in psychotic illness. Scientific reports 87 24345775
2014 FKBP5 expression in human adipose tissue increases following dexamethasone exposure and is associated with insulin resistance. Metabolism: clinical and experimental 82 24997500
2005 Androgen mediated regulation and functional implications of fkbp51 expression in prostate cancer. The Journal of urology 82 15821585
2021 Mineralocorticoid receptors dampen glucocorticoid receptor sensitivity to stress via regulation of FKBP5. Cell reports 80 34077736
1998 The RNA-splicing factor PSF/p54 controls DNA-topoisomerase I activity by a direct interaction. The Journal of biological chemistry 79 9756848
2019 Biological Actions of the Hsp90-binding Immunophilins FKBP51 and FKBP52. Biomolecules 78 30717249
2018 Structure and pro-toxic mechanism of the human Hsp90/PPIase/Tau complex. Nature communications 72 30382094
2010 FKBP5 and resistant attachment predict cortisol reactivity in infants: gene-environment interaction. Psychoneuroendocrinology 71 20547006
2004 The African swine fever virus dynein-binding protein p54 induces infected cell apoptosis. FEBS letters 71 15225638
2015 p54(nrb)/NONO regulates lipid metabolism and breast cancer growth through SREBP-1A. Oncogene 70 26148231
1999 Overexpression of rck/p54, a DEAD box protein, in human colorectal tumours. British journal of cancer 70 10360675
1994 Characterization and molecular basis of heterogeneity of the African swine fever virus envelope protein p54. Journal of virology 69 7933107
2005 Induction and mode of action of the viral stress-inducible murine proteins, P56 and P54. Virology 61 16023166
2002 RNA helicase p54 (DDX6) is a shuttling protein involved in nuclear assembly of stored mRNP particles. Journal of cell science 61 11839790
2019 Focus on FKBP51: A molecular link between stress and metabolic disorders. Molecular metabolism 58 31668388
1994 Interleukin 1 alpha activates two forms of p54 alpha mitogen-activated protein kinase in rabbit liver. The Journal of experimental medicine 58 7964479
2023 Cannabidiol alleviates neuroinflammation and attenuates neuropathic pain via targeting FKBP5. Brain, behavior, and immunity 54 37196785
2015 FKBP51 inhibits GSK3β and augments the effects of distinct psychotropic medications. Molecular psychiatry 53 25849320
2011 Organization and function of the FKBP52 and FKBP51 genes. Current opinion in pharmacology 53 21514887
2020 The glucocorticoid receptor-FKBP51 complex contributes to fear conditioning and posttraumatic stress disorder. The Journal of clinical investigation 52 31929189
2018 GxE effects of FKBP5 and traumatic life events on PTSD: A meta-analysis. Journal of affective disorders 52 30273884
2021 Modulating FKBP5/FKBP51 and autophagy lowers HTT (huntingtin) levels. Autophagy 51 34024231
2016 FK506 binding protein 51 integrates pathways of adaptation: FKBP51 shapes the reactivity to environmental change. BioEssays : news and reviews in molecular, cellular and developmental biology 49 27374865
2018 DNA methylation of FKBP5 and response to exposure-based psychological therapy. American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics 47 30334356
2009 hnRNP M interacts with PSF and p54(nrb) and co-localizes within defined nuclear structures. Experimental cell research 46 19874820
2016 MicroRNA-511 Binds to FKBP5 mRNA, Which Encodes a Chaperone Protein, and Regulates Neuronal Differentiation. The Journal of biological chemistry 45 27334923
2014 FKBP51 controls cellular adipogenesis through p38 kinase-mediated phosphorylation of GRα and PPARγ. Molecular endocrinology (Baltimore, Md.) 45 24933247
2014 FKBP51 reciprocally regulates GRα and PPARγ activation via the Akt-p38 pathway. Molecular endocrinology (Baltimore, Md.) 44 24933248
2011 FKBP51 regulation of AKT/protein kinase B phosphorylation. Current opinion in pharmacology 44 21498116
1996 A novel plant peptidyl-prolyl-cis-trans-isomerase (PPIase): cDNA cloning, structural analysis, enzymatic activity and expression. Plant molecular biology 44 8980498
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2023 Associations of psychiatric disease and ageing with FKBP5 expression converge on superficial layer neurons of the neocortex. Acta neuropathologica 42 36729133
2016 Regulation of PCGEM1 by p54/nrb in prostate cancer. Scientific reports 41 27682980
2021 Structure-Based Design of High-Affinity Macrocyclic FKBP51 Inhibitors. Journal of medicinal chemistry 40 33666419
2020 Epitope mapping of African swine fever virus (ASFV) structural protein, p54. Virus research 40 32004574
2019 Pink1 regulates FKBP5 interaction with AKT/PHLPP and protects neurons from neurotoxin stress induced by MPP. Journal of neurochemistry 39 30734931
2008 Brm transactivates the telomerase reverse transcriptase (TERT) gene and modulates the splicing patterns of its transcripts in concert with p54(nrb). The Biochemical journal 39 18042045
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2002 Calcium- and FK506-independent interaction between the immunophilin FKBP51 and calcineurin. Journal of cellular biochemistry 33 11813252
2019 Loss of FKBP5 Affects Neuron Synaptic Plasticity: An Electrophysiology Insight. Neuroscience 32 30685540
2013 Glucocorticoid induction of occludin expression and endothelial barrier requires transcription factor p54 NONO. Investigative ophthalmology & visual science 32 23640037
1997 Chloroplast endoribonuclease p54 involved in RNA 3'-end processing is regulated by phosphorylation and redox state. Nucleic acids research 32 9171092
2021 Characterization of Anti-p54 Monoclonal Antibodies and Their Potential Use for African Swine Fever Virus Diagnosis. Pathogens (Basel, Switzerland) 31 33562314
2020 USP53 promotes apoptosis and inhibits glycolysis in lung adenocarcinoma through FKBP51-AKT1 signaling. Molecular carcinogenesis 31 32511815
2018 Gears-In-Motion: The Interplay of WW and PPIase Domains in Pin1. Frontiers in oncology 31 30460195
2012 Identification of RNA targets for the nuclear multidomain cyclophilin atCyp59 and their effect on PPIase activity. Nucleic acids research 31 23248006
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2022 Inhibition of FKBP51 induces stress resilience and alters hippocampal neurogenesis. Molecular psychiatry 28 36104438
2016 Hsp90-binding immunophilin FKBP51 forms complexes with hTERT enhancing telomerase activity. Molecular oncology 28 27233944
2015 Schizophrenia in the spectrum of gene-stress interactions: the FKBP5 example. Schizophrenia bulletin 28 25592294
2018 Intergenerational gene × environment interaction of FKBP5 and childhood maltreatment on hair steroids. Psychoneuroendocrinology 27 29674169
2021 Decidual cell FKBP51-progesterone receptor binding mediates maternal stress-induced preterm birth. Proceedings of the National Academy of Sciences of the United States of America 26 33836562
2015 Association between FKBP5 Functional Polymorphisms and Completed Suicide. Neuropsychobiology 26 26630184
2018 Overexpression of p54nrb/NONO induces differential EPHA6 splicing and contributes to castration-resistant prostate cancer growth. Oncotarget 25 29535823
2017 A FKBP5 mutation is associated with Paget's disease of bone and enhances osteoclastogenesis. Experimental & molecular medicine 25 28524179
2022 FKBP52 and FKBP51 differentially regulate the stability of estrogen receptor in breast cancer. Proceedings of the National Academy of Sciences of the United States of America 24 35394865
2019 The Role of SurA PPIase Domains in Preventing Aggregation of the Outer-Membrane Proteins tOmpA and OmpT. Journal of molecular biology 24 30716334
2016 Different interactomes for p70-S6K1 and p54-S6K2 revealed by proteomic analysis. Proteomics 24 27493124
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2019 Interactions between FKBP5 variation and environmental stressors in adolescent Major Depression. Psychoneuroendocrinology 23 30953930
2018 Deletion of the glucocorticoid receptor chaperone FKBP51 prevents glucocorticoid-induced skin atrophy. Oncotarget 23 30410676
2022 Mediobasal hypothalamic FKBP51 acts as a molecular switch linking autophagy to whole-body metabolism. Science advances 22 35263141
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2023 FKBP5 activates mitophagy by ablating PPAR-γ to shape a benign remyelination environment. Cell death & disease 21 37952053
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2023 The inhibition of FKBP5 protects β-cell survival under inflammation stress via AKT/FOXO1 signaling. Cell death discovery 20 37452039
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