{"gene":"FKBP5","run_date":"2026-04-28T17:46:03","timeline":{"discoveries":[{"year":2012,"finding":"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.","method":"Epigenetic analysis (bisulfite sequencing/pyrosequencing of GRE-containing intronic CpG sites), chromatin interaction assays, allele-specific methylation analysis in human cohorts","journal":"Nature neuroscience","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal methods (methylation, chromatin interaction, gene expression), replicated in human cohorts and cell lines","pmids":["23201972"],"is_preprint":false},{"year":2010,"finding":"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.","method":"Co-immunoprecipitation, in vitro microtubule stabilization assay, PPIase activity assays with domain mutants, cell-based tau phosphorylation analysis","journal":"The Journal of neuroscience","confidence":"High","confidence_rationale":"Tier 1-2 — in vitro reconstitution with mutagenesis and multiple orthogonal assays in single study","pmids":["20071522"],"is_preprint":false},{"year":2018,"finding":"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.","method":"NMR solution structure determination, ATPase activity assays, mass spectrometry cross-linking","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1 — NMR structure with functional ATPase validation, rigorous structural determination","pmids":["30382094"],"is_preprint":false},{"year":2017,"finding":"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.","method":"Co-immunoprecipitation, Fkbp5 knockout mice, pharmacological inhibition (SAFit2), glucose uptake assays, Western blotting","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 — reciprocal Co-IP plus KO mouse model plus pharmacological validation, multiple orthogonal methods","pmids":["29170369"],"is_preprint":false},{"year":2017,"finding":"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.","method":"Co-immunoprecipitation, ubiquitination assays, deubiquitinase activity assays, cell proliferation assays, tumor xenograft models","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 1-2 — ubiquitination reconstitution assay plus in vivo xenograft, multiple methods","pmids":["28363942"],"is_preprint":false},{"year":2015,"finding":"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.","method":"Co-immunoprecipitation, reporter gene assays, FKBP51 knockout mouse behavioral studies, pharmacological treatments","journal":"Molecular psychiatry","confidence":"High","confidence_rationale":"Tier 2 — reciprocal Co-IP, domain mapping, KO mouse model, behavioral validation","pmids":["25849320"],"is_preprint":false},{"year":2014,"finding":"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.","method":"FKBP51 knockout MEFs, reporter gene assays, pharmacological p38 inhibition, phosphorylation analysis by Western blot","journal":"Molecular endocrinology","confidence":"High","confidence_rationale":"Tier 2 — genetic KO with pharmacological rescue, multiple phosphorylation sites identified, orthogonal reporter and localization assays","pmids":["24933248"],"is_preprint":false},{"year":2014,"finding":"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.","method":"FKBP51 knockout MEFs, stable knockdown in 3T3-L1 cells, lipid accumulation assays, fatty acid synthase activity, gene expression profiling, p38 inhibitor rescue","journal":"Molecular endocrinology","confidence":"High","confidence_rationale":"Tier 2 — KO MEF model with full mechanistic rescue, multiple assay types","pmids":["24933247"],"is_preprint":false},{"year":2020,"finding":"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.","method":"Co-immunoprecipitation from human PTSD blood samples and mouse brain, peptide disruption experiments, fear-conditioning mouse model, behavioral assays","journal":"The Journal of clinical investigation","confidence":"High","confidence_rationale":"Tier 2 — reciprocal Co-IP in human samples and mice, peptide rescue with multiple molecular readouts","pmids":["31929189"],"is_preprint":false},{"year":2011,"finding":"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.","method":"Co-immunoprecipitation, AR reporter gene assay, stable overexpression clones, Northern/Western blot","journal":"The Journal of urology","confidence":"Medium","confidence_rationale":"Tier 2-3 — Co-IP and functional reporter assay in single study, no domain mutagenesis","pmids":["15821585"],"is_preprint":false},{"year":2002,"finding":"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.","method":"GST pulldown with purified calcineurin, co-immunoprecipitation from T cell lysates, calmodulin-Sepharose precipitation, deletion mutagenesis of FKBP51","journal":"Journal of cellular biochemistry","confidence":"Medium","confidence_rationale":"Tier 2 — in vitro pulldown with purified proteins plus mutagenesis, but functional consequences of interaction not fully defined","pmids":["11813252"],"is_preprint":false},{"year":2019,"finding":"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+.","method":"Co-immunoprecipitation, in vitro kinase assay, AAV-FKBP5 overexpression in primary neurons, Pink1 KO mouse cortical neurons, shRNA knockdown","journal":"Journal of neurochemistry","confidence":"Medium","confidence_rationale":"Tier 2 — in vitro kinase assay plus Co-IP and genetic models, but limited mechanistic follow-through on phosphorylation site","pmids":["30734931"],"is_preprint":false},{"year":2021,"finding":"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.","method":"Co-immunoprecipitation, siRNA knockdown, SAFit2 pharmacological inhibition, autophagic flux assays, in vivo SAFit2 treatment of HD mouse models","journal":"Autophagy","confidence":"Medium","confidence_rationale":"Tier 2 — Co-IP, genetic, and pharmacological approaches with autophagy flux readouts, replicated in vivo","pmids":["34024231"],"is_preprint":false},{"year":2022,"finding":"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.","method":"Mass spectrometry-based metabolomics, Co-immunoprecipitation, MBH-specific viral vector knockout/overexpression in mice, high-fat diet models","journal":"Science advances","confidence":"High","confidence_rationale":"Tier 1-2 — MS-identified protein-protein interactions confirmed by Co-IP, region-specific in vivo manipulation with defined metabolic phenotypes","pmids":["35263141"],"is_preprint":false},{"year":2023,"finding":"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.","method":"Cardiomyocyte-specific knockdown mouse model, intracardiac programmed stimulation, Co-immunoprecipitation, optical mapping, cellular electrophysiology, 17-AAG rescue experiments","journal":"Circulation research","confidence":"High","confidence_rationale":"Tier 2 — tissue-specific KD mouse with mechanistic rescue by Hsp90 inhibitor, multiple orthogonal methods","pmids":["37154033"],"is_preprint":false},{"year":2021,"finding":"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.","method":"Co-immunoprecipitation of FKBP51-PR from human decidual cells, Fkbp5 knockout mouse restraint-stress model, immunohistochemistry, gene expression analysis","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 — Co-IP from human tissue plus complete genetic rescue in KO mouse model, mechanistic pathway defined","pmids":["33836562"],"is_preprint":false},{"year":2021,"finding":"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.","method":"Biotinylated-oligonucleotide immunoprecipitation, pharmacological MR inhibition, region- and cell-type-specific MR/GR deletion mouse models","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 2 — direct chromatin binding assay plus region-specific genetic deletion with physiological readouts","pmids":["34077736"],"is_preprint":false},{"year":2018,"finding":"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.","method":"Co-immunoprecipitation with anti-FKBP51 antibodies, siRNA knockdown, NF-κB nuclear translocation assay, cytokine secretion assays","journal":"European journal of immunology","confidence":"Medium","confidence_rationale":"Tier 3 — single Co-IP confirming complex, supported by functional knockdown with defined readouts","pmids":["30169894"],"is_preprint":false},{"year":2020,"finding":"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.","method":"FKBP5 knockout cells, Co-immunoprecipitation, IAV infection assays, NF-κB reporter assays","journal":"Viruses","confidence":"Medium","confidence_rationale":"Tier 2-3 — KO phenotype with Co-IP, single study","pmids":["32580383"],"is_preprint":false},{"year":2023,"finding":"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.","method":"In vitro protein fluorescence titration, CETSA, molecular docking, site-directed mutagenesis (Y113A), NF-κB pathway assays, CCI mouse model","journal":"Brain, behavior, and immunity","confidence":"Medium","confidence_rationale":"Tier 2 — direct binding assay with mutagenesis validation and functional NF-κB readouts, single study","pmids":["37196785"],"is_preprint":false},{"year":2017,"finding":"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.","method":"Co-immunoprecipitation and mass spectrometry, RhoA activity assays, F-actin imaging, Boyden chamber invasion assays, siRNA knockdown and overexpression","journal":"Cancer science","confidence":"Medium","confidence_rationale":"Tier 2-3 — MS-identified partners confirmed by Co-IP, RhoA activity assays, functional KD/OE phenotypes, single study","pmids":["28032931"],"is_preprint":false},{"year":2016,"finding":"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.","method":"Luciferase reporter assay, RNA pulldown assay, miR-511 overexpression in cells and primary neurons, in silico target prediction","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 — direct 3'-UTR binding confirmed by luciferase and RNA pulldown, functional validation in primary neurons","pmids":["27334923"],"is_preprint":false},{"year":2016,"finding":"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.","method":"Co-immunoprecipitation, telomerase activity assay (TRAP), Hsp90 inhibitor treatment, confocal microscopy","journal":"Molecular oncology","confidence":"Medium","confidence_rationale":"Tier 2-3 — Co-IP with functional telomerase activity readout, localization study, single lab","pmids":["27233944"],"is_preprint":false},{"year":2021,"finding":"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.","method":"X-ray crystallography (6 crystal structures), competitive binding assays, medicinal chemistry","journal":"Journal of medicinal chemistry","confidence":"High","confidence_rationale":"Tier 1 — multiple crystal structures with functional selectivity validation","pmids":["33666419"],"is_preprint":false},{"year":2019,"finding":"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.","method":"Fkbp5 knockout mice, electrophysiology (LTP, mEPSC, mIPSC recording), Western blot for receptor expression, GABA quantification","journal":"Neuroscience","confidence":"Medium","confidence_rationale":"Tier 2 — KO mouse with electrophysiological and molecular readouts, defined cellular phenotype","pmids":["30685540"],"is_preprint":false},{"year":2023,"finding":"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.","method":"Fkbp5 knockout mouse cuprizone demyelination model, mitophagy assays, PPAR-γ expression analysis, Co-immunoprecipitation","journal":"Cell death & disease","confidence":"Low","confidence_rationale":"Tier 3 — KO mouse phenotype with mechanistic proposal but limited direct biochemical evidence for FKBP5-PPAR-γ interaction","pmids":["37952053"],"is_preprint":false},{"year":2017,"finding":"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.","method":"Whole-exome sequencing, FKBP51V55L knock-in transgenic mice, osteoclast differentiation assays, AKT phosphorylation assays, micro-CT","journal":"Experimental & molecular medicine","confidence":"Medium","confidence_rationale":"Tier 2 — knock-in mouse model with defined cellular phenotype and AKT signaling mechanism, single study","pmids":["28524179"],"is_preprint":false},{"year":2022,"finding":"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.","method":"siRNA knockdown of FKBP51/FKBP52, Western blot for ERα protein levels, breast cancer cell proliferation assays","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"Medium","confidence_rationale":"Tier 2-3 — functional KD with defined protein stability readout, but mechanism of destabilization not fully characterized, single study","pmids":["35394865"],"is_preprint":false},{"year":2020,"finding":"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.","method":"Co-immunoprecipitation, ubiquitination assay, siRNA/overexpression functional assays, tumor xenograft model","journal":"Molecular carcinogenesis","confidence":"Medium","confidence_rationale":"Tier 2-3 — Co-IP and ubiquitination assay with in vivo tumor model, single study","pmids":["32511815"],"is_preprint":false},{"year":2023,"finding":"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.","method":"siRNA knockdown, SAFit2 pharmacological inhibition, human and mouse primary islets, FOXO1 rescue experiments, Western blotting for pFOXO1(S256)","journal":"Cell death discovery","confidence":"Medium","confidence_rationale":"Tier 2 — genetic and pharmacological approaches with epistasis rescue experiment in primary human islets","pmids":["37452039"],"is_preprint":false}],"current_model":"FKBP51 (encoded by FKBP5) is an Hsp90 co-chaperone with PPIase activity that acts as a multifunctional scaffolding protein: it inhibits glucocorticoid receptor (GR) sensitivity via the Hsp90 receptor-chaperone complex (forming an ultrashort negative-feedback loop with GR), regulates AKT signaling by facilitating PHLPP-mediated dephosphorylation of AKT (and is stabilized by deubiquitinases USP49/USP53), modulates tau phosphorylation and microtubule stability through its PPIase domain within Hsp90/FKBP51/Tau ternary complexes, controls NF-κB activation by scaffolding the IKK complex, regulates adipogenesis and metabolic homeostasis via the Akt-p38-PPARγ/GRα axis and autophagy through LKB1/AMPK/WIPI complexes, and undergoes allele-specific, stress-dependent epigenetic regulation through DNA demethylation at intronic glucocorticoid response elements."},"narrative":{"teleology":[{"year":2002,"claim":"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","pmids":["11813252"],"confidence":"Medium","gaps":["Functional consequence of calcineurin–FKBP51 interaction on NFAT or calcineurin phosphatase activity not defined","No in vivo validation"]},{"year":2010,"claim":"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","pmids":["20071522"],"confidence":"High","gaps":["In vivo tauopathy phenotype of FKBP5 manipulation not yet shown in this study","Structural basis of tau recognition by the PPIase pocket unknown"]},{"year":2011,"claim":"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","pmids":["15821585"],"confidence":"Medium","gaps":["Domain requirements for AR interaction not mapped","No reciprocal Co-IP or in vivo confirmation"]},{"year":2012,"claim":"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","pmids":["23201972"],"confidence":"High","gaps":["Whether demethylation is reversible in adulthood not established","Causal chain from demethylation to psychiatric disease phenotype not fully delineated"]},{"year":2014,"claim":"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","pmids":["24933247","24933248"],"confidence":"High","gaps":["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"]},{"year":2015,"claim":"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","pmids":["25849320"],"confidence":"High","gaps":["Direct versus Hsp90-scaffolded interaction with GSK3β not resolved","Downstream tau phosphorylation effects in tauopathy models not tested"]},{"year":2016,"claim":"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","pmids":["27233944"],"confidence":"Medium","gaps":["Physiological relevance for telomere length maintenance in vivo not demonstrated","Whether PPIase activity is involved not tested"]},{"year":2017,"claim":"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","pmids":["28363942"],"confidence":"High","gaps":["Identity of the E3 ubiquitin ligase targeting FKBP51 unknown","Whether USP49-FKBP51 axis operates in non-cancer contexts unclear"]},{"year":2017,"claim":"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","pmids":["29170369"],"confidence":"High","gaps":["Whether FKBP51-AS160 interaction is direct or Hsp90-mediated not resolved","Systemic glucose homeostasis phenotype in whole-body KO not fully characterized"]},{"year":2017,"claim":"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","pmids":["28524179"],"confidence":"Medium","gaps":["Structural consequence of V55L on PHLPP scaffolding not defined","Single pedigree; broader genetic replication lacking"]},{"year":2018,"claim":"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","pmids":["30382094"],"confidence":"High","gaps":["How phosphorylation of specific tau sites alters ternary complex conformation not fully mapped","No structure of FKBP51 with GR client bound"]},{"year":2018,"claim":"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","pmids":["30169894"],"confidence":"Medium","gaps":["Whether FKBP51 binds IKK directly or through Hsp90 not resolved","Single Co-IP without reciprocal validation for IKK interaction"]},{"year":2019,"claim":"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","pmids":["30734931"],"confidence":"Medium","gaps":["Exact phosphorylation site on FKBP51 not identified","In vivo dopaminergic neuron phenotype not characterized"]},{"year":2020,"claim":"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","pmids":["31929189"],"confidence":"High","gaps":["Peptide pharmacokinetics and selectivity in vivo not fully characterized","Whether complex disruption affects other FKBP51 client interactions unknown"]},{"year":2021,"claim":"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","pmids":["33836562"],"confidence":"High","gaps":["Whether FKBP51 PPIase activity or TPR domain mediates PR inhibition not defined","Human genetic association with preterm birth not established"]},{"year":2021,"claim":"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","pmids":["34077736"],"confidence":"High","gaps":["Whether MR and GR bind the same or distinct regulatory elements not resolved","Interaction with the epigenetic demethylation mechanism at rs1360780 not tested"]},{"year":2021,"claim":"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","pmids":["34024231"],"confidence":"Medium","gaps":["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"]},{"year":2022,"claim":"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","pmids":["35263141"],"confidence":"High","gaps":["Whether the LKB1/AMPK/WIPI scaffolding function operates outside hypothalamus not tested","Direct structural evidence for the multiprotein assembly lacking"]},{"year":2023,"claim":"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","pmids":["37154033"],"confidence":"High","gaps":["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"]},{"year":2023,"claim":"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","pmids":["37196785"],"confidence":"Medium","gaps":["CBD selectivity for FKBP51 over FKBP52 not established","Whether CBD binding affects other FKBP51 functions (GR, AKT) not tested"]},{"year":null,"claim":"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.","evidence":"","pmids":[],"confidence":"Low","gaps":["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":{"molecular_activity":[{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[4,6,7,8,15,27,28]},{"term_id":"GO:0044183","term_label":"protein folding chaperone","supporting_discovery_ids":[1,2,9,14,22]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[3,4,13,17,18,28]}],"localization":[{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[3,4,17]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[8,15,22]},{"term_id":"GO:0005739","term_label":"mitochondrion","supporting_discovery_ids":[22]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[3,4,5,6,8,11,26,28,29]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[17,18,19]},{"term_id":"R-HSA-9612973","term_label":"Autophagy","supporting_discovery_ids":[12,13]},{"term_id":"R-HSA-8953897","term_label":"Cellular responses to stimuli","supporting_discovery_ids":[0,14,16]},{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[3,7,29]},{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[4,28]}],"complexes":["Hsp90-FKBP51-GR co-chaperone complex","Hsp90-FKBP51-Tau ternary complex","FKBP51-PHLPP-AKT scaffold complex","FKBP51-LKB1-AMPK-WIPI autophagy complex"],"partners":["HSP90AA1","NR3C1","PHLPP1","AKT1","GSK3B","CHUK","TBC1D4","PGR"],"other_free_text":[]},"mechanistic_narrative":"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]."},"prefetch_data":{"uniprot":{"accession":"Q13451","full_name":"Peptidyl-prolyl cis-trans isomerase FKBP5","aliases":["51 kDa FK506-binding protein","51 kDa FKBP","FKBP-51","54 kDa progesterone receptor-associated immunophilin","Androgen-regulated protein 6","FF1 antigen","FK506-binding protein 5","FKBP-5","FKBP54","p54","HSP90-binding immunophilin","Rotamase"],"length_aa":457,"mass_kda":51.2,"function":"Immunophilin protein with PPIase and co-chaperone activities (PubMed:11350175). Component of unligated steroid receptors heterocomplexes through interaction with heat-shock protein 90 (HSP90). Plays a role in the intracellular trafficking of heterooligomeric forms of steroid hormone receptors maintaining the complex into the cytoplasm when unliganded (PubMed:12538866). Acts as a regulator of Akt/AKT1 activity by promoting the interaction between Akt/AKT1 and PHLPP1, thereby enhancing dephosphorylation and subsequent activation of Akt/AKT1 (PubMed:28147277, PubMed:28363942). Interacts with IKBKE and IKBKB which facilitates IKK complex assembly leading to increased IKBKE and IKBKB kinase activity, NF-kappa-B activation, and IFN production (PubMed:26101251, PubMed:31434731)","subcellular_location":"Cytoplasm; Nucleus","url":"https://www.uniprot.org/uniprotkb/Q13451/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/FKBP5","classification":"Not 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TXNIP","url":"https://www.omim.org/entry/606599"},{"mim_id":"605644","title":"KALLIKREIN-RELATED PEPTIDASE 8; KLK8","url":"https://www.omim.org/entry/605644"},{"mim_id":"602623","title":"FK506-BINDING PROTEIN 5; FKBP5","url":"https://www.omim.org/entry/602623"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Nucleoplasm","reliability":"Approved"},{"location":"Nucleoli fibrillar center","reliability":"Additional"},{"location":"Cytosol","reliability":"Additional"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in all","driving_tissues":[{"tissue":"skeletal muscle","ntpm":833.2},{"tissue":"tongue","ntpm":864.2}],"url":"https://www.proteinatlas.org/search/FKBP5"},"hgnc":{"alias_symbol":["FKBP51","FKBP54","PPIase","P54","Ptg-10"],"prev_symbol":[]},"alphafold":{"accession":"Q13451","domains":[{"cath_id":"3.10.50.40","chopping":"17-139","consensus_level":"high","plddt":96.521,"start":17,"end":139},{"cath_id":"3.10.50.40","chopping":"149-252","consensus_level":"high","plddt":97.6868,"start":149,"end":252},{"cath_id":"1.25.40.10","chopping":"262-398","consensus_level":"medium","plddt":97.8791,"start":262,"end":398}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q13451","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q13451-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q13451-F1-predicted_aligned_error_v6.png","plddt_mean":92.5},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=FKBP5","jax_strain_url":"https://www.jax.org/strain/search?query=FKBP5"},"sequence":{"accession":"Q13451","fasta_url":"https://rest.uniprot.org/uniprotkb/Q13451.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q13451/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q13451"}},"corpus_meta":[{"pmid":"23201972","id":"PMC_23201972","title":"Allele-specific 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NF-κB regulatory pathway in cancer.","date":"2011","source":"Current opinion in pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/21565553","citation_count":35,"is_preprint":false},{"pmid":"11813252","id":"PMC_11813252","title":"Calcium- and FK506-independent interaction between the immunophilin FKBP51 and calcineurin.","date":"2002","source":"Journal of cellular biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/11813252","citation_count":33,"is_preprint":false},{"pmid":"27664120","id":"PMC_27664120","title":"Reduced DNA methylation of FKBP5 in Cushing's syndrome.","date":"2016","source":"Endocrine","url":"https://pubmed.ncbi.nlm.nih.gov/27664120","citation_count":33,"is_preprint":false},{"pmid":"23640037","id":"PMC_23640037","title":"Glucocorticoid induction of occludin expression and endothelial barrier requires transcription factor p54 NONO.","date":"2013","source":"Investigative ophthalmology & visual 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multidomain cyclophilin atCyp59 and their effect on PPIase activity.","date":"2012","source":"Nucleic acids research","url":"https://pubmed.ncbi.nlm.nih.gov/23248006","citation_count":31,"is_preprint":false},{"pmid":"32511815","id":"PMC_32511815","title":"USP53 promotes apoptosis and inhibits glycolysis in lung adenocarcinoma through FKBP51-AKT1 signaling.","date":"2020","source":"Molecular carcinogenesis","url":"https://pubmed.ncbi.nlm.nih.gov/32511815","citation_count":31,"is_preprint":false},{"pmid":"33562314","id":"PMC_33562314","title":"Characterization of Anti-p54 Monoclonal Antibodies and Their Potential Use for African Swine Fever Virus Diagnosis.","date":"2021","source":"Pathogens (Basel, Switzerland)","url":"https://pubmed.ncbi.nlm.nih.gov/33562314","citation_count":31,"is_preprint":false},{"pmid":"32580383","id":"PMC_32580383","title":"FKBP5 Regulates RIG-I-Mediated NF-κB Activation and Influenza A Virus Infection.","date":"2020","source":"Viruses","url":"https://pubmed.ncbi.nlm.nih.gov/32580383","citation_count":29,"is_preprint":false},{"pmid":"36104438","id":"PMC_36104438","title":"Inhibition of FKBP51 induces stress resilience and alters hippocampal neurogenesis.","date":"2022","source":"Molecular psychiatry","url":"https://pubmed.ncbi.nlm.nih.gov/36104438","citation_count":28,"is_preprint":false},{"pmid":"27233944","id":"PMC_27233944","title":"Hsp90-binding immunophilin FKBP51 forms complexes with hTERT enhancing telomerase activity.","date":"2016","source":"Molecular oncology","url":"https://pubmed.ncbi.nlm.nih.gov/27233944","citation_count":28,"is_preprint":false},{"pmid":"25592294","id":"PMC_25592294","title":"Schizophrenia in the spectrum of gene-stress interactions: the FKBP5 example.","date":"2015","source":"Schizophrenia 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Suicide.","date":"2015","source":"Neuropsychobiology","url":"https://pubmed.ncbi.nlm.nih.gov/26630184","citation_count":26,"is_preprint":false},{"pmid":"28524179","id":"PMC_28524179","title":"A FKBP5 mutation is associated with Paget's disease of bone and enhances osteoclastogenesis.","date":"2017","source":"Experimental & molecular medicine","url":"https://pubmed.ncbi.nlm.nih.gov/28524179","citation_count":25,"is_preprint":false},{"pmid":"29535823","id":"PMC_29535823","title":"Overexpression of p54nrb/NONO induces differential EPHA6 splicing and contributes to castration-resistant prostate cancer growth.","date":"2018","source":"Oncotarget","url":"https://pubmed.ncbi.nlm.nih.gov/29535823","citation_count":25,"is_preprint":false},{"pmid":"26424511","id":"PMC_26424511","title":"Psychiatric symptoms in adolescents: FKBP5 genotype--early life adversity interaction effects.","date":"2015","source":"European child & adolescent psychiatry","url":"https://pubmed.ncbi.nlm.nih.gov/26424511","citation_count":24,"is_preprint":false},{"pmid":"35394865","id":"PMC_35394865","title":"FKBP52 and FKBP51 differentially regulate the stability of estrogen receptor in breast cancer.","date":"2022","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/35394865","citation_count":24,"is_preprint":false},{"pmid":"27493124","id":"PMC_27493124","title":"Different interactomes for p70-S6K1 and p54-S6K2 revealed by proteomic analysis.","date":"2016","source":"Proteomics","url":"https://pubmed.ncbi.nlm.nih.gov/27493124","citation_count":24,"is_preprint":false},{"pmid":"30716334","id":"PMC_30716334","title":"The Role of SurA PPIase Domains in Preventing Aggregation of the Outer-Membrane Proteins tOmpA and OmpT.","date":"2019","source":"Journal of molecular biology","url":"https://pubmed.ncbi.nlm.nih.gov/30716334","citation_count":24,"is_preprint":false},{"pmid":"34433110","id":"PMC_34433110","title":"Regulatory functions of FKBP5 intronic regions associated with psychiatric disorders.","date":"2021","source":"Journal of psychiatric research","url":"https://pubmed.ncbi.nlm.nih.gov/34433110","citation_count":23,"is_preprint":false},{"pmid":"30953930","id":"PMC_30953930","title":"Interactions between FKBP5 variation and environmental stressors in adolescent Major Depression.","date":"2019","source":"Psychoneuroendocrinology","url":"https://pubmed.ncbi.nlm.nih.gov/30953930","citation_count":23,"is_preprint":false},{"pmid":"30410676","id":"PMC_30410676","title":"Deletion of the glucocorticoid receptor chaperone FKBP51 prevents glucocorticoid-induced skin atrophy.","date":"2018","source":"Oncotarget","url":"https://pubmed.ncbi.nlm.nih.gov/30410676","citation_count":23,"is_preprint":false},{"pmid":"34079086","id":"PMC_34079086","title":"Nuclear scaffold protein p54nrb/NONO facilitates the hypoxia-enhanced progression of hepatocellular carcinoma.","date":"2021","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/34079086","citation_count":22,"is_preprint":false},{"pmid":"35263141","id":"PMC_35263141","title":"Mediobasal hypothalamic FKBP51 acts as a molecular switch linking autophagy to whole-body metabolism.","date":"2022","source":"Science advances","url":"https://pubmed.ncbi.nlm.nih.gov/35263141","citation_count":22,"is_preprint":false},{"pmid":"37952053","id":"PMC_37952053","title":"FKBP5 activates mitophagy by ablating PPAR-γ to shape a benign remyelination environment.","date":"2023","source":"Cell death & disease","url":"https://pubmed.ncbi.nlm.nih.gov/37952053","citation_count":21,"is_preprint":false},{"pmid":"33255215","id":"PMC_33255215","title":"Adverse Childhood Experiences and Methylation of the FKBP5 Gene in Patients with Psychotic Disorders.","date":"2020","source":"Journal of clinical medicine","url":"https://pubmed.ncbi.nlm.nih.gov/33255215","citation_count":21,"is_preprint":false},{"pmid":"31754722","id":"PMC_31754722","title":"Regulation of FKBP51 and FKBP52 functions by post-translational modifications.","date":"2019","source":"Biochemical Society transactions","url":"https://pubmed.ncbi.nlm.nih.gov/31754722","citation_count":20,"is_preprint":false},{"pmid":"27638035","id":"PMC_27638035","title":"Association between FKBP5 and CRHR1 genes with suicidal behavior: A systematic review.","date":"2016","source":"Behavioural brain research","url":"https://pubmed.ncbi.nlm.nih.gov/27638035","citation_count":20,"is_preprint":false},{"pmid":"37452039","id":"PMC_37452039","title":"The inhibition of FKBP5 protects β-cell survival under inflammation stress via AKT/FOXO1 signaling.","date":"2023","source":"Cell death 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stress.","date":"2017","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/28254433","citation_count":19,"is_preprint":false},{"pmid":"26468663","id":"PMC_26468663","title":"Vaccine potential of bacterial macrophage infectivity potentiator (MIP)-like peptidyl prolyl cis/trans isomerase (PPIase) proteins.","date":"2015","source":"Expert review of vaccines","url":"https://pubmed.ncbi.nlm.nih.gov/26468663","citation_count":18,"is_preprint":false},{"pmid":"32042745","id":"PMC_32042745","title":"Restoration of FKBP51 protein promotes the progression of castration resistant prostate cancer.","date":"2019","source":"Annals of translational medicine","url":"https://pubmed.ncbi.nlm.nih.gov/32042745","citation_count":18,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":48396,"output_tokens":7510,"usd":0.128919},"stage2":{"model":"claude-opus-4-6","input_tokens":11377,"output_tokens":5281,"usd":0.283365},"total_usd":0.412284,"stage1_batch_id":"msgbatch_0118RScg3WGaGkaZRtWZbtce","stage2_batch_id":"msgbatch_01Cpfzvtbj42aqp5oYZ5Te2s","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2012,\n      \"finding\": \"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.\",\n      \"method\": \"Epigenetic analysis (bisulfite sequencing/pyrosequencing of GRE-containing intronic CpG sites), chromatin interaction assays, allele-specific methylation analysis in human cohorts\",\n      \"journal\": \"Nature neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods (methylation, chromatin interaction, gene expression), replicated in human cohorts and cell lines\",\n      \"pmids\": [\"23201972\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"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.\",\n      \"method\": \"Co-immunoprecipitation, in vitro microtubule stabilization assay, PPIase activity assays with domain mutants, cell-based tau phosphorylation analysis\",\n      \"journal\": \"The Journal of neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — in vitro reconstitution with mutagenesis and multiple orthogonal assays in single study\",\n      \"pmids\": [\"20071522\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"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.\",\n      \"method\": \"NMR solution structure determination, ATPase activity assays, mass spectrometry cross-linking\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — NMR structure with functional ATPase validation, rigorous structural determination\",\n      \"pmids\": [\"30382094\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"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.\",\n      \"method\": \"Co-immunoprecipitation, Fkbp5 knockout mice, pharmacological inhibition (SAFit2), glucose uptake assays, Western blotting\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal Co-IP plus KO mouse model plus pharmacological validation, multiple orthogonal methods\",\n      \"pmids\": [\"29170369\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"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.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assays, deubiquitinase activity assays, cell proliferation assays, tumor xenograft models\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — ubiquitination reconstitution assay plus in vivo xenograft, multiple methods\",\n      \"pmids\": [\"28363942\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"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.\",\n      \"method\": \"Co-immunoprecipitation, reporter gene assays, FKBP51 knockout mouse behavioral studies, pharmacological treatments\",\n      \"journal\": \"Molecular psychiatry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal Co-IP, domain mapping, KO mouse model, behavioral validation\",\n      \"pmids\": [\"25849320\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"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.\",\n      \"method\": \"FKBP51 knockout MEFs, reporter gene assays, pharmacological p38 inhibition, phosphorylation analysis by Western blot\",\n      \"journal\": \"Molecular endocrinology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic KO with pharmacological rescue, multiple phosphorylation sites identified, orthogonal reporter and localization assays\",\n      \"pmids\": [\"24933248\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"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.\",\n      \"method\": \"FKBP51 knockout MEFs, stable knockdown in 3T3-L1 cells, lipid accumulation assays, fatty acid synthase activity, gene expression profiling, p38 inhibitor rescue\",\n      \"journal\": \"Molecular endocrinology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — KO MEF model with full mechanistic rescue, multiple assay types\",\n      \"pmids\": [\"24933247\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"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.\",\n      \"method\": \"Co-immunoprecipitation from human PTSD blood samples and mouse brain, peptide disruption experiments, fear-conditioning mouse model, behavioral assays\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal Co-IP in human samples and mice, peptide rescue with multiple molecular readouts\",\n      \"pmids\": [\"31929189\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"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.\",\n      \"method\": \"Co-immunoprecipitation, AR reporter gene assay, stable overexpression clones, Northern/Western blot\",\n      \"journal\": \"The Journal of urology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — Co-IP and functional reporter assay in single study, no domain mutagenesis\",\n      \"pmids\": [\"15821585\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"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.\",\n      \"method\": \"GST pulldown with purified calcineurin, co-immunoprecipitation from T cell lysates, calmodulin-Sepharose precipitation, deletion mutagenesis of FKBP51\",\n      \"journal\": \"Journal of cellular biochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — in vitro pulldown with purified proteins plus mutagenesis, but functional consequences of interaction not fully defined\",\n      \"pmids\": [\"11813252\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"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+.\",\n      \"method\": \"Co-immunoprecipitation, in vitro kinase assay, AAV-FKBP5 overexpression in primary neurons, Pink1 KO mouse cortical neurons, shRNA knockdown\",\n      \"journal\": \"Journal of neurochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — in vitro kinase assay plus Co-IP and genetic models, but limited mechanistic follow-through on phosphorylation site\",\n      \"pmids\": [\"30734931\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"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.\",\n      \"method\": \"Co-immunoprecipitation, siRNA knockdown, SAFit2 pharmacological inhibition, autophagic flux assays, in vivo SAFit2 treatment of HD mouse models\",\n      \"journal\": \"Autophagy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — Co-IP, genetic, and pharmacological approaches with autophagy flux readouts, replicated in vivo\",\n      \"pmids\": [\"34024231\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"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.\",\n      \"method\": \"Mass spectrometry-based metabolomics, Co-immunoprecipitation, MBH-specific viral vector knockout/overexpression in mice, high-fat diet models\",\n      \"journal\": \"Science advances\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — MS-identified protein-protein interactions confirmed by Co-IP, region-specific in vivo manipulation with defined metabolic phenotypes\",\n      \"pmids\": [\"35263141\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"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.\",\n      \"method\": \"Cardiomyocyte-specific knockdown mouse model, intracardiac programmed stimulation, Co-immunoprecipitation, optical mapping, cellular electrophysiology, 17-AAG rescue experiments\",\n      \"journal\": \"Circulation research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — tissue-specific KD mouse with mechanistic rescue by Hsp90 inhibitor, multiple orthogonal methods\",\n      \"pmids\": [\"37154033\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"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.\",\n      \"method\": \"Co-immunoprecipitation of FKBP51-PR from human decidual cells, Fkbp5 knockout mouse restraint-stress model, immunohistochemistry, gene expression analysis\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — Co-IP from human tissue plus complete genetic rescue in KO mouse model, mechanistic pathway defined\",\n      \"pmids\": [\"33836562\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"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.\",\n      \"method\": \"Biotinylated-oligonucleotide immunoprecipitation, pharmacological MR inhibition, region- and cell-type-specific MR/GR deletion mouse models\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — direct chromatin binding assay plus region-specific genetic deletion with physiological readouts\",\n      \"pmids\": [\"34077736\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"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.\",\n      \"method\": \"Co-immunoprecipitation with anti-FKBP51 antibodies, siRNA knockdown, NF-κB nuclear translocation assay, cytokine secretion assays\",\n      \"journal\": \"European journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — single Co-IP confirming complex, supported by functional knockdown with defined readouts\",\n      \"pmids\": [\"30169894\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"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.\",\n      \"method\": \"FKBP5 knockout cells, Co-immunoprecipitation, IAV infection assays, NF-κB reporter assays\",\n      \"journal\": \"Viruses\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — KO phenotype with Co-IP, single study\",\n      \"pmids\": [\"32580383\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"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.\",\n      \"method\": \"In vitro protein fluorescence titration, CETSA, molecular docking, site-directed mutagenesis (Y113A), NF-κB pathway assays, CCI mouse model\",\n      \"journal\": \"Brain, behavior, and immunity\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct binding assay with mutagenesis validation and functional NF-κB readouts, single study\",\n      \"pmids\": [\"37196785\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"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.\",\n      \"method\": \"Co-immunoprecipitation and mass spectrometry, RhoA activity assays, F-actin imaging, Boyden chamber invasion assays, siRNA knockdown and overexpression\",\n      \"journal\": \"Cancer science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — MS-identified partners confirmed by Co-IP, RhoA activity assays, functional KD/OE phenotypes, single study\",\n      \"pmids\": [\"28032931\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"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.\",\n      \"method\": \"Luciferase reporter assay, RNA pulldown assay, miR-511 overexpression in cells and primary neurons, in silico target prediction\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct 3'-UTR binding confirmed by luciferase and RNA pulldown, functional validation in primary neurons\",\n      \"pmids\": [\"27334923\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"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.\",\n      \"method\": \"Co-immunoprecipitation, telomerase activity assay (TRAP), Hsp90 inhibitor treatment, confocal microscopy\",\n      \"journal\": \"Molecular oncology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — Co-IP with functional telomerase activity readout, localization study, single lab\",\n      \"pmids\": [\"27233944\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"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.\",\n      \"method\": \"X-ray crystallography (6 crystal structures), competitive binding assays, medicinal chemistry\",\n      \"journal\": \"Journal of medicinal chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — multiple crystal structures with functional selectivity validation\",\n      \"pmids\": [\"33666419\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"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.\",\n      \"method\": \"Fkbp5 knockout mice, electrophysiology (LTP, mEPSC, mIPSC recording), Western blot for receptor expression, GABA quantification\",\n      \"journal\": \"Neuroscience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — KO mouse with electrophysiological and molecular readouts, defined cellular phenotype\",\n      \"pmids\": [\"30685540\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"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.\",\n      \"method\": \"Fkbp5 knockout mouse cuprizone demyelination model, mitophagy assays, PPAR-γ expression analysis, Co-immunoprecipitation\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — KO mouse phenotype with mechanistic proposal but limited direct biochemical evidence for FKBP5-PPAR-γ interaction\",\n      \"pmids\": [\"37952053\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"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.\",\n      \"method\": \"Whole-exome sequencing, FKBP51V55L knock-in transgenic mice, osteoclast differentiation assays, AKT phosphorylation assays, micro-CT\",\n      \"journal\": \"Experimental & molecular medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — knock-in mouse model with defined cellular phenotype and AKT signaling mechanism, single study\",\n      \"pmids\": [\"28524179\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"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.\",\n      \"method\": \"siRNA knockdown of FKBP51/FKBP52, Western blot for ERα protein levels, breast cancer cell proliferation assays\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — functional KD with defined protein stability readout, but mechanism of destabilization not fully characterized, single study\",\n      \"pmids\": [\"35394865\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"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.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay, siRNA/overexpression functional assays, tumor xenograft model\",\n      \"journal\": \"Molecular carcinogenesis\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — Co-IP and ubiquitination assay with in vivo tumor model, single study\",\n      \"pmids\": [\"32511815\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"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.\",\n      \"method\": \"siRNA knockdown, SAFit2 pharmacological inhibition, human and mouse primary islets, FOXO1 rescue experiments, Western blotting for pFOXO1(S256)\",\n      \"journal\": \"Cell death discovery\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — genetic and pharmacological approaches with epistasis rescue experiment in primary human islets\",\n      \"pmids\": [\"37452039\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"FKBP51 (encoded by FKBP5) is an Hsp90 co-chaperone with PPIase activity that acts as a multifunctional scaffolding protein: it inhibits glucocorticoid receptor (GR) sensitivity via the Hsp90 receptor-chaperone complex (forming an ultrashort negative-feedback loop with GR), regulates AKT signaling by facilitating PHLPP-mediated dephosphorylation of AKT (and is stabilized by deubiquitinases USP49/USP53), modulates tau phosphorylation and microtubule stability through its PPIase domain within Hsp90/FKBP51/Tau ternary complexes, controls NF-κB activation by scaffolding the IKK complex, regulates adipogenesis and metabolic homeostasis via the Akt-p38-PPARγ/GRα axis and autophagy through LKB1/AMPK/WIPI complexes, and undergoes allele-specific, stress-dependent epigenetic regulation through DNA demethylation at intronic glucocorticoid response elements.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"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].\",\n  \"teleology\": [\n    {\n      \"year\": 2002,\n      \"claim\": \"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.\",\n      \"evidence\": \"GST pulldown with purified calcineurin, Co-IP from T cells, deletion mutagenesis\",\n      \"pmids\": [\"11813252\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional consequence of calcineurin–FKBP51 interaction on NFAT or calcineurin phosphatase activity not defined\", \"No in vivo validation\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"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.\",\n      \"evidence\": \"Co-IP, in vitro microtubule stabilization, PPIase domain mutant analysis, tau phosphorylation assays\",\n      \"pmids\": [\"20071522\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"In vivo tauopathy phenotype of FKBP5 manipulation not yet shown in this study\", \"Structural basis of tau recognition by the PPIase pocket unknown\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"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.\",\n      \"evidence\": \"Co-IP, AR reporter assay, stable overexpression in LNCaP cells\",\n      \"pmids\": [\"15821585\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Domain requirements for AR interaction not mapped\", \"No reciprocal Co-IP or in vivo confirmation\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"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.\",\n      \"evidence\": \"Bisulfite sequencing, chromatin interaction assays, allele-specific methylation in human cohorts and cell lines\",\n      \"pmids\": [\"23201972\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether demethylation is reversible in adulthood not established\", \"Causal chain from demethylation to psychiatric disease phenotype not fully delineated\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"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.\",\n      \"evidence\": \"FKBP51 KO MEFs, 3T3-L1 knockdown, lipid accumulation, p38 inhibitor rescue, phosphorylation analysis\",\n      \"pmids\": [\"24933247\", \"24933248\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"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\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"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.\",\n      \"evidence\": \"Co-IP with domain mapping, reporter assays, FKBP51 KO mouse behavioral studies, pharmacological lithium/paroxetine challenge\",\n      \"pmids\": [\"25849320\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct versus Hsp90-scaffolded interaction with GSK3β not resolved\", \"Downstream tau phosphorylation effects in tauopathy models not tested\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"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.\",\n      \"evidence\": \"Co-IP, TRAP telomerase activity assay, Hsp90 inhibitor disruption, confocal microscopy\",\n      \"pmids\": [\"27233944\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Physiological relevance for telomere length maintenance in vivo not demonstrated\", \"Whether PPIase activity is involved not tested\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"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.\",\n      \"evidence\": \"Ubiquitination reconstitution, Co-IP, deubiquitinase assays, xenograft tumor models\",\n      \"pmids\": [\"28363942\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Identity of the E3 ubiquitin ligase targeting FKBP51 unknown\", \"Whether USP49-FKBP51 axis operates in non-cancer contexts unclear\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"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.\",\n      \"evidence\": \"Co-IP, Fkbp5 KO mice, SAFit2 treatment, glucose uptake assays in skeletal myotubes\",\n      \"pmids\": [\"29170369\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether FKBP51-AS160 interaction is direct or Hsp90-mediated not resolved\", \"Systemic glucose homeostasis phenotype in whole-body KO not fully characterized\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"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.\",\n      \"evidence\": \"Whole-exome sequencing, V55L knock-in mice, osteoclast differentiation assays, micro-CT\",\n      \"pmids\": [\"28524179\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Structural consequence of V55L on PHLPP scaffolding not defined\", \"Single pedigree; broader genetic replication lacking\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"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.\",\n      \"evidence\": \"NMR solution structure, ATPase activity assays, XL-MS cross-linking\",\n      \"pmids\": [\"30382094\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How phosphorylation of specific tau sites alters ternary complex conformation not fully mapped\", \"No structure of FKBP51 with GR client bound\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"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.\",\n      \"evidence\": \"Co-IP, siRNA knockdown, NF-κB nuclear translocation and cytokine assays\",\n      \"pmids\": [\"30169894\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether FKBP51 binds IKK directly or through Hsp90 not resolved\", \"Single Co-IP without reciprocal validation for IKK interaction\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"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.\",\n      \"evidence\": \"In vitro kinase assay, Co-IP, PINK1 KO neurons, shRNA knockdown\",\n      \"pmids\": [\"30734931\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Exact phosphorylation site on FKBP51 not identified\", \"In vivo dopaminergic neuron phenotype not characterized\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"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.\",\n      \"evidence\": \"Co-IP from human PTSD blood and mouse brain, peptide disruption, fear-conditioning behavioral assays\",\n      \"pmids\": [\"31929189\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Peptide pharmacokinetics and selectivity in vivo not fully characterized\", \"Whether complex disruption affects other FKBP51 client interactions unknown\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"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.\",\n      \"evidence\": \"Co-IP of FKBP51-PR from human decidua, Fkbp5 KO restraint-stress mouse model\",\n      \"pmids\": [\"33836562\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether FKBP51 PPIase activity or TPR domain mediates PR inhibition not defined\", \"Human genetic association with preterm birth not established\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"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.\",\n      \"evidence\": \"Biotinylated-oligonucleotide IP, pharmacological MR inhibition, cell-type-specific MR/GR deletion mice\",\n      \"pmids\": [\"34077736\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether MR and GR bind the same or distinct regulatory elements not resolved\", \"Interaction with the epigenetic demethylation mechanism at rs1360780 not tested\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"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.\",\n      \"evidence\": \"Co-IP, siRNA, SAFit2 treatment, autophagic flux assays, HD mouse models\",\n      \"pmids\": [\"34024231\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"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\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"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.\",\n      \"evidence\": \"MS-based interactomics, Co-IP, MBH-specific viral KO/OE in mice, HFD models\",\n      \"pmids\": [\"35263141\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether the LKB1/AMPK/WIPI scaffolding function operates outside hypothalamus not tested\", \"Direct structural evidence for the multiprotein assembly lacking\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"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.\",\n      \"evidence\": \"Cardiomyocyte-specific KD mice, intracardiac stimulation, Co-IP, optical mapping, 17-AAG rescue\",\n      \"pmids\": [\"37154033\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"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\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"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.\",\n      \"evidence\": \"Protein fluorescence titration, CETSA, Y113A mutagenesis, NF-κB pathway assays, CCI mouse model\",\n      \"pmids\": [\"37196785\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"CBD selectivity for FKBP51 over FKBP52 not established\", \"Whether CBD binding affects other FKBP51 functions (GR, AKT) not tested\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"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.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"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\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [4, 6, 7, 8, 15, 27, 28]},\n      {\"term_id\": \"GO:0044183\", \"supporting_discovery_ids\": [1, 2, 9, 14, 22]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [3, 4, 13, 17, 18, 28]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [3, 4, 17]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [8, 15, 22]},\n      {\"term_id\": \"GO:0005739\", \"supporting_discovery_ids\": [22]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [3, 4, 5, 6, 8, 11, 26, 28, 29]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [17, 18, 19]},\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [12, 13]},\n      {\"term_id\": \"R-HSA-8953897\", \"supporting_discovery_ids\": [0, 14, 16]},\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [3, 7, 29]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [4, 28]}\n    ],\n    \"complexes\": [\n      \"Hsp90-FKBP51-GR co-chaperone complex\",\n      \"Hsp90-FKBP51-Tau ternary complex\",\n      \"FKBP51-PHLPP-AKT scaffold complex\",\n      \"FKBP51-LKB1-AMPK-WIPI autophagy complex\"\n    ],\n    \"partners\": [\n      \"HSP90AA1\",\n      \"NR3C1\",\n      \"PHLPP1\",\n      \"AKT1\",\n      \"GSK3B\",\n      \"CHUK\",\n      \"TBC1D4\",\n      \"PGR\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}