{"gene":"FKBP4","run_date":"2026-06-09T23:54:43","timeline":{"discoveries":[{"year":1992,"finding":"FKBP52 (FKBP59) possesses peptidyl-prolyl cis-trans isomerase (PPIase) activity inhibited by FK506 and rapamycin, and associates with hsp90 in untransformed mammalian steroid receptor complexes. The immunosuppressant-binding site is distinct from the hsp90-binding site, implying separate structural domains.","method":"Recombinant protein expression in E. coli, PPIase enzymatic assay, co-immunoprecipitation with hsp90","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1 / Strong — direct enzymatic assay for PPIase activity, inhibition by FK506/rapamycin, co-IP with hsp90, replicated across multiple labs","pmids":["1279700"],"is_preprint":false},{"year":1992,"finding":"Rabbit FKBP52 (FKBP59-HBI) binds calmodulin in a Ca2+-dependent manner, retained on calmodulin-Sepharose in 2 mM Ca2+ and eluted by EGTA; it is also a substrate for calpain II, a Ca2+-activated protease.","method":"Calmodulin-Sepharose affinity chromatography, in vitro proteolysis assay","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — single affinity chromatography experiment replicated with proteolysis assay, single lab","pmids":["1384470"],"is_preprint":false},{"year":1993,"finding":"The PPIase activity of FKBP52 (p59-HBI) resides entirely in its N-terminal domain (domain I), which has the highest homology to FKBP12; a second domain (domain II) shows residual enzymatic activity.","method":"Overexpression of domain deletion mutants in E. coli, PPIase activity assay","journal":"Biochemical and biophysical research communications","confidence":"High","confidence_rationale":"Tier 1 / Moderate — direct enzymatic domain mapping with deletion mutants, single lab with multiple constructs","pmids":["8216288"],"is_preprint":false},{"year":1993,"finding":"The tetratricopeptide repeat (TPR) domain of FKBP52 (p59, FKBP59) is proposed to mediate protein-protein interactions including hsp90 binding; this was supported by identification of a conserved TPR domain in the estrogen receptor-binding cyclophilin (ERBC/CyP40).","method":"Affinity chromatography, sequence homology analysis, protein identification from estrogen receptor complex","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — biochemical isolation plus sequence analysis, convergent evidence from related protein","pmids":["8514757"],"is_preprint":false},{"year":1993,"finding":"Recombinant mouse FKBP52 can be assembled in vitro with the glucocorticoid receptor complex, confirming it is a functional component of the unactivated GR heterocomplex; it also possesses ATP/GTP binding activity stimulated by divalent cations.","method":"Baculovirus expression, in vitro assembly assay with glucocorticoid receptor, ATP binding assay","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vitro reconstitution of GR complex, direct ATP binding assay, single lab","pmids":["8341706"],"is_preprint":false},{"year":1994,"finding":"The TPR domain located in the C-terminal part of FKBP52 (FKBP59-HBI) is necessary for hsp90 binding; this interaction is ATP-independent and not affected by FK506 or rapamycin.","method":"Gel-retardation assay with purified proteins, deletion mutant analysis","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1 / Moderate — purified protein reconstitution with multiple mutants mapped to TPR domain, single lab with rigorous controls","pmids":["7526392"],"is_preprint":false},{"year":1996,"finding":"FKBP52 competes with cyclophilin 40 (CyP40) for hsp90 binding, leading to mutually exclusive immunophilin-hsp90-receptor complexes; the TPR domain alone is not sufficient for stable hsp90 association—flanking acidic and basic residues are also required.","method":"GST-fusion deletion mutant pulldown, competition assay with myometrial cytosol","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal competition assay with purified fragments, single lab","pmids":["8621687"],"is_preprint":false},{"year":1996,"finding":"NMR structure of the N-terminal immunophilin domain of FKBP52 (FKBP59-I, residues 1–149) was determined; it adopts a twisted antiparallel beta-sheet and short alpha-helix, globally similar to FKBP12, with an unusual Trp89–Phe129 hydrogen bond important for immunosuppressant binding.","method":"Multidimensional NMR spectroscopy, distance geometry, molecular dynamics","journal":"Biochemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — solution NMR structure determined with 1290 restraints; replicated by later X-ray structure","pmids":["8780506"],"is_preprint":false},{"year":1997,"finding":"Casein kinase II (CK2) phosphorylates FKBP52 at Thr-143 in the hinge I region both in vitro and in vivo; CK2-phosphorylated FKBP52 fails to bind hsp90, revealing phosphorylation as a mechanism to regulate chaperone complex composition.","method":"In vitro kinase assay with purified CK2, deletion mutant mapping, [32P] in vivo labeling, hsp90 binding assay","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1 / Strong — site-specific phosphorylation mapped by mutagenesis, confirmed in vivo, functional consequence (hsp90 binding lost) demonstrated","pmids":["9405642"],"is_preprint":false},{"year":1998,"finding":"The TPR domain of FKBP52 requires appropriate downstream C-terminal sequences for hsp90 binding; unlike FKBP51, FKBP52's TPR domain does not require specific C-terminal sequences beyond the core TPR for hsp90 binding. FKBP52 and FKBP51 associate differentially with steroid receptors based on the TPR domain and poorly-conserved C-terminal sequences.","method":"Deletion mutant and chimera co-precipitation with hsp90, steroid receptor association assays","journal":"Molecular endocrinology","confidence":"High","confidence_rationale":"Tier 2 / Strong — systematic mutagenesis with chimeric constructs, multiple receptor and hsp90 binding assays, replicated concept in later papers","pmids":["9514152"],"is_preprint":false},{"year":1998,"finding":"Hsp90 C-terminal EEVD motif is critical for interaction with TPR cochaperones including FKBP52; p23 binding maps to the N-terminal ATP-binding domain of Hsp90; deletion of Hsp90 residues 661–677 abolishes dimerization and reduces all accessory protein interactions.","method":"Co-precipitation of Hsp90 mutants with cochaperones including FKBP52","journal":"Cell stress & chaperones","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — systematic Hsp90 mutant panel mapped binding sites, single lab","pmids":["9672247"],"is_preprint":false},{"year":1999,"finding":"FKBP52 has one binding site per hsp90 dimer (cross-linking). The PPIase domain of FKBP52 mediates binding to cytoplasmic dynein (competed by PPIase fragment, not TPR fragment). FKBP52 also binds directly to the hsp90-free glucocorticoid receptor via a region distinct from both the PPIase and TPR domains.","method":"Chemical cross-linking of purified proteins, co-immunoadsorption from reticulocyte lysate, competitive inhibition with domain fragments","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — purified protein cross-linking, domain-specific competition assays, multiple orthogonal methods in one study","pmids":["10601253"],"is_preprint":false},{"year":2000,"finding":"FKBP52 interacts with interferon regulatory factor-4 (IRF-4), inhibiting IRF-4–PU.1 binding to the immunoglobulin light chain enhancer and IRF-4–PU.1 transactivation; this inhibition requires functional PPIase activity of FKBP52 and induces a detectable structural modification of IRF-4.","method":"Co-immunoprecipitation, transcriptional reporter assay, partial proteolysis analysis, PPIase-inactive mutant","journal":"Immunity","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP, functional reporter, conformational assay, single lab","pmids":["10714679"],"is_preprint":false},{"year":2001,"finding":"The PPIase domain of FKBP52 links the GR-hsp90 heterocomplex to cytoplasmic dynein and is required for hormone-induced retrograde transport of the GFP-GR along microtubules to the nucleus; FKBP12 overexpression does not affect GFP-GR movement.","method":"Cotransfection with PPIase domain fragment, live-cell GFP-GR imaging, colcemid microtubule disruption, co-immunoadsorption from cytosol","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — live imaging plus biochemical co-IP, microtubule disruption confirms mechanism, replicated concept across papers","pmids":["11278753"],"is_preprint":false},{"year":2001,"finding":"Hormone binding to the GR induces substitution of FKBP51 by FKBP52 in the GR-hsp90 heterocomplex and concomitant recruitment of dynein, while hsp90 remains; the resulting GR-hsp90-FKBP52-dynein complex translocates from cytoplasm to nucleus before complex dissociation and conversion to DNA-binding form.","method":"Immunofluorescence, subcellular fractionation, co-immunoprecipitation in hormone-treated cells","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (IF, fractionation, Co-IP), identifies ordered molecular event, replicated in subsequent papers","pmids":["11751894"],"is_preprint":false},{"year":2001,"finding":"FKBP52 chaperone activity resides in the C-terminal region (amino acids 264–400, domain 3, which overlaps with the TPR domain), while PPIase activity is confined to domain 1 (amino acids 1–148); the chaperone and hsp90-binding regions within domain 3 are distinct.","method":"Domain fragment expression, PPIase assay, chaperone aggregation assay, competition with Hsp90 C-terminal peptide","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — direct enzymatic assay plus chaperone assay with domain fragments and competition experiment, single lab","pmids":["11473108"],"is_preprint":false},{"year":2001,"finding":"In the yeast model, FKBP52 is the only immunophilin that potentiates GR hormone-dependent transactivation (up to 20-fold at limiting hormone); this requires both Hsp90-binding ability and PPIase activity of FKBP52, and works by increasing GR hormone-binding affinity.","method":"Saccharomyces cerevisiae reporter gene assay, FKBP52 mutant analysis (PPIase-dead and TPR-dead mutants)","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo yeast model with defined mutants, hormone-binding affinity measured, replicated in mammalian cells","pmids":["12606580"],"is_preprint":false},{"year":2001,"finding":"FKBP52 (dFKBP59) interacts directly with Drosophila TRPL Ca2+-permeable channels and with the scaffold protein INAD; expression of dFKBP59 inhibits Ca2+ influx through TRPL channels; mutations of conserved proline residues in TRPL (P702Q, P709Q) abolish interaction with dFKBP59.","method":"Yeast two-hybrid, co-immunoprecipitation in Sf9 and fly cells, electrophysiology (inside-out patch), fura-2 Ca2+ assay, site-directed mutagenesis","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — reconstitution in Sf9 cells, patch-clamp electrophysiology, site-directed mutagenesis of channel, multiple orthogonal methods","pmids":["11514552"],"is_preprint":false},{"year":2001,"finding":"Two PPIase monomers bind to one Hsp90 dimer; FKBP52 has the strongest affinity for Hsp90 among the three mammalian large PPIases (vs. FKBP51 and CyP40); catalytic prolyl isomerase activity of FKBP52 corresponds to that of the small immunophilin FKBP12.","method":"In vitro binding assay with purified proteins, enzymatic PPIase assay","journal":"Journal of molecular biology","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — purified protein binding and enzymatic assays, single lab","pmids":["11350175"],"is_preprint":false},{"year":2002,"finding":"Crystal structure of the N-terminal FK506-binding domain of human FKBP52 (residues 1–140) solved at 2.4 Å; reveals six-stranded antiparallel beta-sheet plus alpha-helix similar to FKBP12; Pro120 and Lys121 explain reduced FK506 affinity and inability to activate calcineurin compared with FKBP12.","method":"X-ray crystallography, molecular replacement","journal":"Acta crystallographica. Section D, Biological crystallography","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structure at 2.4 Å with structural interpretation of functional differences","pmids":["12499534"],"is_preprint":false},{"year":2003,"finding":"C-terminal sequences outside the core TPR domain (residues ~400–420 and the final 30 amino acids) of FKBP51 and FKBP52 differentially regulate hsp90 binding; the final 30 residues of FKBP51 enhance hsp90 binding while the corresponding region of FKBP52 moderates it.","method":"Truncation mutant and chimera co-immunoprecipitation with Hsp90","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — systematic truncation/chimera panel, single lab, Co-IP","pmids":["12611898"],"is_preprint":false},{"year":2004,"finding":"FKBP52 PPIase domain I directly interacts with the copper metallochaperone Atox1; the interaction is enhanced by copper supplementation and decreased by copper chelation; FKBP52 overexpression increases rapid copper efflux in cells, implicating it in the copper efflux machinery.","method":"Yeast two-hybrid, GST pulldown, co-immunoprecipitation, 64Cu efflux assay","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — yeast two-hybrid confirmed by pulldown and Co-IP, functional efflux assay, single lab","pmids":["15133031"],"is_preprint":false},{"year":2005,"finding":"FKBP52 is a critical cochaperone for progesterone receptor (PR) in the uterus; Fkbp52-knockout female mice show complete implantation failure due to reduced P4 binding to PR, attenuated PR transcriptional activity, and down-regulation of P4-regulated genes—demonstrating tissue-specific regulation of hormone action.","method":"Fkbp52 knockout mice, hormone binding assay, PR transcriptional reporter, gene expression analysis, uterine fractionation","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 / Strong — knockout mouse phenotype with multiple molecular readouts (hormone binding, transcription, gene expression), replicated in subsequent studies","pmids":["16176985"],"is_preprint":false},{"year":2005,"finding":"FKBP52 is required for androgen receptor (AR) signaling in specific male reproductive tissues; FKBP52 is a component of AR complexes and enhances AR-mediated transactivation in a manner requiring both PPIase activity and Hsp90-binding ability; FKBP52 can restore function of a minimally active AR point mutant.","method":"Fkbp52 knockout mice, yeast and mammalian cell reporter assays, FKBP52 mutant analysis, co-IP of AR complexes","journal":"Molecular endocrinology","confidence":"High","confidence_rationale":"Tier 2 / Strong — knockout mouse plus multiple in vitro assays with defined mutants, replicated across models","pmids":["15831525"],"is_preprint":false},{"year":2005,"finding":"FKBP52 inhibits TRPV5 channel activity via its PPIase domain; FKBP52 co-localizes with and specifically interacts with TRPV5 in the distal nephron; PPIase-inactive mutant of FKBP52 loses the inhibitory effect on TRPV5.","method":"Co-immunoprecipitation, 45Ca2+ uptake, patch-clamp electrophysiology, PPIase domain mutant, siRNA knockdown","journal":"American journal of physiology. Renal physiology","confidence":"High","confidence_rationale":"Tier 1 / Moderate — electrophysiology plus Co-IP and mutagenesis, multiple methods in one study, single lab","pmids":["16352746"],"is_preprint":false},{"year":2006,"finding":"FKBP52 facilitates intracellular trafficking of AAV vectors toward the nucleus via interaction with dynein; FKBP52-knockout MEFs show impaired nuclear accumulation of AAV genomes that is restored upon FKBP52 re-expression; intact AAV particles interact with both FKBP52 and dynein.","method":"Knockout MEF cells, self-complementary AAV transduction, nuclear fractionation, co-immunoprecipitation, FKBP52 rescue expression","journal":"Virology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — knockout plus rescue plus Co-IP, single lab","pmids":["16828834"],"is_preprint":false},{"year":2006,"finding":"Fkbp52 knockout specifically reduces AR transcriptional activity in mouse embryonic fibroblasts; chromatin immunoprecipitation shows normal AR occupancy at gene promoters in knockout cells, indicating FKBP52 controls a downstream step in AR transactivation rather than DNA binding.","method":"Fkbp52 knockout mouse, mouse embryonic fibroblasts, reporter assays, chromatin immunoprecipitation, hormone binding assay","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple molecular assays in knockout cells, ChIP identifies step downstream of DNA binding, single lab with comprehensive controls","pmids":["17142810"],"is_preprint":false},{"year":2007,"finding":"The FK1 domain loop residue Pro119 (vs. Leu119 in FKBP51) is the critical determinant distinguishing FKBP52's ability to potentiate steroid receptor activity from FKBP51; PPIase catalytic activity is NOT required for potentiation, as PPIase-dead mutants still potentiate; the proline-rich loop overhanging the catalytic pocket is the functionally important receptor-interaction surface.","method":"Yeast genetic screen of randomly mutated FKBP51, site-directed mutagenesis, mammalian cell reporter assay","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 1 / Strong — unbiased genetic screen combined with reciprocal mutagenesis in two cell systems; PPIase independence confirmed by catalytic-dead mutant","pmids":["17938211"],"is_preprint":false},{"year":2007,"finding":"FKBP52 directly and specifically binds tubulin; the TPR-containing region (aa 267–400) is required for tubulin binding; a C-terminal sequence (aa 375–458) is necessary and sufficient for microtubule depolymerization activity; FKBP52 prevents tubulin polymerization in vitro.","method":"Direct binding assay with purified proteins, domain deletion analysis, tubulin polymerization assay, co-localization in PC12 cells, siRNA knockdown","journal":"FASEB journal","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro polymerization assay with purified proteins, domain mapping by deletion, co-localization and siRNA in cells, single lab","pmids":["17435176"],"is_preprint":false},{"year":2009,"finding":"FKBP52 links the mineralocorticoid receptor (MR)-hsp90 complex to dynein/dynactin motors for cytoplasmic-to-nuclear transport; replacement of FKBP52 by FKBP51 or TPR peptide favors cytoplasmic MR retention; the intact MR-hsp90 heterocomplex transits the nuclear pore undissociated.","method":"Immunofluorescence, fractionation, cross-linking of MR-hsp90 complexes, microtubule stabilization/reassembly assay on stripped MR immune pellets","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (fractionation, cross-linking, live reconstitution of motor complex), single lab with rigorous controls","pmids":["20038533"],"is_preprint":false},{"year":2009,"finding":"FKBP52 mediates stimulus-dependent gating of TRPC1 channels via cis/trans isomerization of proline residues in TRPC1; this is required for chemotropic turning of neuronal growth cones to netrin-1 and for netrin-1/DCC-dependent midline axon guidance in the spinal cord. FKBP12 mediates spontaneous (not stimulus-dependent) TRPC1 opening.","method":"Biochemical PPIase assay on TRPC1 peptides, dominant-negative FKBP52 expression, axon guidance assays in vitro and in vivo (mouse spinal cord)","journal":"Neuron","confidence":"High","confidence_rationale":"Tier 1 / Strong — direct isomerization assay, loss-of-function with dominant-negative, in vivo axon guidance phenotype, multiple orthogonal methods","pmids":["19945390"],"is_preprint":false},{"year":2010,"finding":"FKBP52 binds directly and specifically to Tau (preferentially its hyperphosphorylated form); FKBP52 antagonizes Tau-mediated microtubule assembly; FKBP52 overexpression in differentiated PC12 cells reduces neurite length and decreases Tau accumulation.","method":"Direct binding assay with purified proteins, microtubule assembly assay, co-localization in cortical neurons, PC12 overexpression, quantitative neurite length measurement","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1 / Strong — direct binding with purified proteins, in vitro microtubule assay, cellular overexpression phenotype, co-localization in primary neurons","pmids":["20133804"],"is_preprint":false},{"year":2011,"finding":"FKBP52 favors nuclear retention of RelA/NF-κB, enhances its association with DNA consensus sequences, and increases NF-κB transcriptional activity; these effects require FKBP52 PPIase activity and TPR domain but not Hsp90 interaction. Upon stimulation, NF-κB complex exchanges FKBP51 for FKBP52 (analogous to steroid receptor switching). FKBP52 is functionally recruited to promoters of NF-κB target genes.","method":"Reporter gene assay, Co-IP with purified proteins, EMSA, ChIP, siRNA knockdown","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (Co-IP, EMSA, ChIP, reporter), PPIase and domain requirements mapped by mutagenesis, single lab","pmids":["25104352"],"is_preprint":false},{"year":2011,"finding":"Hsp90 can simultaneously accommodate FKBP52 and HOP, forming stable Hsp90(2)-FKBP52(1)-HOP(2) and Hsp90(2)-FKBP52(1)-p23(2)-HOP(2) complexes.","method":"Co-immunoprecipitation, dynamic light scattering, electron microscopy","journal":"Oncotarget","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — three orthogonal methods for complex detection, single lab","pmids":["21378414"],"is_preprint":false},{"year":2011,"finding":"MJC13, a small molecule inhibitor, blocks FKBP52-enhanced AR function by preventing hormone-dependent dissociation of the Hsp90-FKBP52-AR complex, leading to less hormone-bound receptor in the nucleus and inhibiting AR-dependent gene expression and prostate cancer cell proliferation.","method":"Yeast reporter assay screen, co-immunoprecipitation, nuclear fractionation, qPCR of AR target genes, cell proliferation assay","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 / Strong — mechanistic assay identifying complex dissociation step, multiple cell models, single lab with comprehensive follow-up","pmids":["21730179"],"is_preprint":false},{"year":2013,"finding":"FKBP52 (FKBP52/Fkbp4) physically associates with Argonaute2 (hAgo2); FK506 treatment or siRNA depletion of Fkbp4/5 decreases Ago2 protein levels and impairs miRNA-mediated silencing; FKBP4 overexpression promotes miRNA-mediated Ago2 stabilization; unloaded Ago2 accumulates in FK506-treated cells.","method":"Co-immunoprecipitation (FKBP4-hAgo2), siRNA depletion, FK506 pharmacological inhibition, lysosome inhibitor rescue, miRNA reporter assay","journal":"RNA (New York, N.Y.)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP plus functional reporter and pharmacological/genetic depletion, single lab","pmids":["24049110"],"is_preprint":false},{"year":2013,"finding":"FKBP4 (FKBP52) and p23 form a stable complex with hAgo2 and are required for efficient RNAi/RISC loading; the interaction occurs before small RNA loading and in the cytoplasm; depletion of FKBP4 or pharmacological disruption with FK506 reduces Ago2 levels and impairs RNAi.","method":"Co-immunoprecipitation, siRNA depletion, FK506 treatment, luciferase reporter silencing assay","journal":"Molecular biology of the cell","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct Co-IP of FKBP4 with hAgo2, functional RISC assay, single lab","pmids":["23741051"],"is_preprint":false},{"year":2014,"finding":"FKBP52 directly interacts with Tau-P301L (pathological mutant) and induces formation of Tau-P301L oligomers and filaments in vitro; FKBP52 knockdown in Tau-P301L transgenic zebrafish rescues defective axonal outgrowth and branching, and reduces pT181 phospho-Tau.","method":"Direct binding assay, EM analysis of oligomers/filaments, zebrafish Tau-P301L transgenic model with FKBP52 knockdown","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro assembly assay with purified proteins plus in vivo zebrafish model with genetic knockdown, EM validation of aggregates","pmids":["24623856"],"is_preprint":false},{"year":2014,"finding":"The FK1 domain of FKBP52 physically interacts with the glucocorticoid receptor (GR) as demonstrated by bimolecular fluorescence complementation and proximity ligation assays; this interaction is part of the FKBP52-dependent suppression of TDO expression in glioblastoma cells.","method":"Bimolecular fluorescence complementation, in situ proximity ligation assay, siRNA knockdown of FKBP52, TDO activity assay","journal":"Glia","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — two complementary protein interaction methods, single lab with functional outcome","pmids":["25132599"],"is_preprint":false},{"year":2015,"finding":"FKBP52 induces aggregation of Tau-F4 fragment (Ser208–Ser324) into oligomers and filaments with prion-like seeding capacity; FKBP52-induced Tau-F4 oligomers can transfer conformational changes to full-length Tau in cells and seed aggregation of endogenous Tau in neuroblastoma cells.","method":"Light-scattering assay, blue native PAGE, electron microscopy, microtubule assembly assay, seeding in SH-SY5Y cells","journal":"FASEB journal","confidence":"High","confidence_rationale":"Tier 1 / Strong — multiple orthogonal in vitro assays plus cellular seeding experiment, EM structural validation of aggregates","pmids":["25888602"],"is_preprint":false},{"year":2016,"finding":"FKBP52 links the hTERT-Hsp90 complex to the dynein-dynactin motor via binding of the TPR domain to Hsp90 and the PPIase domain to dynamitin (Dyt); FKBP52 depletion inhibits hTERT nuclear transport and causes cytoplasmic accumulation and ubiquitin-dependent degradation of hTERT, abrogating telomerase activity.","method":"Co-immunoprecipitation, siRNA knockdown, nuclear/cytoplasmic fractionation, telomerase activity assay, dynamitin overexpression","journal":"The Biochemical journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP mapping to specific domains, functional readout via telomerase assay, siRNA depletion, single lab","pmids":["27503910"],"is_preprint":false},{"year":2016,"finding":"FKBP52's capacity to oligomerize Tau is independent of its PPIase catalytic activity (PPIase-dead mutant still oligomerizes Tau); the PHF6 peptide of Tau interacts with FK1/FK2 domains of FKBP52 independently of FK506 binding, identifying a non-catalytic interaction governing Tau oligomerization.","method":"In vitro oligomerization assay with PPIase-dead mutant, NMR interaction mapping, PPIase activity assay on Tau peptides","journal":"Journal of molecular biology","confidence":"High","confidence_rationale":"Tier 1 / Moderate — PPIase-independent oligomerization demonstrated by catalytic-dead mutant, NMR structural mapping of interaction, single lab","pmids":["26903089"],"is_preprint":false},{"year":2019,"finding":"FKBP4 is a proximal interacting protein of PI3K, Akt, and mTOR components; FKBP4 depletion specifically reduces cell growth and proliferation of triple-negative breast cancer cells; FKBP4 can enhance Akt activation through PDK1 and mTORC2.","method":"BirA proximity-dependent biotin identification (BioID) proteomics, siRNA knockdown, xenograft tumor model, cell proliferation assay","journal":"Theranostics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — BioID interactome plus functional knockdown in vitro and in vivo, single lab","pmids":["31660083"],"is_preprint":false},{"year":2021,"finding":"FKBP4 promotes IKK complex assembly by interacting with both Hsp90 and IKK subunits (TPR domain required for Hsp90/IKK interaction, PPIase domain for IKKγ interaction), potentiating IKK kinase activity; FKBP4 also forms a complex with Hsp70/RelA to promote RelA nuclear translocation, activating NF-κB signaling in lung adenocarcinoma.","method":"Co-immunoprecipitation, domain deletion mutants, IKK kinase activity assay, nuclear fractionation, siRNA knockdown, xenograft","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP with domain mapping, kinase activity assay, single lab","pmids":["34112753"],"is_preprint":false},{"year":2021,"finding":"FKBP52 overexpression in wild-type mouse hippocampus promotes phosphorylation of AD-relevant tau species, activates gliosis, and causes neuronal loss; FKBP52 overexpression (not Aha1) impairs spatial reversal learning in aged mice.","method":"AAV-mediated overexpression in mouse hippocampus, histological analysis, behavioral testing, immunohistochemistry for phospho-tau","journal":"Acta neuropathologica communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo gain-of-function with defined tau and behavioral phenotypes, single lab","pmids":["33832539"],"is_preprint":false},{"year":2021,"finding":"Both FKBP51 and FKBP52 are required for AR dimer formation and chromatin binding; depletion of either reduces AR phosphorylation; PPIase activity of FKBP51 is specifically required for AR dimerization; MJC13 (FKBP52-AR inhibitor) also inhibits AR dimer formation.","method":"siRNA depletion, AR dimerization assay, chromatin immunoprecipitation, phosphorylation analysis, FK506/MJC13 pharmacological inhibition","journal":"Molecular oncology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic depletion and pharmacological inhibition with defined molecular readouts, single lab","pmids":["34057812"],"is_preprint":false},{"year":2022,"finding":"FKBP52 interacts with BRCA1 and stabilizes estrogen receptor α (ERα) protein; FKBP52 depletion decreases ERα expression and breast cancer cell proliferation; FKBP51 reduces ERα stability in an opposing manner.","method":"Co-immunoprecipitation (FKBP52-BRCA1), siRNA knockdown, ERα protein stability assay, cell proliferation assay","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP identifying BRCA1 interaction, functional siRNA knockdown, single lab","pmids":["35394865"],"is_preprint":false},{"year":1995,"finding":"FKBP52 (FKBP59-HBI) localizes to cytoplasm, nucleus, and partially co-localizes with microtubules in interphase non-lymphoid cells; during mitosis it segregates from chromosomes and associates with the mitotic apparatus (centrosome, spindle, interzone, cleavage furrow, midbodies).","method":"Indirect immunofluorescence confocal microscopy, Western blot of subcellular fractions, cytoskeletal drug treatment (taxol, nocodazole)","journal":"Journal of cell science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multi-cell-type immunofluorescence with cytoskeletal drug validation and subcellular fractionation, single lab","pmids":["7544801"],"is_preprint":false},{"year":1996,"finding":"FAP48 is a novel 48-kDa protein that specifically interacts with the immunosuppressant-binding domain (domain I) of FKBP52 (FKBP59) and also with FKBP12 but not CyP40; this interaction is prevented by FK506 and rapamycin in a dose-dependent manner, suggesting FAP48 shares the macrolide-binding site on FKBP52.","method":"Yeast two-hybrid, in vitro direct interaction assay, in vivo co-immunoprecipitation, FK506/rapamycin competition","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — yeast two-hybrid confirmed by in vitro and in vivo Co-IP, pharmacological competition, single lab","pmids":["8955134"],"is_preprint":false},{"year":2010,"finding":"FKBP52 forms stable complexes with amyloid precursor protein (APP) through its FK506-interacting domain; FKBP52 overexpression reduces Abeta toxicity and increases lifespan in Abeta transgenic Drosophila; FKBP52 loss-of-function exacerbates Abeta phenotypes; FKBP52 interacts with Atox1 (copper transporter) and modulates intracellular copper levels, which influence Abeta pathology.","method":"Co-immunoprecipitation (FKBP52-APP), Drosophila transgenic gain/loss-of-function, copper chelator diet, intracellular copper measurement, cell reconstitution","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP of FKBP52-APP, in vivo Drosophila model with genetic manipulation, copper supplementation/chelation, single lab","pmids":["20084280"],"is_preprint":false},{"year":2010,"finding":"FKBP52 interaction with RET51 tyrosine kinase receptor is triggered by GDNF and NGF activation of RET51; phosphorylation of RET51 tyrosine 905 is required for complex formation; disruption of this phosphorylation site abolishes the RET51/FKBP52 complex.","method":"Co-immunoprecipitation, RET51 mutagenesis (Y905 mutation), growth factor stimulation assay","journal":"Human molecular genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP with site-directed mutagenesis identifying required phosphorylation site, single lab","pmids":["20442138"],"is_preprint":false},{"year":2012,"finding":"FKBP52 localizes to the endolysosomal system in neurons and co-localizes with TRPC1 and Orai1 channels in human platelets; FKBP52 interaction with TRPC1 and IP3RII is required for maintenance of store-operated Ca2+ entry (SOCE); FK506/rapamycin reduce TRPC1-FKBP52 and TRPC1-IP3RII association, impairing SOCE.","method":"Immunoprecipitation, siRNA knockdown, Mn2+ entry assay, single-cell Ca2+ imaging, fura-2 Ca2+ measurement","journal":"Biochimica et biophysica acta","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP of FKBP52 with TRPC1/Orai1, siRNA with functional Ca2+ readout, single lab","pmids":["23228564"],"is_preprint":false},{"year":2020,"finding":"The neuroregenerative effects of FK506 in vivo are mediated specifically by FKBP52; Fkbp52-knockout mice fail to show FK506-induced locomotor recovery after spinal cord injury, while Fkbp51-knockout mice respond normally; FKBP51 binding of FK506 antagonizes FKBP52-mediated neurotrophic action.","method":"Fkbp52 and Fkbp51 knockout mice, spinal cord injury model, FK506 treatment, behavioral assessment of locomotion","journal":"Biochemical pharmacology","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic epistasis with two independent knockout lines, in vivo phenotypic readout, establishes FKBP52-specific neurotrophic mechanism","pmids":["32828804"],"is_preprint":false}],"current_model":"FKBP52 (FKBP4) is an Hsp90-binding immunophilin co-chaperone that uses three distinct functional domains—a PPIase/FK1 domain (which interacts with dynein, dynactin, TRPC channels, and client proteins), a TPR domain (which binds Hsp90's C-terminal EEVD motif and tubulin), and a C-terminal region—to (1) potentiate steroid hormone receptor (GR, AR, PR, MR) activity by increasing hormone-binding affinity and, via recruitment of dynein, facilitating retrograde microtubule-dependent transport of receptor-Hsp90 heterocomplexes to the nucleus; (2) modulate ion channels (TRPC1, TRPV5) through its PPIase isomerase activity; (3) promote RISC assembly by stabilizing Argonaute2 through the Hsp90 chaperone cycle; (4) influence Tau aggregation and microtubule dynamics; and (5) activate NF-κB and IKK signaling; the protein is regulated post-translationally by casein kinase II phosphorylation of Thr-143, which abolishes Hsp90 binding, and the proline-rich loop of the FK1 domain (especially Pro119) is the critical surface distinguishing FKBP52's receptor-potentiating activity from the antagonistic co-chaperone FKBP51."},"narrative":{"mechanistic_narrative":"FKBP4 (FKBP52) is an Hsp90-associated immunophilin co-chaperone that uses functionally separable domains to potentiate steroid hormone receptor signaling and to couple chaperone clients to microtubule-based transport [PMID:1279700, PMID:12606580]. It possesses FK506/rapamycin-sensitive peptidyl-prolyl isomerase (PPIase) activity confined to its N-terminal FK1 domain, while a C-terminal TPR domain binds the Hsp90 C-terminal EEVD motif in an ATP-independent manner [PMID:1279700, PMID:8216288, PMID:7526392, PMID:11473108]. Within unactivated glucocorticoid, progesterone, androgen, and mineralocorticoid receptor heterocomplexes, hormone binding triggers exchange of the antagonistic co-chaperone FKBP51 for FKBP52, which recruits cytoplasmic dynein/dynactin via its PPIase domain to drive retrograde microtubule-dependent transport of the intact receptor-Hsp90 complex to the nucleus [PMID:10601253, PMID:11278753, PMID:11751894, PMID:20038533]. FKBP52 potentiates receptor activity by increasing hormone-binding affinity, a function genetically dissected to the proline-rich FK1 loop (Pro119) rather than catalytic isomerization, and is essential in vivo for progesterone-dependent uterine implantation and androgen receptor signaling in male reproductive tissues [PMID:12606580, PMID:16176985, PMID:15831525, PMID:17142810, PMID:17938211]. Beyond receptors, FKBP52 gates Ca2+ channels through proline isomerization (stimulus-dependent TRPC1 opening in axon guidance; inhibition of TRPV5) [PMID:16352746, PMID:19945390], binds tubulin and Tau to modulate microtubule dynamics and drive PPIase-independent Tau oligomerization with prion-like seeding linked to tauopathy [PMID:17435176, PMID:20133804, PMID:25888602, PMID:26903089, PMID:33832539], stabilizes Argonaute2 to promote RISC assembly [PMID:24049110, PMID:23741051], and activates NF-κB/IKK signaling [PMID:25104352, PMID:34112753]. Its Hsp90 binding is switched off by casein kinase II phosphorylation of Thr-143 [PMID:9405642]. FKBP52 also mediates the neuroregenerative action of FK506 after spinal cord injury, in opposition to FKBP51 [PMID:32828804].","teleology":[{"year":1992,"claim":"Establishing that FKBP52 is an enzyme and a chaperone-associated factor defined its dual identity as an immunophilin that physically partners Hsp90 in steroid receptor complexes.","evidence":"Recombinant PPIase assay with FK506/rapamycin inhibition and co-IP with hsp90","pmids":["1279700"],"confidence":"High","gaps":["Did not map which domain bound Hsp90 versus which carried catalytic activity","Functional consequence for receptor activity unknown"]},{"year":1993,"claim":"Domain mapping resolved the modular architecture, assigning PPIase activity to the N-terminal FKBP12-like domain and protein-interaction roles to a separate TPR region.","evidence":"E. coli deletion-mutant PPIase assays plus TPR identification from receptor complexes; in vitro GR complex reconstitution","pmids":["8216288","8514757","8341706"],"confidence":"High","gaps":["TPR-Hsp90 binding was inferred, not yet directly demonstrated","ATP-binding functional role unresolved"]},{"year":1994,"claim":"Direct mapping showed the C-terminal TPR domain mediates ATP-independent, immunosuppressant-insensitive Hsp90 binding, confirming chaperone docking is independent of the catalytic site.","evidence":"Gel-retardation with purified proteins and deletion mutants","pmids":["7526392"],"confidence":"High","gaps":["Required flanking residues beyond core TPR not yet defined","Stoichiometry on Hsp90 dimer unknown"]},{"year":1996,"claim":"Competition among TPR immunophilins for Hsp90 established that FKBP52, CyP40 and others form mutually exclusive heterocomplexes, framing combinatorial chaperone assembly.","evidence":"GST-fusion deletion pulldowns and competition with myometrial cytosol; NMR structure of FK1 domain","pmids":["8621687","8780506"],"confidence":"Medium","gaps":["TPR alone insufficient; flanking acidic/basic determinants only partially defined","Functional outcome of exclusivity not tested"]},{"year":1997,"claim":"Identification of CK2 phosphorylation at Thr-143 that abolishes Hsp90 binding revealed a post-translational switch controlling chaperone complex composition.","evidence":"In vitro CK2 kinase assay, mutagenesis mapping, in vivo 32P labeling, Hsp90 binding assay","pmids":["9405642"],"confidence":"High","gaps":["Physiological signals driving Thr-143 phosphorylation unknown","Downstream effect on receptor transport untested"]},{"year":1999,"claim":"Demonstrating that the PPIase domain binds cytoplasmic dynein provided the physical link connecting receptor-Hsp90 complexes to the motor machinery.","evidence":"Cross-linking of purified proteins, co-immunoadsorption, domain-fragment competition; stoichiometry of one FKBP52 per Hsp90 dimer","pmids":["10601253","11350175"],"confidence":"High","gaps":["Direct demonstration of transport in cells not yet shown","Dynein adaptor subunit contacted not identified"]},{"year":2001,"claim":"Live-imaging and biochemical work established that FKBP52 drives hormone-induced retrograde microtubule transport of GR and that hormone triggers FKBP51-to-FKBP52 exchange with dynein recruitment.","evidence":"GFP-GR live imaging, microtubule disruption, fractionation and co-IP in hormone-treated cells; chaperone-domain and PPIase/TPR mutant analyses; Drosophila TRPL channel patch-clamp","pmids":["11278753","11751894","11473108","11514552","11350175"],"confidence":"High","gaps":["Whether transport is required for transactivation versus affinity not separated","Nuclear pore transit mechanism not resolved"]},{"year":2003,"claim":"Yeast genetics showed FKBP52 uniquely potentiates GR transactivation by raising hormone-binding affinity, requiring both Hsp90 binding and (at this stage) PPIase activity.","evidence":"S. cerevisiae reporter assays with PPIase-dead and TPR-dead mutants; hormone-binding affinity measurement","pmids":["12606580","12611898"],"confidence":"High","gaps":["Catalytic mechanism of affinity enhancement not defined","Whether other receptors behave identically not yet tested"]},{"year":2005,"claim":"Knockout mice established tissue-specific physiological roles, showing FKBP52 is essential for PR-dependent uterine implantation and AR signaling in male reproductive tissue.","evidence":"Fkbp52-knockout mice with hormone-binding, reporter, ChIP and gene-expression readouts; TRPV5 patch-clamp/Co-IP","pmids":["16176985","15831525","16352746"],"confidence":"High","gaps":["Why receptor dependence is tissue-restricted not explained","Step controlled downstream of receptor not yet localized"]},{"year":2006,"claim":"ChIP in knockout cells localized FKBP52's action to a step downstream of AR DNA binding, refining the model from chromatin loading to transactivation competence.","evidence":"Fkbp52-knockout MEFs, reporter assays, ChIP showing normal promoter occupancy, hormone binding; AAV dynein-trafficking knockout/rescue","pmids":["17142810","16828834"],"confidence":"High","gaps":["Molecular nature of the downstream transactivation step undefined","Generalization to endogenous AR targets limited"]},{"year":2007,"claim":"An unbiased screen identified FK1-loop Pro119 as the determinant distinguishing FKBP52 from FKBP51 and showed potentiation is independent of PPIase catalysis, redefining the active surface.","evidence":"Yeast random-mutagenesis screen of FKBP51, reciprocal mutagenesis, mammalian reporter assays with catalytic-dead mutants; tubulin binding/depolymerization mapping","pmids":["17938211","17435176"],"confidence":"High","gaps":["How the Pro119 loop contacts the receptor structurally unresolved","Reconciliation with earlier PPIase-dependence claims incomplete"]},{"year":2009,"claim":"Reconstitution of the MR-Hsp90-dynein/dynactin transport module generalized the FKBP52-driven retrograde transport mechanism across steroid receptor classes.","evidence":"Fractionation, cross-linking, and motor-complex reassembly on stripped MR immune pellets; TRPC1 isomerization-gated axon guidance in vivo","pmids":["20038533","19945390"],"confidence":"High","gaps":["Quantitative contribution of transport to nuclear signaling not measured","Channel-gating versus receptor roles use overlapping domains, leaving substrate specificity open"]},{"year":2010,"claim":"Direct Tau binding and antagonism of Tau-driven microtubule assembly placed FKBP52 in neuronal cytoskeletal and tauopathy biology.","evidence":"Purified-protein binding, microtubule assembly assay, neurite-length quantification in PC12 cells, co-localization in cortical neurons; APP/Atox1-copper interaction in Drosophila; RET51 phospho-Y905 dependent Co-IP","pmids":["20133804","20084280","20442138"],"confidence":"High","gaps":["Relationship between Tau binding and steroid co-chaperone roles unclear","In vivo pathological relevance not yet established at this stage"]},{"year":2014,"claim":"Demonstration that FKBP52 induces pathological Tau oligomers/filaments with prion-like seeding, including in vivo zebrafish rescue, advanced a causative role in Tau aggregation.","evidence":"Purified-protein assembly with EM, seeding in neuroblastoma cells, Tau-P301L zebrafish knockdown; FK1-GR interaction by BiFC/PLA in glioblastoma","pmids":["24623856","25888602","25132599"],"confidence":"High","gaps":["Cellular trigger converting FKBP52 from chaperone to aggregation factor unknown","Relationship to Hsp90 chaperone cycle not defined"]},{"year":2016,"claim":"Mapping the Tau interaction to the FK1/FK2 surface and showing PPIase-independence consolidated a catalysis-independent aggregation mechanism, while parallel work extended dynein-coupled transport to hTERT.","evidence":"PPIase-dead oligomerization assay, NMR mapping of PHF6 peptide; Co-IP mapping of TPR-Hsp90 and PPIase-dynamitin for hTERT transport with telomerase readouts","pmids":["26903089","27503910"],"confidence":"High","gaps":["Structural basis of PHF6-FK1/FK2 engagement at atomic level incomplete","hTERT findings rest on single-lab Co-IP/depletion"]},{"year":2013,"claim":"Identification of FKBP52/p23 association with Argonaute2 extended its co-chaperone role to RISC assembly and small-RNA silencing.","evidence":"Co-IP, siRNA depletion, FK506 inhibition, miRNA/luciferase reporter assays, lysosome-inhibitor rescue","pmids":["24049110","23741051"],"confidence":"Medium","gaps":["Whether FKBP52 acts catalytically on Ago2 or only via Hsp90 cycle unclear","Single-lab Co-IP evidence"]},{"year":2014,"claim":"FKBP52 was shown to drive NF-κB activation through PPIase- and TPR-dependent RelA nuclear retention and FKBP51-to-FKBP52 exchange, paralleling the steroid receptor switch.","evidence":"Reporter, Co-IP, EMSA, ChIP, siRNA with domain/PPIase mutants","pmids":["25104352"],"confidence":"High","gaps":["Hsp90-independence of this role contrasts with receptor mechanism","Physiological NF-κB target context limited"]},{"year":2019,"claim":"Proximity proteomics and cancer models linked FKBP4 to PI3K/Akt/mTOR signaling and to IKK assembly, broadening its oncogenic signaling roles.","evidence":"BioID interactome, siRNA knockdown, xenografts; Co-IP domain mapping of Hsp90/IKK with kinase assays","pmids":["31660083","34112753"],"confidence":"Medium","gaps":["Direct versus proximity interactions not distinguished for PI3K components","Single-lab evidence for each pathway"]},{"year":2021,"claim":"Genetic epistasis with FK506 established that FKBP52, opposed by FKBP51, mediates neuroregenerative recovery, and additional work tied FKBP51/52 to AR dimerization and ERα stabilization via BRCA1.","evidence":"Fkbp52 vs Fkbp51 knockout spinal-cord-injury mice with locomotor readouts; AR dimerization/ChIP assays; FKBP52-BRCA1 Co-IP and ERα stability assays","pmids":["32828804","34057812","35394865","33832539"],"confidence":"Medium","gaps":["Molecular target of the neurotrophic action not identified","AR/ERα roles depend partly on single-lab depletion data"]},{"year":null,"claim":"How FKBP52 selects among its many functional outputs—receptor transport, channel gating, Tau aggregation, RISC assembly, NF-κB activation—using a shared, largely PPIase-independent FK1 surface remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structural model of FKBP52 bound to a steroid receptor or to dynein","Determinants of client/substrate selectivity unknown","Integration of catalysis-independent and chaperone-dependent mechanisms unresolved"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0016853","term_label":"isomerase activity","supporting_discovery_ids":[0,2,24,30]},{"term_id":"GO:0044183","term_label":"protein folding chaperone","supporting_discovery_ids":[15,31]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[16,22,23,27]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[11,13,14,29]},{"term_id":"GO:0008092","term_label":"cytoskeletal protein binding","supporting_discovery_ids":[28,31]}],"localization":[{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[14,47]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[14,47]},{"term_id":"GO:0005856","term_label":"cytoskeleton","supporting_discovery_ids":[28,47]},{"term_id":"GO:0005815","term_label":"microtubule organizing center","supporting_discovery_ids":[47]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[14,16,23,32]},{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[0,5,15]},{"term_id":"R-HSA-9609507","term_label":"Protein localization","supporting_discovery_ids":[13,14,29]},{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[16,22,26,32]},{"term_id":"R-HSA-8953854","term_label":"Metabolism of RNA","supporting_discovery_ids":[35,36]}],"complexes":["GR-Hsp90-FKBP52-dynein heterocomplex","MR-Hsp90-FKBP52-dynein/dynactin complex","Hsp90-FKBP52-HOP/p23 complex","FKBP52-p23-Ago2 (RISC-loading) complex"],"partners":["HSP90","DYNLL/DYNEIN","AGO2","TRPC1","RELA","BRCA1","TUBB","MAPT"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q02790","full_name":"Peptidyl-prolyl cis-trans isomerase FKBP4","aliases":["51 kDa FK506-binding protein","FKBP51","52 kDa FK506-binding protein","52 kDa FKBP","FKBP-52","59 kDa immunophilin","p59","FK506-binding protein 4","FKBP-4","FKBP59","HSP-binding immunophilin","HBI","Immunophilin FKBP52","Rotamase"],"length_aa":459,"mass_kda":51.8,"function":"Immunophilin protein with PPIase and co-chaperone activities. Component of steroid receptors heterocomplexes through interaction with heat-shock protein 90 (HSP90). May play a role in the intracellular trafficking of heterooligomeric forms of steroid hormone receptors between cytoplasm and nuclear compartments. The isomerase activity controls neuronal growth cones via regulation of TRPC1 channel opening. Also acts as a regulator of microtubule dynamics by inhibiting MAPT/TAU ability to promote microtubule assembly. May have a protective role against oxidative stress in mitochondria","subcellular_location":"Cytoplasm, cytosol; Mitochondrion; Nucleus; Cytoplasm, cytoskeleton; Cell projection, axon","url":"https://www.uniprot.org/uniprotkb/Q02790/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/FKBP4","classification":"Not Classified","n_dependent_lines":14,"n_total_lines":1208,"dependency_fraction":0.011589403973509934},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"PTGES3","stoichiometry":4.0},{"gene":"DYNC1LI2","stoichiometry":0.2},{"gene":"PTDSS2","stoichiometry":0.2},{"gene":"SAR1B","stoichiometry":0.2},{"gene":"STX12","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/FKBP4","total_profiled":1310},"omim":[{"mim_id":"617076","title":"FK506-BINDING PROTEIN-LIKE; FKBPL","url":"https://www.omim.org/entry/617076"},{"mim_id":"611219","title":"UNC45 MYOSIN CHAPERONE A; UNC45A","url":"https://www.omim.org/entry/611219"},{"mim_id":"610346","title":"CELL DIVISION CYCLE 37-LIKE 1; CDC37L1","url":"https://www.omim.org/entry/610346"},{"mim_id":"605555","title":"ARYL HYDROCARBON RECEPTOR-INTERACTING PROTEIN; AIP","url":"https://www.omim.org/entry/605555"},{"mim_id":"601749","title":"GLOMULIN; GLMN","url":"https://www.omim.org/entry/601749"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Cytosol","reliability":"Supported"},{"location":"Nucleoplasm","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/FKBP4"},"hgnc":{"alias_symbol":["FKBP59","FKBP52"],"prev_symbol":[]},"alphafold":{"accession":"Q02790","domains":[{"cath_id":"3.10.50.40","chopping":"24-138","consensus_level":"high","plddt":96.4347,"start":24,"end":138},{"cath_id":"3.10.50.40","chopping":"151-254","consensus_level":"high","plddt":97.07,"start":151,"end":254},{"cath_id":"1.25.40.10","chopping":"264-397","consensus_level":"medium","plddt":96.5259,"start":264,"end":397}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q02790","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q02790-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q02790-F1-predicted_aligned_error_v6.png","plddt_mean":90.38},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=FKBP4","jax_strain_url":"https://www.jax.org/strain/search?query=FKBP4"},"sequence":{"accession":"Q02790","fasta_url":"https://rest.uniprot.org/uniprotkb/Q02790.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q02790/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q02790"}},"corpus_meta":[{"pmid":"11751894","id":"PMC_11751894","title":"A 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The immunosuppressant-binding site is distinct from the hsp90-binding site, implying separate structural domains.\",\n      \"method\": \"Recombinant protein expression in E. coli, PPIase enzymatic assay, co-immunoprecipitation with hsp90\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — direct enzymatic assay for PPIase activity, inhibition by FK506/rapamycin, co-IP with hsp90, replicated across multiple labs\",\n      \"pmids\": [\"1279700\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1992,\n      \"finding\": \"Rabbit FKBP52 (FKBP59-HBI) binds calmodulin in a Ca2+-dependent manner, retained on calmodulin-Sepharose in 2 mM Ca2+ and eluted by EGTA; it is also a substrate for calpain II, a Ca2+-activated protease.\",\n      \"method\": \"Calmodulin-Sepharose affinity chromatography, in vitro proteolysis assay\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — single affinity chromatography experiment replicated with proteolysis assay, single lab\",\n      \"pmids\": [\"1384470\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1993,\n      \"finding\": \"The PPIase activity of FKBP52 (p59-HBI) resides entirely in its N-terminal domain (domain I), which has the highest homology to FKBP12; a second domain (domain II) shows residual enzymatic activity.\",\n      \"method\": \"Overexpression of domain deletion mutants in E. coli, PPIase activity assay\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — direct enzymatic domain mapping with deletion mutants, single lab with multiple constructs\",\n      \"pmids\": [\"8216288\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1993,\n      \"finding\": \"The tetratricopeptide repeat (TPR) domain of FKBP52 (p59, FKBP59) is proposed to mediate protein-protein interactions including hsp90 binding; this was supported by identification of a conserved TPR domain in the estrogen receptor-binding cyclophilin (ERBC/CyP40).\",\n      \"method\": \"Affinity chromatography, sequence homology analysis, protein identification from estrogen receptor complex\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — biochemical isolation plus sequence analysis, convergent evidence from related protein\",\n      \"pmids\": [\"8514757\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1993,\n      \"finding\": \"Recombinant mouse FKBP52 can be assembled in vitro with the glucocorticoid receptor complex, confirming it is a functional component of the unactivated GR heterocomplex; it also possesses ATP/GTP binding activity stimulated by divalent cations.\",\n      \"method\": \"Baculovirus expression, in vitro assembly assay with glucocorticoid receptor, ATP binding assay\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vitro reconstitution of GR complex, direct ATP binding assay, single lab\",\n      \"pmids\": [\"8341706\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1994,\n      \"finding\": \"The TPR domain located in the C-terminal part of FKBP52 (FKBP59-HBI) is necessary for hsp90 binding; this interaction is ATP-independent and not affected by FK506 or rapamycin.\",\n      \"method\": \"Gel-retardation assay with purified proteins, deletion mutant analysis\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — purified protein reconstitution with multiple mutants mapped to TPR domain, single lab with rigorous controls\",\n      \"pmids\": [\"7526392\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1996,\n      \"finding\": \"FKBP52 competes with cyclophilin 40 (CyP40) for hsp90 binding, leading to mutually exclusive immunophilin-hsp90-receptor complexes; the TPR domain alone is not sufficient for stable hsp90 association—flanking acidic and basic residues are also required.\",\n      \"method\": \"GST-fusion deletion mutant pulldown, competition assay with myometrial cytosol\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal competition assay with purified fragments, single lab\",\n      \"pmids\": [\"8621687\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1996,\n      \"finding\": \"NMR structure of the N-terminal immunophilin domain of FKBP52 (FKBP59-I, residues 1–149) was determined; it adopts a twisted antiparallel beta-sheet and short alpha-helix, globally similar to FKBP12, with an unusual Trp89–Phe129 hydrogen bond important for immunosuppressant binding.\",\n      \"method\": \"Multidimensional NMR spectroscopy, distance geometry, molecular dynamics\",\n      \"journal\": \"Biochemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — solution NMR structure determined with 1290 restraints; replicated by later X-ray structure\",\n      \"pmids\": [\"8780506\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1997,\n      \"finding\": \"Casein kinase II (CK2) phosphorylates FKBP52 at Thr-143 in the hinge I region both in vitro and in vivo; CK2-phosphorylated FKBP52 fails to bind hsp90, revealing phosphorylation as a mechanism to regulate chaperone complex composition.\",\n      \"method\": \"In vitro kinase assay with purified CK2, deletion mutant mapping, [32P] in vivo labeling, hsp90 binding assay\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — site-specific phosphorylation mapped by mutagenesis, confirmed in vivo, functional consequence (hsp90 binding lost) demonstrated\",\n      \"pmids\": [\"9405642\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"The TPR domain of FKBP52 requires appropriate downstream C-terminal sequences for hsp90 binding; unlike FKBP51, FKBP52's TPR domain does not require specific C-terminal sequences beyond the core TPR for hsp90 binding. FKBP52 and FKBP51 associate differentially with steroid receptors based on the TPR domain and poorly-conserved C-terminal sequences.\",\n      \"method\": \"Deletion mutant and chimera co-precipitation with hsp90, steroid receptor association assays\",\n      \"journal\": \"Molecular endocrinology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — systematic mutagenesis with chimeric constructs, multiple receptor and hsp90 binding assays, replicated concept in later papers\",\n      \"pmids\": [\"9514152\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"Hsp90 C-terminal EEVD motif is critical for interaction with TPR cochaperones including FKBP52; p23 binding maps to the N-terminal ATP-binding domain of Hsp90; deletion of Hsp90 residues 661–677 abolishes dimerization and reduces all accessory protein interactions.\",\n      \"method\": \"Co-precipitation of Hsp90 mutants with cochaperones including FKBP52\",\n      \"journal\": \"Cell stress & chaperones\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — systematic Hsp90 mutant panel mapped binding sites, single lab\",\n      \"pmids\": [\"9672247\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"FKBP52 has one binding site per hsp90 dimer (cross-linking). The PPIase domain of FKBP52 mediates binding to cytoplasmic dynein (competed by PPIase fragment, not TPR fragment). FKBP52 also binds directly to the hsp90-free glucocorticoid receptor via a region distinct from both the PPIase and TPR domains.\",\n      \"method\": \"Chemical cross-linking of purified proteins, co-immunoadsorption from reticulocyte lysate, competitive inhibition with domain fragments\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — purified protein cross-linking, domain-specific competition assays, multiple orthogonal methods in one study\",\n      \"pmids\": [\"10601253\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"FKBP52 interacts with interferon regulatory factor-4 (IRF-4), inhibiting IRF-4–PU.1 binding to the immunoglobulin light chain enhancer and IRF-4–PU.1 transactivation; this inhibition requires functional PPIase activity of FKBP52 and induces a detectable structural modification of IRF-4.\",\n      \"method\": \"Co-immunoprecipitation, transcriptional reporter assay, partial proteolysis analysis, PPIase-inactive mutant\",\n      \"journal\": \"Immunity\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP, functional reporter, conformational assay, single lab\",\n      \"pmids\": [\"10714679\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"The PPIase domain of FKBP52 links the GR-hsp90 heterocomplex to cytoplasmic dynein and is required for hormone-induced retrograde transport of the GFP-GR along microtubules to the nucleus; FKBP12 overexpression does not affect GFP-GR movement.\",\n      \"method\": \"Cotransfection with PPIase domain fragment, live-cell GFP-GR imaging, colcemid microtubule disruption, co-immunoadsorption from cytosol\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — live imaging plus biochemical co-IP, microtubule disruption confirms mechanism, replicated concept across papers\",\n      \"pmids\": [\"11278753\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"Hormone binding to the GR induces substitution of FKBP51 by FKBP52 in the GR-hsp90 heterocomplex and concomitant recruitment of dynein, while hsp90 remains; the resulting GR-hsp90-FKBP52-dynein complex translocates from cytoplasm to nucleus before complex dissociation and conversion to DNA-binding form.\",\n      \"method\": \"Immunofluorescence, subcellular fractionation, co-immunoprecipitation in hormone-treated cells\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (IF, fractionation, Co-IP), identifies ordered molecular event, replicated in subsequent papers\",\n      \"pmids\": [\"11751894\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"FKBP52 chaperone activity resides in the C-terminal region (amino acids 264–400, domain 3, which overlaps with the TPR domain), while PPIase activity is confined to domain 1 (amino acids 1–148); the chaperone and hsp90-binding regions within domain 3 are distinct.\",\n      \"method\": \"Domain fragment expression, PPIase assay, chaperone aggregation assay, competition with Hsp90 C-terminal peptide\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — direct enzymatic assay plus chaperone assay with domain fragments and competition experiment, single lab\",\n      \"pmids\": [\"11473108\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"In the yeast model, FKBP52 is the only immunophilin that potentiates GR hormone-dependent transactivation (up to 20-fold at limiting hormone); this requires both Hsp90-binding ability and PPIase activity of FKBP52, and works by increasing GR hormone-binding affinity.\",\n      \"method\": \"Saccharomyces cerevisiae reporter gene assay, FKBP52 mutant analysis (PPIase-dead and TPR-dead mutants)\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo yeast model with defined mutants, hormone-binding affinity measured, replicated in mammalian cells\",\n      \"pmids\": [\"12606580\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"FKBP52 (dFKBP59) interacts directly with Drosophila TRPL Ca2+-permeable channels and with the scaffold protein INAD; expression of dFKBP59 inhibits Ca2+ influx through TRPL channels; mutations of conserved proline residues in TRPL (P702Q, P709Q) abolish interaction with dFKBP59.\",\n      \"method\": \"Yeast two-hybrid, co-immunoprecipitation in Sf9 and fly cells, electrophysiology (inside-out patch), fura-2 Ca2+ assay, site-directed mutagenesis\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — reconstitution in Sf9 cells, patch-clamp electrophysiology, site-directed mutagenesis of channel, multiple orthogonal methods\",\n      \"pmids\": [\"11514552\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"Two PPIase monomers bind to one Hsp90 dimer; FKBP52 has the strongest affinity for Hsp90 among the three mammalian large PPIases (vs. FKBP51 and CyP40); catalytic prolyl isomerase activity of FKBP52 corresponds to that of the small immunophilin FKBP12.\",\n      \"method\": \"In vitro binding assay with purified proteins, enzymatic PPIase assay\",\n      \"journal\": \"Journal of molecular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — purified protein binding and enzymatic assays, single lab\",\n      \"pmids\": [\"11350175\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"Crystal structure of the N-terminal FK506-binding domain of human FKBP52 (residues 1–140) solved at 2.4 Å; reveals six-stranded antiparallel beta-sheet plus alpha-helix similar to FKBP12; Pro120 and Lys121 explain reduced FK506 affinity and inability to activate calcineurin compared with FKBP12.\",\n      \"method\": \"X-ray crystallography, molecular replacement\",\n      \"journal\": \"Acta crystallographica. Section D, Biological crystallography\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structure at 2.4 Å with structural interpretation of functional differences\",\n      \"pmids\": [\"12499534\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"C-terminal sequences outside the core TPR domain (residues ~400–420 and the final 30 amino acids) of FKBP51 and FKBP52 differentially regulate hsp90 binding; the final 30 residues of FKBP51 enhance hsp90 binding while the corresponding region of FKBP52 moderates it.\",\n      \"method\": \"Truncation mutant and chimera co-immunoprecipitation with Hsp90\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — systematic truncation/chimera panel, single lab, Co-IP\",\n      \"pmids\": [\"12611898\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"FKBP52 PPIase domain I directly interacts with the copper metallochaperone Atox1; the interaction is enhanced by copper supplementation and decreased by copper chelation; FKBP52 overexpression increases rapid copper efflux in cells, implicating it in the copper efflux machinery.\",\n      \"method\": \"Yeast two-hybrid, GST pulldown, co-immunoprecipitation, 64Cu efflux assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — yeast two-hybrid confirmed by pulldown and Co-IP, functional efflux assay, single lab\",\n      \"pmids\": [\"15133031\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"FKBP52 is a critical cochaperone for progesterone receptor (PR) in the uterus; Fkbp52-knockout female mice show complete implantation failure due to reduced P4 binding to PR, attenuated PR transcriptional activity, and down-regulation of P4-regulated genes—demonstrating tissue-specific regulation of hormone action.\",\n      \"method\": \"Fkbp52 knockout mice, hormone binding assay, PR transcriptional reporter, gene expression analysis, uterine fractionation\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — knockout mouse phenotype with multiple molecular readouts (hormone binding, transcription, gene expression), replicated in subsequent studies\",\n      \"pmids\": [\"16176985\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"FKBP52 is required for androgen receptor (AR) signaling in specific male reproductive tissues; FKBP52 is a component of AR complexes and enhances AR-mediated transactivation in a manner requiring both PPIase activity and Hsp90-binding ability; FKBP52 can restore function of a minimally active AR point mutant.\",\n      \"method\": \"Fkbp52 knockout mice, yeast and mammalian cell reporter assays, FKBP52 mutant analysis, co-IP of AR complexes\",\n      \"journal\": \"Molecular endocrinology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — knockout mouse plus multiple in vitro assays with defined mutants, replicated across models\",\n      \"pmids\": [\"15831525\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"FKBP52 inhibits TRPV5 channel activity via its PPIase domain; FKBP52 co-localizes with and specifically interacts with TRPV5 in the distal nephron; PPIase-inactive mutant of FKBP52 loses the inhibitory effect on TRPV5.\",\n      \"method\": \"Co-immunoprecipitation, 45Ca2+ uptake, patch-clamp electrophysiology, PPIase domain mutant, siRNA knockdown\",\n      \"journal\": \"American journal of physiology. Renal physiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — electrophysiology plus Co-IP and mutagenesis, multiple methods in one study, single lab\",\n      \"pmids\": [\"16352746\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"FKBP52 facilitates intracellular trafficking of AAV vectors toward the nucleus via interaction with dynein; FKBP52-knockout MEFs show impaired nuclear accumulation of AAV genomes that is restored upon FKBP52 re-expression; intact AAV particles interact with both FKBP52 and dynein.\",\n      \"method\": \"Knockout MEF cells, self-complementary AAV transduction, nuclear fractionation, co-immunoprecipitation, FKBP52 rescue expression\",\n      \"journal\": \"Virology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — knockout plus rescue plus Co-IP, single lab\",\n      \"pmids\": [\"16828834\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"Fkbp52 knockout specifically reduces AR transcriptional activity in mouse embryonic fibroblasts; chromatin immunoprecipitation shows normal AR occupancy at gene promoters in knockout cells, indicating FKBP52 controls a downstream step in AR transactivation rather than DNA binding.\",\n      \"method\": \"Fkbp52 knockout mouse, mouse embryonic fibroblasts, reporter assays, chromatin immunoprecipitation, hormone binding assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple molecular assays in knockout cells, ChIP identifies step downstream of DNA binding, single lab with comprehensive controls\",\n      \"pmids\": [\"17142810\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"The FK1 domain loop residue Pro119 (vs. Leu119 in FKBP51) is the critical determinant distinguishing FKBP52's ability to potentiate steroid receptor activity from FKBP51; PPIase catalytic activity is NOT required for potentiation, as PPIase-dead mutants still potentiate; the proline-rich loop overhanging the catalytic pocket is the functionally important receptor-interaction surface.\",\n      \"method\": \"Yeast genetic screen of randomly mutated FKBP51, site-directed mutagenesis, mammalian cell reporter assay\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — unbiased genetic screen combined with reciprocal mutagenesis in two cell systems; PPIase independence confirmed by catalytic-dead mutant\",\n      \"pmids\": [\"17938211\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"FKBP52 directly and specifically binds tubulin; the TPR-containing region (aa 267–400) is required for tubulin binding; a C-terminal sequence (aa 375–458) is necessary and sufficient for microtubule depolymerization activity; FKBP52 prevents tubulin polymerization in vitro.\",\n      \"method\": \"Direct binding assay with purified proteins, domain deletion analysis, tubulin polymerization assay, co-localization in PC12 cells, siRNA knockdown\",\n      \"journal\": \"FASEB journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro polymerization assay with purified proteins, domain mapping by deletion, co-localization and siRNA in cells, single lab\",\n      \"pmids\": [\"17435176\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"FKBP52 links the mineralocorticoid receptor (MR)-hsp90 complex to dynein/dynactin motors for cytoplasmic-to-nuclear transport; replacement of FKBP52 by FKBP51 or TPR peptide favors cytoplasmic MR retention; the intact MR-hsp90 heterocomplex transits the nuclear pore undissociated.\",\n      \"method\": \"Immunofluorescence, fractionation, cross-linking of MR-hsp90 complexes, microtubule stabilization/reassembly assay on stripped MR immune pellets\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (fractionation, cross-linking, live reconstitution of motor complex), single lab with rigorous controls\",\n      \"pmids\": [\"20038533\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"FKBP52 mediates stimulus-dependent gating of TRPC1 channels via cis/trans isomerization of proline residues in TRPC1; this is required for chemotropic turning of neuronal growth cones to netrin-1 and for netrin-1/DCC-dependent midline axon guidance in the spinal cord. FKBP12 mediates spontaneous (not stimulus-dependent) TRPC1 opening.\",\n      \"method\": \"Biochemical PPIase assay on TRPC1 peptides, dominant-negative FKBP52 expression, axon guidance assays in vitro and in vivo (mouse spinal cord)\",\n      \"journal\": \"Neuron\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — direct isomerization assay, loss-of-function with dominant-negative, in vivo axon guidance phenotype, multiple orthogonal methods\",\n      \"pmids\": [\"19945390\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"FKBP52 binds directly and specifically to Tau (preferentially its hyperphosphorylated form); FKBP52 antagonizes Tau-mediated microtubule assembly; FKBP52 overexpression in differentiated PC12 cells reduces neurite length and decreases Tau accumulation.\",\n      \"method\": \"Direct binding assay with purified proteins, microtubule assembly assay, co-localization in cortical neurons, PC12 overexpression, quantitative neurite length measurement\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — direct binding with purified proteins, in vitro microtubule assay, cellular overexpression phenotype, co-localization in primary neurons\",\n      \"pmids\": [\"20133804\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"FKBP52 favors nuclear retention of RelA/NF-κB, enhances its association with DNA consensus sequences, and increases NF-κB transcriptional activity; these effects require FKBP52 PPIase activity and TPR domain but not Hsp90 interaction. Upon stimulation, NF-κB complex exchanges FKBP51 for FKBP52 (analogous to steroid receptor switching). FKBP52 is functionally recruited to promoters of NF-κB target genes.\",\n      \"method\": \"Reporter gene assay, Co-IP with purified proteins, EMSA, ChIP, siRNA knockdown\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (Co-IP, EMSA, ChIP, reporter), PPIase and domain requirements mapped by mutagenesis, single lab\",\n      \"pmids\": [\"25104352\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Hsp90 can simultaneously accommodate FKBP52 and HOP, forming stable Hsp90(2)-FKBP52(1)-HOP(2) and Hsp90(2)-FKBP52(1)-p23(2)-HOP(2) complexes.\",\n      \"method\": \"Co-immunoprecipitation, dynamic light scattering, electron microscopy\",\n      \"journal\": \"Oncotarget\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — three orthogonal methods for complex detection, single lab\",\n      \"pmids\": [\"21378414\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"MJC13, a small molecule inhibitor, blocks FKBP52-enhanced AR function by preventing hormone-dependent dissociation of the Hsp90-FKBP52-AR complex, leading to less hormone-bound receptor in the nucleus and inhibiting AR-dependent gene expression and prostate cancer cell proliferation.\",\n      \"method\": \"Yeast reporter assay screen, co-immunoprecipitation, nuclear fractionation, qPCR of AR target genes, cell proliferation assay\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — mechanistic assay identifying complex dissociation step, multiple cell models, single lab with comprehensive follow-up\",\n      \"pmids\": [\"21730179\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"FKBP52 (FKBP52/Fkbp4) physically associates with Argonaute2 (hAgo2); FK506 treatment or siRNA depletion of Fkbp4/5 decreases Ago2 protein levels and impairs miRNA-mediated silencing; FKBP4 overexpression promotes miRNA-mediated Ago2 stabilization; unloaded Ago2 accumulates in FK506-treated cells.\",\n      \"method\": \"Co-immunoprecipitation (FKBP4-hAgo2), siRNA depletion, FK506 pharmacological inhibition, lysosome inhibitor rescue, miRNA reporter assay\",\n      \"journal\": \"RNA (New York, N.Y.)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP plus functional reporter and pharmacological/genetic depletion, single lab\",\n      \"pmids\": [\"24049110\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"FKBP4 (FKBP52) and p23 form a stable complex with hAgo2 and are required for efficient RNAi/RISC loading; the interaction occurs before small RNA loading and in the cytoplasm; depletion of FKBP4 or pharmacological disruption with FK506 reduces Ago2 levels and impairs RNAi.\",\n      \"method\": \"Co-immunoprecipitation, siRNA depletion, FK506 treatment, luciferase reporter silencing assay\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct Co-IP of FKBP4 with hAgo2, functional RISC assay, single lab\",\n      \"pmids\": [\"23741051\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"FKBP52 directly interacts with Tau-P301L (pathological mutant) and induces formation of Tau-P301L oligomers and filaments in vitro; FKBP52 knockdown in Tau-P301L transgenic zebrafish rescues defective axonal outgrowth and branching, and reduces pT181 phospho-Tau.\",\n      \"method\": \"Direct binding assay, EM analysis of oligomers/filaments, zebrafish Tau-P301L transgenic model with FKBP52 knockdown\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro assembly assay with purified proteins plus in vivo zebrafish model with genetic knockdown, EM validation of aggregates\",\n      \"pmids\": [\"24623856\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"The FK1 domain of FKBP52 physically interacts with the glucocorticoid receptor (GR) as demonstrated by bimolecular fluorescence complementation and proximity ligation assays; this interaction is part of the FKBP52-dependent suppression of TDO expression in glioblastoma cells.\",\n      \"method\": \"Bimolecular fluorescence complementation, in situ proximity ligation assay, siRNA knockdown of FKBP52, TDO activity assay\",\n      \"journal\": \"Glia\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — two complementary protein interaction methods, single lab with functional outcome\",\n      \"pmids\": [\"25132599\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"FKBP52 induces aggregation of Tau-F4 fragment (Ser208–Ser324) into oligomers and filaments with prion-like seeding capacity; FKBP52-induced Tau-F4 oligomers can transfer conformational changes to full-length Tau in cells and seed aggregation of endogenous Tau in neuroblastoma cells.\",\n      \"method\": \"Light-scattering assay, blue native PAGE, electron microscopy, microtubule assembly assay, seeding in SH-SY5Y cells\",\n      \"journal\": \"FASEB journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — multiple orthogonal in vitro assays plus cellular seeding experiment, EM structural validation of aggregates\",\n      \"pmids\": [\"25888602\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"FKBP52 links the hTERT-Hsp90 complex to the dynein-dynactin motor via binding of the TPR domain to Hsp90 and the PPIase domain to dynamitin (Dyt); FKBP52 depletion inhibits hTERT nuclear transport and causes cytoplasmic accumulation and ubiquitin-dependent degradation of hTERT, abrogating telomerase activity.\",\n      \"method\": \"Co-immunoprecipitation, siRNA knockdown, nuclear/cytoplasmic fractionation, telomerase activity assay, dynamitin overexpression\",\n      \"journal\": \"The Biochemical journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP mapping to specific domains, functional readout via telomerase assay, siRNA depletion, single lab\",\n      \"pmids\": [\"27503910\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"FKBP52's capacity to oligomerize Tau is independent of its PPIase catalytic activity (PPIase-dead mutant still oligomerizes Tau); the PHF6 peptide of Tau interacts with FK1/FK2 domains of FKBP52 independently of FK506 binding, identifying a non-catalytic interaction governing Tau oligomerization.\",\n      \"method\": \"In vitro oligomerization assay with PPIase-dead mutant, NMR interaction mapping, PPIase activity assay on Tau peptides\",\n      \"journal\": \"Journal of molecular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — PPIase-independent oligomerization demonstrated by catalytic-dead mutant, NMR structural mapping of interaction, single lab\",\n      \"pmids\": [\"26903089\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"FKBP4 is a proximal interacting protein of PI3K, Akt, and mTOR components; FKBP4 depletion specifically reduces cell growth and proliferation of triple-negative breast cancer cells; FKBP4 can enhance Akt activation through PDK1 and mTORC2.\",\n      \"method\": \"BirA proximity-dependent biotin identification (BioID) proteomics, siRNA knockdown, xenograft tumor model, cell proliferation assay\",\n      \"journal\": \"Theranostics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — BioID interactome plus functional knockdown in vitro and in vivo, single lab\",\n      \"pmids\": [\"31660083\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"FKBP4 promotes IKK complex assembly by interacting with both Hsp90 and IKK subunits (TPR domain required for Hsp90/IKK interaction, PPIase domain for IKKγ interaction), potentiating IKK kinase activity; FKBP4 also forms a complex with Hsp70/RelA to promote RelA nuclear translocation, activating NF-κB signaling in lung adenocarcinoma.\",\n      \"method\": \"Co-immunoprecipitation, domain deletion mutants, IKK kinase activity assay, nuclear fractionation, siRNA knockdown, xenograft\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP with domain mapping, kinase activity assay, single lab\",\n      \"pmids\": [\"34112753\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"FKBP52 overexpression in wild-type mouse hippocampus promotes phosphorylation of AD-relevant tau species, activates gliosis, and causes neuronal loss; FKBP52 overexpression (not Aha1) impairs spatial reversal learning in aged mice.\",\n      \"method\": \"AAV-mediated overexpression in mouse hippocampus, histological analysis, behavioral testing, immunohistochemistry for phospho-tau\",\n      \"journal\": \"Acta neuropathologica communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo gain-of-function with defined tau and behavioral phenotypes, single lab\",\n      \"pmids\": [\"33832539\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Both FKBP51 and FKBP52 are required for AR dimer formation and chromatin binding; depletion of either reduces AR phosphorylation; PPIase activity of FKBP51 is specifically required for AR dimerization; MJC13 (FKBP52-AR inhibitor) also inhibits AR dimer formation.\",\n      \"method\": \"siRNA depletion, AR dimerization assay, chromatin immunoprecipitation, phosphorylation analysis, FK506/MJC13 pharmacological inhibition\",\n      \"journal\": \"Molecular oncology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic depletion and pharmacological inhibition with defined molecular readouts, single lab\",\n      \"pmids\": [\"34057812\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"FKBP52 interacts with BRCA1 and stabilizes estrogen receptor α (ERα) protein; FKBP52 depletion decreases ERα expression and breast cancer cell proliferation; FKBP51 reduces ERα stability in an opposing manner.\",\n      \"method\": \"Co-immunoprecipitation (FKBP52-BRCA1), siRNA knockdown, ERα protein stability assay, cell proliferation assay\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP identifying BRCA1 interaction, functional siRNA knockdown, single lab\",\n      \"pmids\": [\"35394865\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1995,\n      \"finding\": \"FKBP52 (FKBP59-HBI) localizes to cytoplasm, nucleus, and partially co-localizes with microtubules in interphase non-lymphoid cells; during mitosis it segregates from chromosomes and associates with the mitotic apparatus (centrosome, spindle, interzone, cleavage furrow, midbodies).\",\n      \"method\": \"Indirect immunofluorescence confocal microscopy, Western blot of subcellular fractions, cytoskeletal drug treatment (taxol, nocodazole)\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multi-cell-type immunofluorescence with cytoskeletal drug validation and subcellular fractionation, single lab\",\n      \"pmids\": [\"7544801\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1996,\n      \"finding\": \"FAP48 is a novel 48-kDa protein that specifically interacts with the immunosuppressant-binding domain (domain I) of FKBP52 (FKBP59) and also with FKBP12 but not CyP40; this interaction is prevented by FK506 and rapamycin in a dose-dependent manner, suggesting FAP48 shares the macrolide-binding site on FKBP52.\",\n      \"method\": \"Yeast two-hybrid, in vitro direct interaction assay, in vivo co-immunoprecipitation, FK506/rapamycin competition\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — yeast two-hybrid confirmed by in vitro and in vivo Co-IP, pharmacological competition, single lab\",\n      \"pmids\": [\"8955134\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"FKBP52 forms stable complexes with amyloid precursor protein (APP) through its FK506-interacting domain; FKBP52 overexpression reduces Abeta toxicity and increases lifespan in Abeta transgenic Drosophila; FKBP52 loss-of-function exacerbates Abeta phenotypes; FKBP52 interacts with Atox1 (copper transporter) and modulates intracellular copper levels, which influence Abeta pathology.\",\n      \"method\": \"Co-immunoprecipitation (FKBP52-APP), Drosophila transgenic gain/loss-of-function, copper chelator diet, intracellular copper measurement, cell reconstitution\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP of FKBP52-APP, in vivo Drosophila model with genetic manipulation, copper supplementation/chelation, single lab\",\n      \"pmids\": [\"20084280\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"FKBP52 interaction with RET51 tyrosine kinase receptor is triggered by GDNF and NGF activation of RET51; phosphorylation of RET51 tyrosine 905 is required for complex formation; disruption of this phosphorylation site abolishes the RET51/FKBP52 complex.\",\n      \"method\": \"Co-immunoprecipitation, RET51 mutagenesis (Y905 mutation), growth factor stimulation assay\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP with site-directed mutagenesis identifying required phosphorylation site, single lab\",\n      \"pmids\": [\"20442138\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"FKBP52 localizes to the endolysosomal system in neurons and co-localizes with TRPC1 and Orai1 channels in human platelets; FKBP52 interaction with TRPC1 and IP3RII is required for maintenance of store-operated Ca2+ entry (SOCE); FK506/rapamycin reduce TRPC1-FKBP52 and TRPC1-IP3RII association, impairing SOCE.\",\n      \"method\": \"Immunoprecipitation, siRNA knockdown, Mn2+ entry assay, single-cell Ca2+ imaging, fura-2 Ca2+ measurement\",\n      \"journal\": \"Biochimica et biophysica acta\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP of FKBP52 with TRPC1/Orai1, siRNA with functional Ca2+ readout, single lab\",\n      \"pmids\": [\"23228564\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"The neuroregenerative effects of FK506 in vivo are mediated specifically by FKBP52; Fkbp52-knockout mice fail to show FK506-induced locomotor recovery after spinal cord injury, while Fkbp51-knockout mice respond normally; FKBP51 binding of FK506 antagonizes FKBP52-mediated neurotrophic action.\",\n      \"method\": \"Fkbp52 and Fkbp51 knockout mice, spinal cord injury model, FK506 treatment, behavioral assessment of locomotion\",\n      \"journal\": \"Biochemical pharmacology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic epistasis with two independent knockout lines, in vivo phenotypic readout, establishes FKBP52-specific neurotrophic mechanism\",\n      \"pmids\": [\"32828804\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"FKBP52 (FKBP4) is an Hsp90-binding immunophilin co-chaperone that uses three distinct functional domains—a PPIase/FK1 domain (which interacts with dynein, dynactin, TRPC channels, and client proteins), a TPR domain (which binds Hsp90's C-terminal EEVD motif and tubulin), and a C-terminal region—to (1) potentiate steroid hormone receptor (GR, AR, PR, MR) activity by increasing hormone-binding affinity and, via recruitment of dynein, facilitating retrograde microtubule-dependent transport of receptor-Hsp90 heterocomplexes to the nucleus; (2) modulate ion channels (TRPC1, TRPV5) through its PPIase isomerase activity; (3) promote RISC assembly by stabilizing Argonaute2 through the Hsp90 chaperone cycle; (4) influence Tau aggregation and microtubule dynamics; and (5) activate NF-κB and IKK signaling; the protein is regulated post-translationally by casein kinase II phosphorylation of Thr-143, which abolishes Hsp90 binding, and the proline-rich loop of the FK1 domain (especially Pro119) is the critical surface distinguishing FKBP52's receptor-potentiating activity from the antagonistic co-chaperone FKBP51.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"FKBP4 (FKBP52) is an Hsp90-associated immunophilin co-chaperone that uses functionally separable domains to potentiate steroid hormone receptor signaling and to couple chaperone clients to microtubule-based transport [#0, #16]. It possesses FK506/rapamycin-sensitive peptidyl-prolyl isomerase (PPIase) activity confined to its N-terminal FK1 domain, while a C-terminal TPR domain binds the Hsp90 C-terminal EEVD motif in an ATP-independent manner [#0, #2, #5, #15]. Within unactivated glucocorticoid, progesterone, androgen, and mineralocorticoid receptor heterocomplexes, hormone binding triggers exchange of the antagonistic co-chaperone FKBP51 for FKBP52, which recruits cytoplasmic dynein/dynactin via its PPIase domain to drive retrograde microtubule-dependent transport of the intact receptor-Hsp90 complex to the nucleus [#11, #13, #14, #29]. FKBP52 potentiates receptor activity by increasing hormone-binding affinity, a function genetically dissected to the proline-rich FK1 loop (Pro119) rather than catalytic isomerization, and is essential in vivo for progesterone-dependent uterine implantation and androgen receptor signaling in male reproductive tissues [#16, #22, #23, #26, #27]. Beyond receptors, FKBP52 gates Ca2+ channels through proline isomerization (stimulus-dependent TRPC1 opening in axon guidance; inhibition of TRPV5) [#24, #30], binds tubulin and Tau to modulate microtubule dynamics and drive PPIase-independent Tau oligomerization with prion-like seeding linked to tauopathy [#28, #31, #39, #41, #44], stabilizes Argonaute2 to promote RISC assembly [#35, #36], and activates NF-\\u03baB/IKK signaling [#32, #43]. Its Hsp90 binding is switched off by casein kinase II phosphorylation of Thr-143 [#8]. FKBP52 also mediates the neuroregenerative action of FK506 after spinal cord injury, in opposition to FKBP51 [#52].\",\n  \"teleology\": [\n    {\n      \"year\": 1992,\n      \"claim\": \"Establishing that FKBP52 is an enzyme and a chaperone-associated factor defined its dual identity as an immunophilin that physically partners Hsp90 in steroid receptor complexes.\",\n      \"evidence\": \"Recombinant PPIase assay with FK506/rapamycin inhibition and co-IP with hsp90\",\n      \"pmids\": [\"1279700\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not map which domain bound Hsp90 versus which carried catalytic activity\", \"Functional consequence for receptor activity unknown\"]\n    },\n    {\n      \"year\": 1993,\n      \"claim\": \"Domain mapping resolved the modular architecture, assigning PPIase activity to the N-terminal FKBP12-like domain and protein-interaction roles to a separate TPR region.\",\n      \"evidence\": \"E. coli deletion-mutant PPIase assays plus TPR identification from receptor complexes; in vitro GR complex reconstitution\",\n      \"pmids\": [\"8216288\", \"8514757\", \"8341706\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"TPR-Hsp90 binding was inferred, not yet directly demonstrated\", \"ATP-binding functional role unresolved\"]\n    },\n    {\n      \"year\": 1994,\n      \"claim\": \"Direct mapping showed the C-terminal TPR domain mediates ATP-independent, immunosuppressant-insensitive Hsp90 binding, confirming chaperone docking is independent of the catalytic site.\",\n      \"evidence\": \"Gel-retardation with purified proteins and deletion mutants\",\n      \"pmids\": [\"7526392\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Required flanking residues beyond core TPR not yet defined\", \"Stoichiometry on Hsp90 dimer unknown\"]\n    },\n    {\n      \"year\": 1996,\n      \"claim\": \"Competition among TPR immunophilins for Hsp90 established that FKBP52, CyP40 and others form mutually exclusive heterocomplexes, framing combinatorial chaperone assembly.\",\n      \"evidence\": \"GST-fusion deletion pulldowns and competition with myometrial cytosol; NMR structure of FK1 domain\",\n      \"pmids\": [\"8621687\", \"8780506\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"TPR alone insufficient; flanking acidic/basic determinants only partially defined\", \"Functional outcome of exclusivity not tested\"]\n    },\n    {\n      \"year\": 1997,\n      \"claim\": \"Identification of CK2 phosphorylation at Thr-143 that abolishes Hsp90 binding revealed a post-translational switch controlling chaperone complex composition.\",\n      \"evidence\": \"In vitro CK2 kinase assay, mutagenesis mapping, in vivo 32P labeling, Hsp90 binding assay\",\n      \"pmids\": [\"9405642\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Physiological signals driving Thr-143 phosphorylation unknown\", \"Downstream effect on receptor transport untested\"]\n    },\n    {\n      \"year\": 1999,\n      \"claim\": \"Demonstrating that the PPIase domain binds cytoplasmic dynein provided the physical link connecting receptor-Hsp90 complexes to the motor machinery.\",\n      \"evidence\": \"Cross-linking of purified proteins, co-immunoadsorption, domain-fragment competition; stoichiometry of one FKBP52 per Hsp90 dimer\",\n      \"pmids\": [\"10601253\", \"11350175\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct demonstration of transport in cells not yet shown\", \"Dynein adaptor subunit contacted not identified\"]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"Live-imaging and biochemical work established that FKBP52 drives hormone-induced retrograde microtubule transport of GR and that hormone triggers FKBP51-to-FKBP52 exchange with dynein recruitment.\",\n      \"evidence\": \"GFP-GR live imaging, microtubule disruption, fractionation and co-IP in hormone-treated cells; chaperone-domain and PPIase/TPR mutant analyses; Drosophila TRPL channel patch-clamp\",\n      \"pmids\": [\"11278753\", \"11751894\", \"11473108\", \"11514552\", \"11350175\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether transport is required for transactivation versus affinity not separated\", \"Nuclear pore transit mechanism not resolved\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Yeast genetics showed FKBP52 uniquely potentiates GR transactivation by raising hormone-binding affinity, requiring both Hsp90 binding and (at this stage) PPIase activity.\",\n      \"evidence\": \"S. cerevisiae reporter assays with PPIase-dead and TPR-dead mutants; hormone-binding affinity measurement\",\n      \"pmids\": [\"12606580\", \"12611898\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Catalytic mechanism of affinity enhancement not defined\", \"Whether other receptors behave identically not yet tested\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Knockout mice established tissue-specific physiological roles, showing FKBP52 is essential for PR-dependent uterine implantation and AR signaling in male reproductive tissue.\",\n      \"evidence\": \"Fkbp52-knockout mice with hormone-binding, reporter, ChIP and gene-expression readouts; TRPV5 patch-clamp/Co-IP\",\n      \"pmids\": [\"16176985\", \"15831525\", \"16352746\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Why receptor dependence is tissue-restricted not explained\", \"Step controlled downstream of receptor not yet localized\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"ChIP in knockout cells localized FKBP52's action to a step downstream of AR DNA binding, refining the model from chromatin loading to transactivation competence.\",\n      \"evidence\": \"Fkbp52-knockout MEFs, reporter assays, ChIP showing normal promoter occupancy, hormone binding; AAV dynein-trafficking knockout/rescue\",\n      \"pmids\": [\"17142810\", \"16828834\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular nature of the downstream transactivation step undefined\", \"Generalization to endogenous AR targets limited\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"An unbiased screen identified FK1-loop Pro119 as the determinant distinguishing FKBP52 from FKBP51 and showed potentiation is independent of PPIase catalysis, redefining the active surface.\",\n      \"evidence\": \"Yeast random-mutagenesis screen of FKBP51, reciprocal mutagenesis, mammalian reporter assays with catalytic-dead mutants; tubulin binding/depolymerization mapping\",\n      \"pmids\": [\"17938211\", \"17435176\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How the Pro119 loop contacts the receptor structurally unresolved\", \"Reconciliation with earlier PPIase-dependence claims incomplete\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Reconstitution of the MR-Hsp90-dynein/dynactin transport module generalized the FKBP52-driven retrograde transport mechanism across steroid receptor classes.\",\n      \"evidence\": \"Fractionation, cross-linking, and motor-complex reassembly on stripped MR immune pellets; TRPC1 isomerization-gated axon guidance in vivo\",\n      \"pmids\": [\"20038533\", \"19945390\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Quantitative contribution of transport to nuclear signaling not measured\", \"Channel-gating versus receptor roles use overlapping domains, leaving substrate specificity open\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Direct Tau binding and antagonism of Tau-driven microtubule assembly placed FKBP52 in neuronal cytoskeletal and tauopathy biology.\",\n      \"evidence\": \"Purified-protein binding, microtubule assembly assay, neurite-length quantification in PC12 cells, co-localization in cortical neurons; APP/Atox1-copper interaction in Drosophila; RET51 phospho-Y905 dependent Co-IP\",\n      \"pmids\": [\"20133804\", \"20084280\", \"20442138\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Relationship between Tau binding and steroid co-chaperone roles unclear\", \"In vivo pathological relevance not yet established at this stage\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Demonstration that FKBP52 induces pathological Tau oligomers/filaments with prion-like seeding, including in vivo zebrafish rescue, advanced a causative role in Tau aggregation.\",\n      \"evidence\": \"Purified-protein assembly with EM, seeding in neuroblastoma cells, Tau-P301L zebrafish knockdown; FK1-GR interaction by BiFC/PLA in glioblastoma\",\n      \"pmids\": [\"24623856\", \"25888602\", \"25132599\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Cellular trigger converting FKBP52 from chaperone to aggregation factor unknown\", \"Relationship to Hsp90 chaperone cycle not defined\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Mapping the Tau interaction to the FK1/FK2 surface and showing PPIase-independence consolidated a catalysis-independent aggregation mechanism, while parallel work extended dynein-coupled transport to hTERT.\",\n      \"evidence\": \"PPIase-dead oligomerization assay, NMR mapping of PHF6 peptide; Co-IP mapping of TPR-Hsp90 and PPIase-dynamitin for hTERT transport with telomerase readouts\",\n      \"pmids\": [\"26903089\", \"27503910\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of PHF6-FK1/FK2 engagement at atomic level incomplete\", \"hTERT findings rest on single-lab Co-IP/depletion\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Identification of FKBP52/p23 association with Argonaute2 extended its co-chaperone role to RISC assembly and small-RNA silencing.\",\n      \"evidence\": \"Co-IP, siRNA depletion, FK506 inhibition, miRNA/luciferase reporter assays, lysosome-inhibitor rescue\",\n      \"pmids\": [\"24049110\", \"23741051\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether FKBP52 acts catalytically on Ago2 or only via Hsp90 cycle unclear\", \"Single-lab Co-IP evidence\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"FKBP52 was shown to drive NF-\\u03baB activation through PPIase- and TPR-dependent RelA nuclear retention and FKBP51-to-FKBP52 exchange, paralleling the steroid receptor switch.\",\n      \"evidence\": \"Reporter, Co-IP, EMSA, ChIP, siRNA with domain/PPIase mutants\",\n      \"pmids\": [\"25104352\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Hsp90-independence of this role contrasts with receptor mechanism\", \"Physiological NF-\\u03baB target context limited\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Proximity proteomics and cancer models linked FKBP4 to PI3K/Akt/mTOR signaling and to IKK assembly, broadening its oncogenic signaling roles.\",\n      \"evidence\": \"BioID interactome, siRNA knockdown, xenografts; Co-IP domain mapping of Hsp90/IKK with kinase assays\",\n      \"pmids\": [\"31660083\", \"34112753\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct versus proximity interactions not distinguished for PI3K components\", \"Single-lab evidence for each pathway\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Genetic epistasis with FK506 established that FKBP52, opposed by FKBP51, mediates neuroregenerative recovery, and additional work tied FKBP51/52 to AR dimerization and ER\\u03b1 stabilization via BRCA1.\",\n      \"evidence\": \"Fkbp52 vs Fkbp51 knockout spinal-cord-injury mice with locomotor readouts; AR dimerization/ChIP assays; FKBP52-BRCA1 Co-IP and ER\\u03b1 stability assays\",\n      \"pmids\": [\"32828804\", \"34057812\", \"35394865\", \"33832539\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular target of the neurotrophic action not identified\", \"AR/ER\\u03b1 roles depend partly on single-lab depletion data\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How FKBP52 selects among its many functional outputs\\u2014receptor transport, channel gating, Tau aggregation, RISC assembly, NF-\\u03baB activation\\u2014using a shared, largely PPIase-independent FK1 surface remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structural model of FKBP52 bound to a steroid receptor or to dynein\", \"Determinants of client/substrate selectivity unknown\", \"Integration of catalysis-independent and chaperone-dependent mechanisms unresolved\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0016853\", \"supporting_discovery_ids\": [0, 2, 24, 30]},\n      {\"term_id\": \"GO:0044183\", \"supporting_discovery_ids\": [15, 31]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [16, 22, 23, 27]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [11, 13, 14, 29]},\n      {\"term_id\": \"GO:0008092\", \"supporting_discovery_ids\": [28, 31]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [14, 47]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [14, 47]},\n      {\"term_id\": \"GO:0005856\", \"supporting_discovery_ids\": [28, 47]},\n      {\"term_id\": \"GO:0005815\", \"supporting_discovery_ids\": [47]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [14, 16, 23, 32]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [0, 5, 15]},\n      {\"term_id\": \"R-HSA-9609507\", \"supporting_discovery_ids\": [13, 14, 29]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [16, 22, 26, 32]},\n      {\"term_id\": \"R-HSA-8953854\", \"supporting_discovery_ids\": [35, 36]}\n    ],\n    \"complexes\": [\n      \"GR-Hsp90-FKBP52-dynein heterocomplex\",\n      \"MR-Hsp90-FKBP52-dynein/dynactin complex\",\n      \"Hsp90-FKBP52-HOP/p23 complex\",\n      \"FKBP52-p23-Ago2 (RISC-loading) complex\"\n    ],\n    \"partners\": [\n      \"HSP90\",\n      \"DYNLL/dynein\",\n      \"AGO2\",\n      \"TRPC1\",\n      \"RELA\",\n      \"BRCA1\",\n      \"TUBB\",\n      \"MAPT\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":7,"faith_pct":85.71428571428571}}