{"gene":"FKBP10","run_date":"2026-06-09T23:54:43","timeline":{"discoveries":[{"year":1995,"finding":"FKBP65 (FKBP10) is a novel 65-kDa FK506-binding protein with four predicted peptidyl-prolyl cis-trans isomerase (PPIase) domains. Recombinant FKBP65 accelerates isomerization of the prolyl peptide bond (N-succinyl-Ala-Ala-Pro-Phe-p-nitroanilide substrate) with catalytic efficiency similar to other FKBPs; this activity is inhibited by FK506 and rapamycin but not cyclosporin A. FKBP65 is also a glycoprotein and phosphoprotein.","method":"Recombinant protein expression, PPIase activity assay, FK506/rapamycin/CsA inhibition, immunoprecipitation, [32P] orthophosphate labeling, Northern blot","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — direct in vitro enzymatic reconstitution with substrate, inhibitor specificity, and multiple orthogonal biochemical characterizations in a single focused study","pmids":["7493967"],"is_preprint":false},{"year":1998,"finding":"Chicken FKBP65 has four PPIase domains arranged in a linear extended structure (~26 nm length, ~3 nm diameter) as shown by analytical ultracentrifugation. Only one of the four domains is inhibited by FK506 (and uniquely by cyclosporin A). FKBP65 catalyzes refolding of type III collagen in vitro (kcat/Km = 4.3×10³ M⁻¹s⁻¹), demonstrating direct collagen-PPIase activity.","method":"Analytical ultracentrifugation, PPIase activity assay with peptide substrates, FK506/CsA inhibition, in vitro collagen refolding assay","journal":"The Biochemical journal","confidence":"High","confidence_rationale":"Tier 1 / Strong — multiple orthogonal in vitro methods including structural analysis and enzymatic reconstitution, single focused study on this protein","pmids":["9461498"],"is_preprint":false},{"year":1998,"finding":"FKBP65 was identified as a binding partner of tropoelastin in the secretory pathway. Chemical cross-linking and co-immunoprecipitation from intact fetal bovine auricular chondrocytes showed FKBP65 and BiP co-precipitate with tropoelastin. The association occurs in the ER and is disrupted before the Golgi, suggesting FKBP65 acts as an ER chaperone for tropoelastin folding prior to secretion.","method":"Bifunctional chemical cross-linking in intact cells, co-immunoprecipitation, SDS-PAGE, microsequencing, brefeldin A and ALLN treatment","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal co-IP with chemical cross-linking in intact cells, pharmacological validation of ER localization of interaction, single focused study with multiple orthogonal methods","pmids":["9442105"],"is_preprint":false},{"year":1998,"finding":"FKBP65 forms immune complexes with hsp90 and the serine/threonine kinase c-Raf-1. The NH2-terminal regulatory domain of c-Raf-1 is required for interaction with FKBP65. GST-FKBP65 pulldown confirmed that full-length FKBP65 interacts with c-Raf-1 but not B-Raf. Association with c-Raf-1 correlates with v-H-RasV12-stimulated activation kinetics in Xenopus oocytes, linking FKBP65 to signal transduction.","method":"Co-immunoprecipitation, GST-FKBP65 pulldown with purified Raf proteins, Xenopus oocyte injection assay","journal":"Cell growth & differentiation","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal co-IP and GST pulldown with purified proteins, single lab, two orthogonal methods","pmids":["9438387"],"is_preprint":false},{"year":2000,"finding":"FKBP65 is localized within the lumen of the ER (not cytosolic) as determined by subcellular fractionation, Triton X-114 phase separation, protease protection assays, and immunofluorescence. FKBP65 co-localizes with tropoelastin, and the two proteins dissociate before reaching the Golgi apparatus.","method":"Subcellular fractionation, Triton X-114 phase separation, protease protection assay, immunofluorescence microscopy, immunohistochemistry","journal":"Molecular biology of the cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — four independent orthogonal localization methods all confirming ER luminal localization, single focused study","pmids":["11071917"],"is_preprint":false},{"year":2005,"finding":"FKBP65 expression is upregulated by TGF-β1 in human lung fibroblasts at the transcriptional level (not mRNA stabilization), and this response is blocked by GGTI-298 (a geranylgeranyl transferase I inhibitor), similar to type I collagen and tropoelastin. FKBP65 does not undergo the unfolded protein response, distinguishing its regulation from general ER stress foldases.","method":"Fibroblast culture with TGF-β1 treatment, RNA polymerase II inhibitor chase, GGTI-298 dose-response, UPR assay","journal":"Cell stress & chaperones","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct pharmacological perturbation with two orthogonal inhibitors confirming transcriptional regulation, single lab","pmids":["16333983"],"is_preprint":false},{"year":2008,"finding":"FKBP65 acts as a molecular chaperone: it is a monomer in solution, inhibits thermal aggregation of citrate synthase, promotes refolding of denatured rhodanese, and delays in vitro fibril formation of type I collagen (indicating interaction with triple-helical collagen). Chaperone activity is comparable to protein-disulfide isomerase. FKBP65 can be isolated from chick embryos on a gelatin-Sepharose column.","method":"Analytical ultracentrifugation, thermal aggregation assay (citrate synthase), rhodanese refolding/aggregation assay, in vitro collagen fibril formation assay, gelatin-Sepharose affinity chromatography","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — multiple reconstituted in vitro chaperone assays with orthogonal substrates, directly establishing chaperone activity","pmids":["18786928"],"is_preprint":false},{"year":2010,"finding":"Loss-of-function mutations in FKBP10 affect type I procollagen secretion in patient cells, identifying FKBP65 as required for normal procollagen secretion/processing in the ER.","method":"Patient fibroblast studies, procollagen secretion analysis in cells homozygous for FKBP10 mutations","journal":"American journal of human genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — patient loss-of-function with cellular secretion phenotype, single lab, multiple families","pmids":["20362275"],"is_preprint":false},{"year":2010,"finding":"Recombinant FKBP65 markedly promotes initiation of tropoelastin coacervation in vitro at a 1:2 molar ratio (TE:FKBP65) and retards maturation of aggregates. This effect is unaffected by rapamycin, demonstrating that PPIase activity of FKBP65 is not required for modulating tropoelastin self-assembly.","method":"In vitro turbidimetric coacervation assay with recombinant FKBP65 and chicken aorta tropoelastin, rapamycin inhibition, comparison to FKBP12","journal":"Biochemistry and cell biology","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — direct in vitro reconstitution with PPIase-independent mechanistic dissection, single lab","pmids":["21102654"],"is_preprint":false},{"year":2011,"finding":"ER stress signals that activate IP3R-mediated ER Ca²⁺ release cause rapid proteasomal degradation of FKBP65 via retrotranslocation (ERAD). Inhibiting IP3R-mediated ER Ca²⁺ release blocks this proteolysis. A defect in the EF1 Ca²⁺-binding EF-hand domain of FKBP65 leads to diminished ER protein levels that are restored by proteasome inhibition; the EF2 mutation does not confer this phenotype.","method":"ER stress induction, proteasome inhibition, cellular fractionation, live imaging of FKBP65-GFP, EF-hand site-directed mutagenesis, immunoblotting","journal":"Cell stress & chaperones","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — pharmacological rescue, mutagenesis, and fractionation in one study; single lab, multiple orthogonal methods","pmids":["21761186"],"is_preprint":false},{"year":2012,"finding":"Loss of FKBP65 (due to FKBP10 mutations) results in diminished hydroxylation of telopeptide lysyl residues of type I collagen that are involved in intermolecular cross-link formation in bone. Procollagen secretion is slightly delayed and stabilization of the intact trimer is incomplete.","method":"Patient fibroblast/bone studies, mass spectrometry of collagen cross-links, collagen electrophoresis, multiple family cohort","journal":"Human molecular genetics","confidence":"High","confidence_rationale":"Tier 2 / Strong — mass spectrometry cross-link analysis across 21 families, replicated finding of telopeptide lysyl hydroxylation defect","pmids":["22949511"],"is_preprint":false},{"year":2012,"finding":"Absence of FKBP65 (FKBP10 null mutation) dramatically decreases collagen deposited in culture matrix despite normal collagen secretion. Mass spectrometry shows absence of hydroxylation of collagen telopeptide lysine required for cross-linking. Normal collagen chain incorporation, helix folding, and Tm indicate a minimal general collagen chaperone role for FKBP65, but a specific requirement for telopeptide lysyl hydroxylase activity or substrate access.","method":"Patient fibroblast studies, collagen electrophoresis, mass spectrometry, thermal stability (Tm), Raman spectroscopy, immunofluorescence of matrix collagen fibrils","journal":"Human mutation","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — multiple orthogonal methods (MS, spectroscopy, IF, electrophoresis) in patient cells with near-null FKBP65, single focused study","pmids":["22718341"],"is_preprint":false},{"year":2013,"finding":"FKBP65 mutations (Kuskokwim syndrome, p.Tyr293del in PPIase domain 3) result in substantially decreased hydroxylation of the telopeptide lysine (2–10% vs 60% in controls) and marked reduction in maturely cross-linked collagen in matrix. Collagen fibrils formed in vitro show subtle loosening of monomer packing. These findings indicate FKBP65 supports collagen telopeptide hydroxylation by lysyl hydroxylase 2, and does so via its PPIase function.","method":"Patient fibroblast analysis, mass spectrometry of collagen cross-links, in vitro fibril formation, immunofluorescence, collagen matrix deposition assay","journal":"Human mutation","confidence":"High","confidence_rationale":"Tier 2 / Strong — mass spectrometry cross-link quantification, in vitro fibril assay, and matrix deposition, replicated across multiple probands","pmids":["23712425"],"is_preprint":false},{"year":2013,"finding":"Both elastin-binding protein (EBP) and FKBP65 bind tropoelastin with strong affinity (FKBP65 Kd ~4-fold higher than EBP). Both proteins modify the kinetics of tropoelastin self-assembly in vitro by limiting growth and maturation of aggregates. The ability of FKBP65 to modulate tropoelastin self-assembly is independent of its PPIase enzymatic activity.","method":"In vitro binding affinity measurements, in vitro tropoelastin self-assembly kinetics assay, PPIase inhibitor controls","journal":"Biochemistry","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — direct in vitro reconstitution with affinity quantification and mechanistic dissection (PPIase-independent), single lab","pmids":["24106871"],"is_preprint":false},{"year":2013,"finding":"Increased FKBP10 levels in Gaucher disease fibroblasts accelerate mutant glucocerebrosidase degradation over folding/trafficking. Decreased ER FKBP10 concentration leads to more mutant enzyme partitioning into the calnexin pro-folding pathway, enhancing folding and activity. This establishes FKBP10 as a regulator of ER proteostasis network balance for lysosomal enzymes.","method":"Mass spectrometry proteomics, siRNA knockdown, glucocerebrosidase activity assay, Gaucher fibroblast model","journal":"Chemistry & biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — MS-identified target validated by loss-of-function with functional enzyme activity readout, single lab, two orthogonal approaches","pmids":["23434032"],"is_preprint":false},{"year":2014,"finding":"Fkbp10-null mouse embryonic fibroblasts show retention of procollagen in the cell layer and associated dilated ER. Type I calvarial collagen from Fkbp10-/- mice shows reduced stable crosslink formation at telopeptide lysines, confirming FKBP65 is required for telopeptide lysine crosslinking in vivo.","method":"Fkbp10-/- knockout mouse model, immunofluorescence, electron microscopy (dilated ER), mass spectrometry of collagen cross-links from calvarial bone","journal":"Human molecular genetics","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic knockout model with direct biochemical (MS cross-link) and cell biological (ER dilation, collagen retention) phenotyping, replicated finding","pmids":["24777781"],"is_preprint":false},{"year":2014,"finding":"HSP47 and FKBP65 act cooperatively during posttranslational maturation of type I procollagen. A destabilizing mutation in HSP47 (SERPINH1) causes secondary mislocalization and destabilization of FKBP65. FKBP65 and HSP47 fail to properly interact in mutant HSP47 cells, placing both in a common cellular pathway for procollagen maturation.","method":"Patient fibroblast studies (SERPINH1 mutation), co-immunoprecipitation of HSP47 and FKBP65, immunofluorescence localization, collagen analysis","journal":"Human molecular genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP and localization studies in disease model cells, single lab, two orthogonal methods","pmids":["25510505"],"is_preprint":false},{"year":2017,"finding":"FKBP65 PPIase activity is required to positively modulate LH2 (lysyl hydroxylase 2) enzymatic activity for hydroxylysine-aldehyde-derived collagen cross-link (HLCC) formation. In Fkbp10-null fibroblasts, HLCCs are diminished and LCCs increased without change in LH2 protein levels; reconstitution with wild-type but not PPIase-domain-mutant FKBP65 rescues the HLCC/LCC ratio. LH2 and FKBP65 are part of a common protein complex.","method":"Fkbp10-null vs wild-type MEFs, collagen cross-link mass spectrometry, reconstitution with WT vs PPIase-mutant FKBP65, co-immunoprecipitation, protein-fragment complementation assay, co-immunofluorescence","journal":"Scientific reports","confidence":"High","confidence_rationale":"Tier 1 / Strong — reconstitution with separation-of-function mutant, mass spectrometry cross-link quantification, and three independent complex-detection methods in one study","pmids":["28378777"],"is_preprint":false},{"year":2017,"finding":"An ER chaperone complex consisting of HSP47, FKBP65, and BiP modulates lysyl hydroxylase 2 (LH2) activity on type I collagen C-telopeptides. FKBP65 and HSP47 modulate LH2 activity (either favoring or repressing it), and BiP enhances complex formation.","method":"Co-immunoprecipitation identifying HSP47-FKBP65-BiP complex, LH2 activity assays in OI patient cells, loss-of-function studies","journal":"Journal of bone and mineral research","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal co-IP identifying multi-protein complex, LH2 functional activity assay, multiple OI patient models, replicated by orthogonal methods","pmids":["28177155"],"is_preprint":false},{"year":2017,"finding":"Osteoblast-specific conditional deletion of Fkbp10 in mice reduces mature hydroxylysine-aldehyde collagen cross-linking in bone (by mass spectrometry) without affecting bone quantity or mineralization degree, but reduces mineral-to-matrix ratio and crystal size (Raman spectroscopy and SAXS) and impairs biomechanical bone strength.","method":"Conditional Fkbp10 knockout (Col1a1-Cre), μCT, histomorphometry, qBEI, mass spectrometry of collagen cross-links, Raman spectroscopy, SAXS, mechanical testing","journal":"Journal of bone and mineral research","confidence":"High","confidence_rationale":"Tier 2 / Strong — tissue-specific KO with multiple orthogonal quantitative methods establishing bone quality phenotype downstream of collagen cross-linking","pmids":["28206698"],"is_preprint":false},{"year":2017,"finding":"FKBP10 knockdown in hypertrophic scar fibroblasts reduces α-smooth muscle actin expression, extracellular matrix component production, TGF-β1 expression, and attenuates Smad signaling pathway activation, demonstrating a role for FKBP65 in regulating fibroblast-to-myofibroblast transition via the TGF-β/Smad axis.","method":"siRNA knockdown in human hypertrophic scar fibroblasts, α-SMA and ECM protein expression analysis, Smad signaling pathway analysis, in vivo mouse scar model with siRNA","journal":"The Journal of investigative dermatology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss-of-function in primary human cells with defined signaling pathway readouts, confirmed in vivo, single lab","pmids":["28774593"],"is_preprint":false},{"year":2018,"finding":"FKBP10 knockdown attenuates adhesion and migration of primary human lung fibroblasts. FKBP10 co-localizes with collagen VI (by IF and proximity ligation assay), and coating culture dishes with collagen VI abolishes the migration defect caused by FKBP10 deficiency, establishing that FKBP10 regulates fibroblast migration primarily through collagen VI synthesis.","method":"siRNA knockdown, immunofluorescence, proximity ligation assay, scratch assay, single-cell time-lapse tracking, collagen VI rescue experiment","journal":"Respiratory research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional rescue experiment with collagen VI identifies mechanistic link, supported by PLA and IF co-localization, single lab","pmids":["29673351"],"is_preprint":false},{"year":2020,"finding":"FKBP10 promotes lung cancer cell growth and stemness via its PPIase activity. FKBP10 interacts with ribosomes, and its downregulation causes reduced translation elongation at the beginning of open reading frames, particularly at proline-encoding codons. Gain- and loss-of-function assays confirmed PPIase activity is required for these translational effects.","method":"Gain/loss-of-function in lung cancer cells and mouse tumor models, ribosome co-immunoprecipitation, ribosome profiling/translation elongation assay, PPIase-domain dependency studies","journal":"Cell reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ribosome co-IP and translation elongation assay with PPIase-dependent mechanism, single lab, two orthogonal methods","pmids":["32187554"],"is_preprint":false},{"year":2021,"finding":"Conditional deletion of Fkbp10 in tendons and ligaments reduces telopeptide lysyl hydroxylation of type I procollagen and collagen cross-linking in tendons, leading to fibrosis, inflammation, and ectopic chondrogenesis with enhanced Gli1 expression (Hedgehog signaling). Genetic inhibition of the Hh pathway attenuates ectopic chondrogenesis and joint deformities and restores gait in Fkbp10 mutants.","method":"Tendon/ligament-specific Fkbp10 conditional KO mouse, mass spectrometry of collagen cross-links, immunohistochemistry (Gli1), genetic Hh pathway inhibition, gait analysis","journal":"Proceedings of the National Academy of Sciences","confidence":"High","confidence_rationale":"Tier 2 / Strong — tissue-specific KO with biochemical (MS), molecular (Gli1/Hh), and functional (gait) readouts, genetic rescue confirms pathway","pmids":["34161280"],"is_preprint":false},{"year":2021,"finding":"FKBP10 interacts with HSP47 (co-immunoprecipitation, GST pulldown, co-immunofluorescence) in glioma cells, and this interaction activates the AKT-CREB-PCNA signaling axis to promote cell proliferation.","method":"GST pulldown, co-immunoprecipitation, confocal immunofluorescence, western blotting (p-AKT, p-CREB, PCNA), CCK-8, colony formation, xenograft tumor model","journal":"Journal of biomedical science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal co-IP and GST pulldown confirming FKBP10-HSP47 interaction, pathway downstream of interaction characterized, single lab","pmids":["33557829"],"is_preprint":false},{"year":2024,"finding":"FKBP10 binds directly to LDHA (lactate dehydrogenase A) through its C-terminal region and enhances LDHA-Y10 phosphorylation, leading to hyperactive Warburg effect and accumulation of histone lactylation in ccRCC cells. This function depends on FKBP10's PPIase domains.","method":"Co-immunoprecipitation (direct binding), in vitro/in vivo proliferation and metastasis assays, LDHA phosphorylation analysis, histone lactylation measurement, PPIase domain dependency, in vivo xenograft","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct co-IP of FKBP10-LDHA interaction with downstream phosphorylation and metabolic readouts, PPIase domain dependency, single lab","pmids":["38233415"],"is_preprint":false},{"year":2024,"finding":"fkbp10a knockout zebrafish show decreased type I collagen lysyl hydroxylation by mass spectrometry and wide skeletal variability, with enlarged collagen fibrils and disturbed elastin layers ultrastructurally. Bmpr1aa was identified as a modifier gene whose reduced expression correlates with increased skeletal severity.","method":"fkbp10a knockout zebrafish, mass spectrometry of collagen lysyl hydroxylation, electron microscopy, whole-exome sequencing, SNP-based linkage analysis, transcriptome analysis","journal":"Journal of bone and mineral research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo genetic KO with MS biochemical validation and modifier gene identification, single lab","pmids":["39566080"],"is_preprint":false},{"year":2025,"finding":"FKBP10 interacts with prelamin A and hinders nuclear entry of prelamin A, leading to decreased nuclear lamin A levels and nuclear atypia in bladder cancer cells. FKBP10 promotes tumor cell invasion and migration but not proliferation through this FKBP10/prelamin A/lamin A axis.","method":"Co-immunoprecipitation (FKBP10-prelamin A interaction), nuclear/cytoplasmic fractionation, lamin A immunofluorescence, invasion/migration assays, loss-of-function knockdown","journal":"International journal of biological sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP of direct interaction with functional nuclear import and invasion phenotype, single lab, two orthogonal methods","pmids":["39781460"],"is_preprint":false},{"year":2025,"finding":"FKBP10 knockdown in hepatic stellate cells (LX-2) attenuates HSC activation, reduces ECM production, and promotes apoptosis. FKBP10 interacts with VPS4A (identified by LC-MS/MS and co-IP), which may facilitate RAS pathway activation. FKBP10 deficiency suppresses RAS signaling in primary HSCs by transcriptomic analysis. In vivo AAV-mediated HSC-specific FKBP10 knockdown reduces fibrosis in CCl4 and BDL mouse models.","method":"siRNA knockdown in LX-2 cells, in vivo AAV6-GFAP-shFKBP10, LC-MS/MS proteomics, co-immunoprecipitation (VPS4A), transcriptomic sequencing, immunohistochemistry","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — MS-identified binding partner validated by co-IP, in vivo rescue, and transcriptomic pathway analysis, single lab","pmids":["42102670"],"is_preprint":false},{"year":2025,"finding":"FKBP10 knockdown inactivates the HSP47/SMAD3 signaling pathway in gluteal muscle contracture fibroblasts: FKBP10 interacts with HSP47, and its knockdown reduces HSP47 and phospho-SMAD3 levels, inhibits fibrosis markers, and ameliorates autophagy defects. HSP47 overexpression reverses the effects of FKBP10 knockdown.","method":"Co-immunoprecipitation (FKBP10-HSP47), western blotting (p-SMAD3, autophagy markers), siRNA knockdown, TGF-β1 stimulation, GMC rat model with FKBP10 knockdown","journal":"The American journal of pathology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP confirming FKBP10-HSP47 interaction, HSP47 epistasis rescue, in vivo rat model, single lab","pmids":["40316212"],"is_preprint":false}],"current_model":"FKBP10 (FKBP65) is an ER-luminal peptidyl-prolyl cis-trans isomerase and molecular chaperone that binds type I procollagen, type III collagen, tropoelastin, and collagen VI in the secretory pathway; its PPIase activity is required to support lysyl hydroxylase 2 (LH2)-mediated telopeptide lysine hydroxylation of type I collagen — likely by facilitating LH2 access or activity as part of an ER chaperone complex with HSP47 and BiP — thereby enabling mature collagen crosslink formation; loss of FKBP65 reduces collagen telopeptide hydroxylysine crosslinks, impairs procollagen secretion, and causes bone fragility and joint contractures (osteogenesis imperfecta/Bruck syndrome), while in cancer contexts FKBP10 additionally associates with ribosomes to promote translational elongation at proline codons, binds LDHA to enhance Y10 phosphorylation and the Warburg effect, and interacts with prelamin A to modulate nuclear lamin A levels and promote invasion."},"narrative":{"mechanistic_narrative":"FKBP10 (FKBP65) is an ER-luminal, multidomain peptidyl-prolyl cis-trans isomerase and molecular chaperone that operates in the secretory pathway to support the folding, post-translational maturation, and assembly of fibrillar extracellular matrix proteins [PMID:7493967, PMID:9461498, PMID:11071917, PMID:18786928]. It contains four PPIase domains arranged in an extended linear structure, of which only one binds FK506, and accelerates isomerization of prolyl peptide bonds as well as the in vitro refolding of type III collagen [PMID:9461498]. Beyond its catalytic activity, FKBP65 functions as a bona fide chaperone, suppressing thermal aggregation of model substrates and delaying type I collagen fibril formation [PMID:18786928], and it binds tropoelastin in the ER to modulate the kinetics of tropoelastin self-assembly through a PPIase-independent mechanism [PMID:9442105, PMID:21102654, PMID:24106871]. Its central physiological role is to enable mature collagen crosslinking: FKBP65 is required for hydroxylation of collagen telopeptide lysines, and its PPIase activity positively modulates lysyl hydroxylase 2 (LH2) within a shared protein complex that also includes HSP47 and BiP, thereby controlling formation of hydroxylysine-aldehyde-derived crosslinks [PMID:22718341, PMID:23712425, PMID:28378777, PMID:28177155]. Loss of FKBP65 impairs procollagen secretion and depletes telopeptide hydroxylysine crosslinks, and tissue-specific deletion in mice degrades bone quality and biomechanical strength and produces tendon fibrosis with ectopic Hedgehog-driven chondrogenesis [PMID:20362275, PMID:24777781, PMID:28206698, PMID:34161280]; loss-of-function FKBP10 mutations cause the human collagen-fragility disorders osteogenesis imperfecta, Bruck syndrome, and Kuskokwim syndrome [PMID:22949511, PMID:23712425]. In cancer settings FKBP10 acquires additional activities: its PPIase function promotes ribosome-associated translational elongation at proline codons [PMID:32187554], it binds LDHA to enhance Y10 phosphorylation and the Warburg effect [PMID:38233415], and it binds prelamin A to restrict its nuclear entry and drive tumor invasion [PMID:39781460]. Across multiple fibrotic and tumor contexts FKBP10 acts through HSP47 to engage TGF-β/SMAD and AKT-CREB signaling [PMID:28774593, PMID:33557829, PMID:40316212].","teleology":[{"year":1995,"claim":"Establishing that FKBP65 is a catalytically active prolyl isomerase defined its core enzymatic identity and distinguished it from cyclosporin-sensitive immunophilins.","evidence":"Recombinant protein PPIase assay with peptide substrate plus FK506/rapamycin/CsA inhibitor specificity","pmids":["7493967"],"confidence":"High","gaps":["Physiological substrates not identified","Role of glycosylation and phosphorylation not defined","Function of the four domains not dissected"]},{"year":1998,"claim":"Structural characterization and a collagen refolding assay showed FKBP65 acts directly on a physiological collagen substrate, linking its PPIase activity to matrix protein folding.","evidence":"Analytical ultracentrifugation, peptide PPIase assays, and in vitro type III collagen refolding with FK506/CsA inhibition","pmids":["9461498"],"confidence":"High","gaps":["In vivo collagen substrate not demonstrated","Roles of the three FK506-insensitive domains unresolved"]},{"year":1998,"claim":"Identification of tropoelastin as an ER binding partner extended FKBP65's role to a second matrix substrate and placed it in a transient pre-Golgi chaperone complex.","evidence":"Chemical cross-linking and co-IP from intact chondrocytes with BiP co-precipitation","pmids":["9442105"],"confidence":"High","gaps":["Whether binding is PPIase-dependent not tested here","Functional consequence for tropoelastin maturation not yet shown"]},{"year":1998,"claim":"A reported FKBP65-hsp90-c-Raf-1 complex linked the protein to signal transduction, but this activity sits apart from its ER-luminal collagen functions.","evidence":"Co-IP and GST-FKBP65 pulldown with purified Raf proteins, Xenopus oocyte assay","pmids":["9438387"],"confidence":"Medium","gaps":["Topological inconsistency with ER-luminal localization not reconciled","Not independently confirmed in later timeline studies","Functional relevance to FKBP65 physiology unclear"]},{"year":2000,"claim":"Rigorous localization established FKBP65 as an ER-luminal protein, framing all its substrate interactions as occurring in the secretory pathway.","evidence":"Subcellular fractionation, Triton X-114 phase separation, protease protection, and immunofluorescence","pmids":["11071917"],"confidence":"High","gaps":["ER retention mechanism not defined","Does not address later cytosolic/ribosomal or nuclear-associated roles"]},{"year":2005,"claim":"Showing TGF-β1 transcriptionally upregulates FKBP65 in coordination with collagen and tropoelastin, and that it escapes the UPR, defined it as a matrix-program foldase rather than a generic stress chaperone.","evidence":"Fibroblast TGF-β1 treatment, Pol II chase, GGTI-298 dose-response, UPR assay","pmids":["16333983"],"confidence":"Medium","gaps":["Transcription factors mediating induction not identified","Link between geranylgeranylation requirement and FKBP65 expression mechanistically unresolved"]},{"year":2008,"claim":"Reconstituted chaperone assays established that FKBP65 prevents substrate aggregation independent of its catalytic site, separating chaperone from isomerase functions.","evidence":"Citrate synthase thermal aggregation, rhodanese refolding, collagen fibril formation, gelatin-Sepharose isolation","pmids":["18786928"],"confidence":"High","gaps":["Structural basis of chaperone activity not defined","Relative contribution of chaperone vs PPIase activity in vivo unresolved"]},{"year":2010,"claim":"Patient loss-of-function studies and a PPIase-independent tropoelastin coacervation assay tied FKBP65 to procollagen secretion in disease and refined its mechanism on elastin.","evidence":"Patient fibroblast secretion analysis; in vitro turbidimetric coacervation with rapamycin controls","pmids":["20362275","21102654"],"confidence":"Medium","gaps":["Molecular cause of secretion defect not pinpointed in 2010","In vivo relevance of tropoelastin coacervation modulation untested"]},{"year":2011,"claim":"Demonstration that ER Ca2+ release triggers ERAD-mediated FKBP65 turnover via an EF-hand-dependent mechanism revealed regulated control of its abundance.","evidence":"ER stress induction, proteasome inhibition, fractionation, EF-hand mutagenesis, FKBP65-GFP imaging","pmids":["21761186"],"confidence":"Medium","gaps":["ERAD machinery components not identified","Physiological trigger for regulated degradation unclear"]},{"year":2012,"claim":"Mass spectrometry across patient cohorts and null cells pinpointed loss of collagen telopeptide lysyl hydroxylation as the central FKBP65 defect, distinguishing a specific crosslinking role from a general chaperone role.","evidence":"Patient/bone studies, MS of collagen crosslinks, electrophoresis, thermal stability, Raman, IF of matrix fibrils","pmids":["22949511","22718341"],"confidence":"High","gaps":["Mechanism by which FKBP65 enables telopeptide hydroxylation not yet defined in 2012","Identity of the responsible hydroxylase not yet established here"]},{"year":2013,"claim":"Kuskokwim-syndrome PPIase-domain mutations linked the telopeptide hydroxylation defect to FKBP65 PPIase function and implicated lysyl hydroxylase 2 as the relevant enzyme, while binding studies refined the PPIase-independent tropoelastin role.","evidence":"Patient fibroblast MS crosslink analysis, in vitro fibril formation; tropoelastin binding affinity and self-assembly kinetics with PPIase controls","pmids":["23712425","24106871"],"confidence":"High","gaps":["Direct FKBP65-LH2 complex not yet demonstrated in 2013","How PPIase activity modulates LH2 not mechanistically resolved"]},{"year":2013,"claim":"Discovery that FKBP10 levels tune the folding-versus-degradation balance for mutant glucocerebrosidase broadened its role to ER proteostasis network regulation beyond matrix proteins.","evidence":"Proteomics, siRNA knockdown, glucocerebrosidase activity assay in Gaucher fibroblasts","pmids":["23434032"],"confidence":"Medium","gaps":["Direct interaction with glucocerebrosidase not shown","Generality across other ER clients untested"]},{"year":2014,"claim":"Genetic knockout in mice and an HSP47-mutation study confirmed FKBP65's in vivo requirement for telopeptide crosslinking and placed FKBP65 and HSP47 in a common procollagen-maturation pathway.","evidence":"Fkbp10-/- MEFs and calvarial collagen MS; SERPINH1 patient cells with HSP47-FKBP65 co-IP and localization","pmids":["24777781","25510505"],"confidence":"High","gaps":["Stoichiometry and organization of the FKBP65-HSP47 complex unresolved in 2014","Whether HSP47 stabilizes FKBP65 generally or only in disease unclear"]},{"year":2017,"claim":"Separation-of-function reconstitution and complex-detection assays established that FKBP65 PPIase activity positively modulates LH2 within an HSP47-FKBP65-BiP complex, defining the molecular mechanism for collagen crosslinking and translating it into bone quality and tendon phenotypes.","evidence":"Fkbp10-null MEF reconstitution with WT vs PPIase-mutant FKBP65, crosslink MS, co-IP/PCA/co-IF; OI patient cell LH2 assays; conditional osteoblast KO with μCT/Raman/SAXS/mechanics","pmids":["28378777","28177155","28206698"],"confidence":"High","gaps":["Direct enzymatic mechanism by which PPIase activity enhances LH2 not resolved","Whether FKBP65 acts on LH2 itself or on the collagen substrate near LH2 unclear"]},{"year":2017,"claim":"Knockdown in scar fibroblasts linked FKBP10 to myofibroblast transition via TGF-β/Smad signaling, extending its role into fibrosis regulation.","evidence":"siRNA in hypertrophic scar fibroblasts with α-SMA/ECM/Smad readouts and in vivo scar model","pmids":["28774593"],"confidence":"Medium","gaps":["Direct molecular link between FKBP10 and Smad pathway not defined here","Whether effect is PPIase-dependent untested"]},{"year":2018,"claim":"Collagen VI rescue experiments showed FKBP10 controls fibroblast adhesion and migration chiefly through collagen VI synthesis, adding another matrix substrate.","evidence":"siRNA, IF, proximity ligation assay, scratch/time-lapse migration, collagen VI coating rescue","pmids":["29673351"],"confidence":"Medium","gaps":["Direct FKBP10-collagen VI biochemical interaction not quantified","Whether collagen VI handling requires PPIase activity untested"]},{"year":2020,"claim":"Ribosome association and ribosome profiling revealed a PPIase-dependent role for FKBP10 in translational elongation at proline codons, a function distinct from its ER chaperone activity.","evidence":"Gain/loss-of-function in lung cancer cells, ribosome co-IP, ribosome profiling, PPIase-domain dependency","pmids":["32187554"],"confidence":"Medium","gaps":["Topological reconciliation with ER-luminal localization unaddressed","Direct ribosomal contact site not mapped"]},{"year":2021,"claim":"Tendon-specific deletion connected FKBP65 loss to ectopic Hedgehog-driven chondrogenesis, and glioma studies tied FKBP10-HSP47 binding to AKT-CREB-PCNA proliferative signaling.","evidence":"Tendon/ligament conditional KO with crosslink MS, Gli1 IHC, genetic Hh rescue, gait analysis; glioma GST pulldown/co-IP and pathway analysis with xenograft","pmids":["34161280","33557829"],"confidence":"High","gaps":["Mechanism linking collagen crosslinking loss to Hh activation not fully defined","Whether the glioma proliferative effect requires PPIase activity untested"]},{"year":2024,"claim":"Direct LDHA binding and an fkbp10a zebrafish knockout extended FKBP10 mechanisms into metabolic reprogramming and confirmed conserved control of collagen lysyl hydroxylation with a Bmpr1aa modifier.","evidence":"Co-IP of FKBP10-LDHA, Y10 phosphorylation and histone lactylation assays, PPIase dependency in ccRCC; zebrafish KO with crosslink MS, EM, and modifier mapping","pmids":["38233415","39566080"],"confidence":"Medium","gaps":["Whether FKBP10 directly catalyzes a step in LDHA activation unresolved","How a luminal chaperone accesses cytosolic LDHA unexplained"]},{"year":2025,"claim":"Prelamin A binding, VPS4A/RAS engagement, and HSP47/SMAD3 regulation defined further FKBP10 functions in tumor invasion and fibrosis across bladder cancer, hepatic stellate cells, and muscle contracture.","evidence":"Co-IP of FKBP10-prelamin A with fractionation and invasion assays; 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report.","date":"2024","source":"Heliyon","url":"https://pubmed.ncbi.nlm.nih.gov/38590901","citation_count":4,"is_preprint":false},{"pmid":"38927610","id":"PMC_38927610","title":"Presentation of Rare Phenotypes Associated with the FKBP10 Gene.","date":"2024","source":"Genes","url":"https://pubmed.ncbi.nlm.nih.gov/38927610","citation_count":3,"is_preprint":false},{"pmid":"29801479","id":"PMC_29801479","title":"Splicing defect in FKBP10 gene causes autosomal recessive osteogenesis imperfecta disease: a case report.","date":"2018","source":"BMC medical genetics","url":"https://pubmed.ncbi.nlm.nih.gov/29801479","citation_count":3,"is_preprint":false},{"pmid":"27362741","id":"PMC_27362741","title":"Novel FKBP10 Mutation in a Patient with Osteogenesis Imperfecta Type XI.","date":"2016","source":"Fetal and pediatric pathology","url":"https://pubmed.ncbi.nlm.nih.gov/27362741","citation_count":3,"is_preprint":false},{"pmid":"40939431","id":"PMC_40939431","title":"Construction and multi-omics analysis of ccRCC mitochondrial related gene machine learning model and validate of key gene FKBP10.","date":"2025","source":"International immunopharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/40939431","citation_count":1,"is_preprint":false},{"pmid":"37422836","id":"PMC_37422836","title":"Mutation In Fkbp10 Gene Cause Bruck Syndrome 1 (Brks1) In A Pakistani Family Of Pashtun Origin.","date":"2023","source":"Journal of Ayub Medical College, Abbottabad : JAMC","url":"https://pubmed.ncbi.nlm.nih.gov/37422836","citation_count":1,"is_preprint":false},{"pmid":"29158687","id":"PMC_29158687","title":"Novel mutation of FKBP10 in a pediatric patient with osteogenesis imperfecta type XI identified by clinical exome sequencing.","date":"2017","source":"The application of clinical genetics","url":"https://pubmed.ncbi.nlm.nih.gov/29158687","citation_count":1,"is_preprint":false},{"pmid":"41694575","id":"PMC_41694575","title":"FKBP10 promotes M2 polarization of macrophage via MEK/ERK/CXCL8 axis and facilitates tumor progression in clear cell renal cell carcinoma.","date":"2026","source":"International journal of biological sciences","url":"https://pubmed.ncbi.nlm.nih.gov/41694575","citation_count":0,"is_preprint":false},{"pmid":"42102670","id":"PMC_42102670","title":"Inhibition of FKBP10 attenuates hepatic stellate cell activation and liver fibrosis via RAS signaling.","date":"2026","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/42102670","citation_count":0,"is_preprint":false},{"pmid":"41969611","id":"PMC_41969611","title":"Integrative Multiomics and Single-Cell Analyses Identify FKBP10 as a Predictor of Radiotherapy Outcome in Colorectal Cancer.","date":"2026","source":"Human mutation","url":"https://pubmed.ncbi.nlm.nih.gov/41969611","citation_count":0,"is_preprint":false},{"pmid":"41422392","id":"PMC_41422392","title":"Novel FKBP10 Mutation in Iranian Patients with Osteogenesis Imperfecta: Insights from Whole-Exome Sequencing to Molecular Dynamics.","date":"2025","source":"Iranian biomedical journal","url":"https://pubmed.ncbi.nlm.nih.gov/41422392","citation_count":0,"is_preprint":false},{"pmid":"41934915","id":"PMC_41934915","title":"Pan-cancer analysis identifies FKBP10 as a regulator of tumor immunosuppression and therapeutic response.","date":"2026","source":"Translational oncology","url":"https://pubmed.ncbi.nlm.nih.gov/41934915","citation_count":0,"is_preprint":false},{"pmid":"41530856","id":"PMC_41530856","title":"Seropositive rheumatoid arthritis in osteogenesis imperfecta type XI (FKBP10 mutation): first case report and literature review.","date":"2026","source":"Orphanet journal of rare diseases","url":"https://pubmed.ncbi.nlm.nih.gov/41530856","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2025.04.17.649276","title":"Engineering patient-derived organotypic bone model to understand osteoanabolic therapy in skeletal disease","date":"2025-04-22","source":"bioRxiv","url":"https://doi.org/10.1101/2025.04.17.649276","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":34632,"output_tokens":8238,"usd":0.113733,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":17673,"output_tokens":6438,"usd":0.124658,"stage2_stop_reason":"end_turn"},"total_usd":0.238391,"stage1_batch_id":"msgbatch_01AsR7g8dGTEiEw9U83bJeWn","stage2_batch_id":"msgbatch_01YV5ZyxtFNUZEjxRcpd9jzb","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1995,\n      \"finding\": \"FKBP65 (FKBP10) is a novel 65-kDa FK506-binding protein with four predicted peptidyl-prolyl cis-trans isomerase (PPIase) domains. Recombinant FKBP65 accelerates isomerization of the prolyl peptide bond (N-succinyl-Ala-Ala-Pro-Phe-p-nitroanilide substrate) with catalytic efficiency similar to other FKBPs; this activity is inhibited by FK506 and rapamycin but not cyclosporin A. FKBP65 is also a glycoprotein and phosphoprotein.\",\n      \"method\": \"Recombinant protein expression, PPIase activity assay, FK506/rapamycin/CsA inhibition, immunoprecipitation, [32P] orthophosphate labeling, Northern blot\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — direct in vitro enzymatic reconstitution with substrate, inhibitor specificity, and multiple orthogonal biochemical characterizations in a single focused study\",\n      \"pmids\": [\"7493967\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"Chicken FKBP65 has four PPIase domains arranged in a linear extended structure (~26 nm length, ~3 nm diameter) as shown by analytical ultracentrifugation. Only one of the four domains is inhibited by FK506 (and uniquely by cyclosporin A). FKBP65 catalyzes refolding of type III collagen in vitro (kcat/Km = 4.3×10³ M⁻¹s⁻¹), demonstrating direct collagen-PPIase activity.\",\n      \"method\": \"Analytical ultracentrifugation, PPIase activity assay with peptide substrates, FK506/CsA inhibition, in vitro collagen refolding assay\",\n      \"journal\": \"The Biochemical journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — multiple orthogonal in vitro methods including structural analysis and enzymatic reconstitution, single focused study on this protein\",\n      \"pmids\": [\"9461498\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"FKBP65 was identified as a binding partner of tropoelastin in the secretory pathway. Chemical cross-linking and co-immunoprecipitation from intact fetal bovine auricular chondrocytes showed FKBP65 and BiP co-precipitate with tropoelastin. The association occurs in the ER and is disrupted before the Golgi, suggesting FKBP65 acts as an ER chaperone for tropoelastin folding prior to secretion.\",\n      \"method\": \"Bifunctional chemical cross-linking in intact cells, co-immunoprecipitation, SDS-PAGE, microsequencing, brefeldin A and ALLN treatment\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal co-IP with chemical cross-linking in intact cells, pharmacological validation of ER localization of interaction, single focused study with multiple orthogonal methods\",\n      \"pmids\": [\"9442105\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"FKBP65 forms immune complexes with hsp90 and the serine/threonine kinase c-Raf-1. The NH2-terminal regulatory domain of c-Raf-1 is required for interaction with FKBP65. GST-FKBP65 pulldown confirmed that full-length FKBP65 interacts with c-Raf-1 but not B-Raf. Association with c-Raf-1 correlates with v-H-RasV12-stimulated activation kinetics in Xenopus oocytes, linking FKBP65 to signal transduction.\",\n      \"method\": \"Co-immunoprecipitation, GST-FKBP65 pulldown with purified Raf proteins, Xenopus oocyte injection assay\",\n      \"journal\": \"Cell growth & differentiation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal co-IP and GST pulldown with purified proteins, single lab, two orthogonal methods\",\n      \"pmids\": [\"9438387\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"FKBP65 is localized within the lumen of the ER (not cytosolic) as determined by subcellular fractionation, Triton X-114 phase separation, protease protection assays, and immunofluorescence. FKBP65 co-localizes with tropoelastin, and the two proteins dissociate before reaching the Golgi apparatus.\",\n      \"method\": \"Subcellular fractionation, Triton X-114 phase separation, protease protection assay, immunofluorescence microscopy, immunohistochemistry\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — four independent orthogonal localization methods all confirming ER luminal localization, single focused study\",\n      \"pmids\": [\"11071917\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"FKBP65 expression is upregulated by TGF-β1 in human lung fibroblasts at the transcriptional level (not mRNA stabilization), and this response is blocked by GGTI-298 (a geranylgeranyl transferase I inhibitor), similar to type I collagen and tropoelastin. FKBP65 does not undergo the unfolded protein response, distinguishing its regulation from general ER stress foldases.\",\n      \"method\": \"Fibroblast culture with TGF-β1 treatment, RNA polymerase II inhibitor chase, GGTI-298 dose-response, UPR assay\",\n      \"journal\": \"Cell stress & chaperones\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct pharmacological perturbation with two orthogonal inhibitors confirming transcriptional regulation, single lab\",\n      \"pmids\": [\"16333983\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"FKBP65 acts as a molecular chaperone: it is a monomer in solution, inhibits thermal aggregation of citrate synthase, promotes refolding of denatured rhodanese, and delays in vitro fibril formation of type I collagen (indicating interaction with triple-helical collagen). Chaperone activity is comparable to protein-disulfide isomerase. FKBP65 can be isolated from chick embryos on a gelatin-Sepharose column.\",\n      \"method\": \"Analytical ultracentrifugation, thermal aggregation assay (citrate synthase), rhodanese refolding/aggregation assay, in vitro collagen fibril formation assay, gelatin-Sepharose affinity chromatography\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — multiple reconstituted in vitro chaperone assays with orthogonal substrates, directly establishing chaperone activity\",\n      \"pmids\": [\"18786928\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Loss-of-function mutations in FKBP10 affect type I procollagen secretion in patient cells, identifying FKBP65 as required for normal procollagen secretion/processing in the ER.\",\n      \"method\": \"Patient fibroblast studies, procollagen secretion analysis in cells homozygous for FKBP10 mutations\",\n      \"journal\": \"American journal of human genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — patient loss-of-function with cellular secretion phenotype, single lab, multiple families\",\n      \"pmids\": [\"20362275\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Recombinant FKBP65 markedly promotes initiation of tropoelastin coacervation in vitro at a 1:2 molar ratio (TE:FKBP65) and retards maturation of aggregates. This effect is unaffected by rapamycin, demonstrating that PPIase activity of FKBP65 is not required for modulating tropoelastin self-assembly.\",\n      \"method\": \"In vitro turbidimetric coacervation assay with recombinant FKBP65 and chicken aorta tropoelastin, rapamycin inhibition, comparison to FKBP12\",\n      \"journal\": \"Biochemistry and cell biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — direct in vitro reconstitution with PPIase-independent mechanistic dissection, single lab\",\n      \"pmids\": [\"21102654\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"ER stress signals that activate IP3R-mediated ER Ca²⁺ release cause rapid proteasomal degradation of FKBP65 via retrotranslocation (ERAD). Inhibiting IP3R-mediated ER Ca²⁺ release blocks this proteolysis. A defect in the EF1 Ca²⁺-binding EF-hand domain of FKBP65 leads to diminished ER protein levels that are restored by proteasome inhibition; the EF2 mutation does not confer this phenotype.\",\n      \"method\": \"ER stress induction, proteasome inhibition, cellular fractionation, live imaging of FKBP65-GFP, EF-hand site-directed mutagenesis, immunoblotting\",\n      \"journal\": \"Cell stress & chaperones\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — pharmacological rescue, mutagenesis, and fractionation in one study; single lab, multiple orthogonal methods\",\n      \"pmids\": [\"21761186\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Loss of FKBP65 (due to FKBP10 mutations) results in diminished hydroxylation of telopeptide lysyl residues of type I collagen that are involved in intermolecular cross-link formation in bone. Procollagen secretion is slightly delayed and stabilization of the intact trimer is incomplete.\",\n      \"method\": \"Patient fibroblast/bone studies, mass spectrometry of collagen cross-links, collagen electrophoresis, multiple family cohort\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — mass spectrometry cross-link analysis across 21 families, replicated finding of telopeptide lysyl hydroxylation defect\",\n      \"pmids\": [\"22949511\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Absence of FKBP65 (FKBP10 null mutation) dramatically decreases collagen deposited in culture matrix despite normal collagen secretion. Mass spectrometry shows absence of hydroxylation of collagen telopeptide lysine required for cross-linking. Normal collagen chain incorporation, helix folding, and Tm indicate a minimal general collagen chaperone role for FKBP65, but a specific requirement for telopeptide lysyl hydroxylase activity or substrate access.\",\n      \"method\": \"Patient fibroblast studies, collagen electrophoresis, mass spectrometry, thermal stability (Tm), Raman spectroscopy, immunofluorescence of matrix collagen fibrils\",\n      \"journal\": \"Human mutation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — multiple orthogonal methods (MS, spectroscopy, IF, electrophoresis) in patient cells with near-null FKBP65, single focused study\",\n      \"pmids\": [\"22718341\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"FKBP65 mutations (Kuskokwim syndrome, p.Tyr293del in PPIase domain 3) result in substantially decreased hydroxylation of the telopeptide lysine (2–10% vs 60% in controls) and marked reduction in maturely cross-linked collagen in matrix. Collagen fibrils formed in vitro show subtle loosening of monomer packing. These findings indicate FKBP65 supports collagen telopeptide hydroxylation by lysyl hydroxylase 2, and does so via its PPIase function.\",\n      \"method\": \"Patient fibroblast analysis, mass spectrometry of collagen cross-links, in vitro fibril formation, immunofluorescence, collagen matrix deposition assay\",\n      \"journal\": \"Human mutation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — mass spectrometry cross-link quantification, in vitro fibril assay, and matrix deposition, replicated across multiple probands\",\n      \"pmids\": [\"23712425\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Both elastin-binding protein (EBP) and FKBP65 bind tropoelastin with strong affinity (FKBP65 Kd ~4-fold higher than EBP). Both proteins modify the kinetics of tropoelastin self-assembly in vitro by limiting growth and maturation of aggregates. The ability of FKBP65 to modulate tropoelastin self-assembly is independent of its PPIase enzymatic activity.\",\n      \"method\": \"In vitro binding affinity measurements, in vitro tropoelastin self-assembly kinetics assay, PPIase inhibitor controls\",\n      \"journal\": \"Biochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — direct in vitro reconstitution with affinity quantification and mechanistic dissection (PPIase-independent), single lab\",\n      \"pmids\": [\"24106871\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Increased FKBP10 levels in Gaucher disease fibroblasts accelerate mutant glucocerebrosidase degradation over folding/trafficking. Decreased ER FKBP10 concentration leads to more mutant enzyme partitioning into the calnexin pro-folding pathway, enhancing folding and activity. This establishes FKBP10 as a regulator of ER proteostasis network balance for lysosomal enzymes.\",\n      \"method\": \"Mass spectrometry proteomics, siRNA knockdown, glucocerebrosidase activity assay, Gaucher fibroblast model\",\n      \"journal\": \"Chemistry & biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — MS-identified target validated by loss-of-function with functional enzyme activity readout, single lab, two orthogonal approaches\",\n      \"pmids\": [\"23434032\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Fkbp10-null mouse embryonic fibroblasts show retention of procollagen in the cell layer and associated dilated ER. Type I calvarial collagen from Fkbp10-/- mice shows reduced stable crosslink formation at telopeptide lysines, confirming FKBP65 is required for telopeptide lysine crosslinking in vivo.\",\n      \"method\": \"Fkbp10-/- knockout mouse model, immunofluorescence, electron microscopy (dilated ER), mass spectrometry of collagen cross-links from calvarial bone\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic knockout model with direct biochemical (MS cross-link) and cell biological (ER dilation, collagen retention) phenotyping, replicated finding\",\n      \"pmids\": [\"24777781\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"HSP47 and FKBP65 act cooperatively during posttranslational maturation of type I procollagen. A destabilizing mutation in HSP47 (SERPINH1) causes secondary mislocalization and destabilization of FKBP65. FKBP65 and HSP47 fail to properly interact in mutant HSP47 cells, placing both in a common cellular pathway for procollagen maturation.\",\n      \"method\": \"Patient fibroblast studies (SERPINH1 mutation), co-immunoprecipitation of HSP47 and FKBP65, immunofluorescence localization, collagen analysis\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP and localization studies in disease model cells, single lab, two orthogonal methods\",\n      \"pmids\": [\"25510505\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"FKBP65 PPIase activity is required to positively modulate LH2 (lysyl hydroxylase 2) enzymatic activity for hydroxylysine-aldehyde-derived collagen cross-link (HLCC) formation. In Fkbp10-null fibroblasts, HLCCs are diminished and LCCs increased without change in LH2 protein levels; reconstitution with wild-type but not PPIase-domain-mutant FKBP65 rescues the HLCC/LCC ratio. LH2 and FKBP65 are part of a common protein complex.\",\n      \"method\": \"Fkbp10-null vs wild-type MEFs, collagen cross-link mass spectrometry, reconstitution with WT vs PPIase-mutant FKBP65, co-immunoprecipitation, protein-fragment complementation assay, co-immunofluorescence\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — reconstitution with separation-of-function mutant, mass spectrometry cross-link quantification, and three independent complex-detection methods in one study\",\n      \"pmids\": [\"28378777\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"An ER chaperone complex consisting of HSP47, FKBP65, and BiP modulates lysyl hydroxylase 2 (LH2) activity on type I collagen C-telopeptides. FKBP65 and HSP47 modulate LH2 activity (either favoring or repressing it), and BiP enhances complex formation.\",\n      \"method\": \"Co-immunoprecipitation identifying HSP47-FKBP65-BiP complex, LH2 activity assays in OI patient cells, loss-of-function studies\",\n      \"journal\": \"Journal of bone and mineral research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal co-IP identifying multi-protein complex, LH2 functional activity assay, multiple OI patient models, replicated by orthogonal methods\",\n      \"pmids\": [\"28177155\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Osteoblast-specific conditional deletion of Fkbp10 in mice reduces mature hydroxylysine-aldehyde collagen cross-linking in bone (by mass spectrometry) without affecting bone quantity or mineralization degree, but reduces mineral-to-matrix ratio and crystal size (Raman spectroscopy and SAXS) and impairs biomechanical bone strength.\",\n      \"method\": \"Conditional Fkbp10 knockout (Col1a1-Cre), μCT, histomorphometry, qBEI, mass spectrometry of collagen cross-links, Raman spectroscopy, SAXS, mechanical testing\",\n      \"journal\": \"Journal of bone and mineral research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — tissue-specific KO with multiple orthogonal quantitative methods establishing bone quality phenotype downstream of collagen cross-linking\",\n      \"pmids\": [\"28206698\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"FKBP10 knockdown in hypertrophic scar fibroblasts reduces α-smooth muscle actin expression, extracellular matrix component production, TGF-β1 expression, and attenuates Smad signaling pathway activation, demonstrating a role for FKBP65 in regulating fibroblast-to-myofibroblast transition via the TGF-β/Smad axis.\",\n      \"method\": \"siRNA knockdown in human hypertrophic scar fibroblasts, α-SMA and ECM protein expression analysis, Smad signaling pathway analysis, in vivo mouse scar model with siRNA\",\n      \"journal\": \"The Journal of investigative dermatology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss-of-function in primary human cells with defined signaling pathway readouts, confirmed in vivo, single lab\",\n      \"pmids\": [\"28774593\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"FKBP10 knockdown attenuates adhesion and migration of primary human lung fibroblasts. FKBP10 co-localizes with collagen VI (by IF and proximity ligation assay), and coating culture dishes with collagen VI abolishes the migration defect caused by FKBP10 deficiency, establishing that FKBP10 regulates fibroblast migration primarily through collagen VI synthesis.\",\n      \"method\": \"siRNA knockdown, immunofluorescence, proximity ligation assay, scratch assay, single-cell time-lapse tracking, collagen VI rescue experiment\",\n      \"journal\": \"Respiratory research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional rescue experiment with collagen VI identifies mechanistic link, supported by PLA and IF co-localization, single lab\",\n      \"pmids\": [\"29673351\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"FKBP10 promotes lung cancer cell growth and stemness via its PPIase activity. FKBP10 interacts with ribosomes, and its downregulation causes reduced translation elongation at the beginning of open reading frames, particularly at proline-encoding codons. Gain- and loss-of-function assays confirmed PPIase activity is required for these translational effects.\",\n      \"method\": \"Gain/loss-of-function in lung cancer cells and mouse tumor models, ribosome co-immunoprecipitation, ribosome profiling/translation elongation assay, PPIase-domain dependency studies\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ribosome co-IP and translation elongation assay with PPIase-dependent mechanism, single lab, two orthogonal methods\",\n      \"pmids\": [\"32187554\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Conditional deletion of Fkbp10 in tendons and ligaments reduces telopeptide lysyl hydroxylation of type I procollagen and collagen cross-linking in tendons, leading to fibrosis, inflammation, and ectopic chondrogenesis with enhanced Gli1 expression (Hedgehog signaling). Genetic inhibition of the Hh pathway attenuates ectopic chondrogenesis and joint deformities and restores gait in Fkbp10 mutants.\",\n      \"method\": \"Tendon/ligament-specific Fkbp10 conditional KO mouse, mass spectrometry of collagen cross-links, immunohistochemistry (Gli1), genetic Hh pathway inhibition, gait analysis\",\n      \"journal\": \"Proceedings of the National Academy of Sciences\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — tissue-specific KO with biochemical (MS), molecular (Gli1/Hh), and functional (gait) readouts, genetic rescue confirms pathway\",\n      \"pmids\": [\"34161280\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"FKBP10 interacts with HSP47 (co-immunoprecipitation, GST pulldown, co-immunofluorescence) in glioma cells, and this interaction activates the AKT-CREB-PCNA signaling axis to promote cell proliferation.\",\n      \"method\": \"GST pulldown, co-immunoprecipitation, confocal immunofluorescence, western blotting (p-AKT, p-CREB, PCNA), CCK-8, colony formation, xenograft tumor model\",\n      \"journal\": \"Journal of biomedical science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal co-IP and GST pulldown confirming FKBP10-HSP47 interaction, pathway downstream of interaction characterized, single lab\",\n      \"pmids\": [\"33557829\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"FKBP10 binds directly to LDHA (lactate dehydrogenase A) through its C-terminal region and enhances LDHA-Y10 phosphorylation, leading to hyperactive Warburg effect and accumulation of histone lactylation in ccRCC cells. This function depends on FKBP10's PPIase domains.\",\n      \"method\": \"Co-immunoprecipitation (direct binding), in vitro/in vivo proliferation and metastasis assays, LDHA phosphorylation analysis, histone lactylation measurement, PPIase domain dependency, in vivo xenograft\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct co-IP of FKBP10-LDHA interaction with downstream phosphorylation and metabolic readouts, PPIase domain dependency, single lab\",\n      \"pmids\": [\"38233415\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"fkbp10a knockout zebrafish show decreased type I collagen lysyl hydroxylation by mass spectrometry and wide skeletal variability, with enlarged collagen fibrils and disturbed elastin layers ultrastructurally. Bmpr1aa was identified as a modifier gene whose reduced expression correlates with increased skeletal severity.\",\n      \"method\": \"fkbp10a knockout zebrafish, mass spectrometry of collagen lysyl hydroxylation, electron microscopy, whole-exome sequencing, SNP-based linkage analysis, transcriptome analysis\",\n      \"journal\": \"Journal of bone and mineral research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo genetic KO with MS biochemical validation and modifier gene identification, single lab\",\n      \"pmids\": [\"39566080\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"FKBP10 interacts with prelamin A and hinders nuclear entry of prelamin A, leading to decreased nuclear lamin A levels and nuclear atypia in bladder cancer cells. FKBP10 promotes tumor cell invasion and migration but not proliferation through this FKBP10/prelamin A/lamin A axis.\",\n      \"method\": \"Co-immunoprecipitation (FKBP10-prelamin A interaction), nuclear/cytoplasmic fractionation, lamin A immunofluorescence, invasion/migration assays, loss-of-function knockdown\",\n      \"journal\": \"International journal of biological sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP of direct interaction with functional nuclear import and invasion phenotype, single lab, two orthogonal methods\",\n      \"pmids\": [\"39781460\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"FKBP10 knockdown in hepatic stellate cells (LX-2) attenuates HSC activation, reduces ECM production, and promotes apoptosis. FKBP10 interacts with VPS4A (identified by LC-MS/MS and co-IP), which may facilitate RAS pathway activation. FKBP10 deficiency suppresses RAS signaling in primary HSCs by transcriptomic analysis. In vivo AAV-mediated HSC-specific FKBP10 knockdown reduces fibrosis in CCl4 and BDL mouse models.\",\n      \"method\": \"siRNA knockdown in LX-2 cells, in vivo AAV6-GFAP-shFKBP10, LC-MS/MS proteomics, co-immunoprecipitation (VPS4A), transcriptomic sequencing, immunohistochemistry\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — MS-identified binding partner validated by co-IP, in vivo rescue, and transcriptomic pathway analysis, single lab\",\n      \"pmids\": [\"42102670\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"FKBP10 knockdown inactivates the HSP47/SMAD3 signaling pathway in gluteal muscle contracture fibroblasts: FKBP10 interacts with HSP47, and its knockdown reduces HSP47 and phospho-SMAD3 levels, inhibits fibrosis markers, and ameliorates autophagy defects. HSP47 overexpression reverses the effects of FKBP10 knockdown.\",\n      \"method\": \"Co-immunoprecipitation (FKBP10-HSP47), western blotting (p-SMAD3, autophagy markers), siRNA knockdown, TGF-β1 stimulation, GMC rat model with FKBP10 knockdown\",\n      \"journal\": \"The American journal of pathology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP confirming FKBP10-HSP47 interaction, HSP47 epistasis rescue, in vivo rat model, single lab\",\n      \"pmids\": [\"40316212\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"FKBP10 (FKBP65) is an ER-luminal peptidyl-prolyl cis-trans isomerase and molecular chaperone that binds type I procollagen, type III collagen, tropoelastin, and collagen VI in the secretory pathway; its PPIase activity is required to support lysyl hydroxylase 2 (LH2)-mediated telopeptide lysine hydroxylation of type I collagen — likely by facilitating LH2 access or activity as part of an ER chaperone complex with HSP47 and BiP — thereby enabling mature collagen crosslink formation; loss of FKBP65 reduces collagen telopeptide hydroxylysine crosslinks, impairs procollagen secretion, and causes bone fragility and joint contractures (osteogenesis imperfecta/Bruck syndrome), while in cancer contexts FKBP10 additionally associates with ribosomes to promote translational elongation at proline codons, binds LDHA to enhance Y10 phosphorylation and the Warburg effect, and interacts with prelamin A to modulate nuclear lamin A levels and promote invasion.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"FKBP10 (FKBP65) is an ER-luminal, multidomain peptidyl-prolyl cis-trans isomerase and molecular chaperone that operates in the secretory pathway to support the folding, post-translational maturation, and assembly of fibrillar extracellular matrix proteins [#0, #1, #4, #6]. It contains four PPIase domains arranged in an extended linear structure, of which only one binds FK506, and accelerates isomerization of prolyl peptide bonds as well as the in vitro refolding of type III collagen [#1]. Beyond its catalytic activity, FKBP65 functions as a bona fide chaperone, suppressing thermal aggregation of model substrates and delaying type I collagen fibril formation [#6], and it binds tropoelastin in the ER to modulate the kinetics of tropoelastin self-assembly through a PPIase-independent mechanism [#2, #8, #13]. Its central physiological role is to enable mature collagen crosslinking: FKBP65 is required for hydroxylation of collagen telopeptide lysines, and its PPIase activity positively modulates lysyl hydroxylase 2 (LH2) within a shared protein complex that also includes HSP47 and BiP, thereby controlling formation of hydroxylysine-aldehyde-derived crosslinks [#11, #12, #17, #18]. Loss of FKBP65 impairs procollagen secretion and depletes telopeptide hydroxylysine crosslinks, and tissue-specific deletion in mice degrades bone quality and biomechanical strength and produces tendon fibrosis with ectopic Hedgehog-driven chondrogenesis [#7, #15, #19, #23]; loss-of-function FKBP10 mutations cause the human collagen-fragility disorders osteogenesis imperfecta, Bruck syndrome, and Kuskokwim syndrome [#10, #12]. In cancer settings FKBP10 acquires additional activities: its PPIase function promotes ribosome-associated translational elongation at proline codons [#22], it binds LDHA to enhance Y10 phosphorylation and the Warburg effect [#25], and it binds prelamin A to restrict its nuclear entry and drive tumor invasion [#27]. Across multiple fibrotic and tumor contexts FKBP10 acts through HSP47 to engage TGF-\\u03b2/SMAD and AKT-CREB signaling [#20, #24, #29].\",\n  \"teleology\": [\n    {\n      \"year\": 1995,\n      \"claim\": \"Establishing that FKBP65 is a catalytically active prolyl isomerase defined its core enzymatic identity and distinguished it from cyclosporin-sensitive immunophilins.\",\n      \"evidence\": \"Recombinant protein PPIase assay with peptide substrate plus FK506/rapamycin/CsA inhibitor specificity\",\n      \"pmids\": [\"7493967\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Physiological substrates not identified\", \"Role of glycosylation and phosphorylation not defined\", \"Function of the four domains not dissected\"]\n    },\n    {\n      \"year\": 1998,\n      \"claim\": \"Structural characterization and a collagen refolding assay showed FKBP65 acts directly on a physiological collagen substrate, linking its PPIase activity to matrix protein folding.\",\n      \"evidence\": \"Analytical ultracentrifugation, peptide PPIase assays, and in vitro type III collagen refolding with FK506/CsA inhibition\",\n      \"pmids\": [\"9461498\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"In vivo collagen substrate not demonstrated\", \"Roles of the three FK506-insensitive domains unresolved\"]\n    },\n    {\n      \"year\": 1998,\n      \"claim\": \"Identification of tropoelastin as an ER binding partner extended FKBP65's role to a second matrix substrate and placed it in a transient pre-Golgi chaperone complex.\",\n      \"evidence\": \"Chemical cross-linking and co-IP from intact chondrocytes with BiP co-precipitation\",\n      \"pmids\": [\"9442105\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether binding is PPIase-dependent not tested here\", \"Functional consequence for tropoelastin maturation not yet shown\"]\n    },\n    {\n      \"year\": 1998,\n      \"claim\": \"A reported FKBP65-hsp90-c-Raf-1 complex linked the protein to signal transduction, but this activity sits apart from its ER-luminal collagen functions.\",\n      \"evidence\": \"Co-IP and GST-FKBP65 pulldown with purified Raf proteins, Xenopus oocyte assay\",\n      \"pmids\": [\"9438387\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Topological inconsistency with ER-luminal localization not reconciled\", \"Not independently confirmed in later timeline studies\", \"Functional relevance to FKBP65 physiology unclear\"]\n    },\n    {\n      \"year\": 2000,\n      \"claim\": \"Rigorous localization established FKBP65 as an ER-luminal protein, framing all its substrate interactions as occurring in the secretory pathway.\",\n      \"evidence\": \"Subcellular fractionation, Triton X-114 phase separation, protease protection, and immunofluorescence\",\n      \"pmids\": [\"11071917\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"ER retention mechanism not defined\", \"Does not address later cytosolic/ribosomal or nuclear-associated roles\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Showing TGF-\\u03b21 transcriptionally upregulates FKBP65 in coordination with collagen and tropoelastin, and that it escapes the UPR, defined it as a matrix-program foldase rather than a generic stress chaperone.\",\n      \"evidence\": \"Fibroblast TGF-\\u03b21 treatment, Pol II chase, GGTI-298 dose-response, UPR assay\",\n      \"pmids\": [\"16333983\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Transcription factors mediating induction not identified\", \"Link between geranylgeranylation requirement and FKBP65 expression mechanistically unresolved\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Reconstituted chaperone assays established that FKBP65 prevents substrate aggregation independent of its catalytic site, separating chaperone from isomerase functions.\",\n      \"evidence\": \"Citrate synthase thermal aggregation, rhodanese refolding, collagen fibril formation, gelatin-Sepharose isolation\",\n      \"pmids\": [\"18786928\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of chaperone activity not defined\", \"Relative contribution of chaperone vs PPIase activity in vivo unresolved\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Patient loss-of-function studies and a PPIase-independent tropoelastin coacervation assay tied FKBP65 to procollagen secretion in disease and refined its mechanism on elastin.\",\n      \"evidence\": \"Patient fibroblast secretion analysis; in vitro turbidimetric coacervation with rapamycin controls\",\n      \"pmids\": [\"20362275\", \"21102654\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular cause of secretion defect not pinpointed in 2010\", \"In vivo relevance of tropoelastin coacervation modulation untested\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Demonstration that ER Ca2+ release triggers ERAD-mediated FKBP65 turnover via an EF-hand-dependent mechanism revealed regulated control of its abundance.\",\n      \"evidence\": \"ER stress induction, proteasome inhibition, fractionation, EF-hand mutagenesis, FKBP65-GFP imaging\",\n      \"pmids\": [\"21761186\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"ERAD machinery components not identified\", \"Physiological trigger for regulated degradation unclear\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Mass spectrometry across patient cohorts and null cells pinpointed loss of collagen telopeptide lysyl hydroxylation as the central FKBP65 defect, distinguishing a specific crosslinking role from a general chaperone role.\",\n      \"evidence\": \"Patient/bone studies, MS of collagen crosslinks, electrophoresis, thermal stability, Raman, IF of matrix fibrils\",\n      \"pmids\": [\"22949511\", \"22718341\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism by which FKBP65 enables telopeptide hydroxylation not yet defined in 2012\", \"Identity of the responsible hydroxylase not yet established here\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Kuskokwim-syndrome PPIase-domain mutations linked the telopeptide hydroxylation defect to FKBP65 PPIase function and implicated lysyl hydroxylase 2 as the relevant enzyme, while binding studies refined the PPIase-independent tropoelastin role.\",\n      \"evidence\": \"Patient fibroblast MS crosslink analysis, in vitro fibril formation; tropoelastin binding affinity and self-assembly kinetics with PPIase controls\",\n      \"pmids\": [\"23712425\", \"24106871\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct FKBP65-LH2 complex not yet demonstrated in 2013\", \"How PPIase activity modulates LH2 not mechanistically resolved\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Discovery that FKBP10 levels tune the folding-versus-degradation balance for mutant glucocerebrosidase broadened its role to ER proteostasis network regulation beyond matrix proteins.\",\n      \"evidence\": \"Proteomics, siRNA knockdown, glucocerebrosidase activity assay in Gaucher fibroblasts\",\n      \"pmids\": [\"23434032\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct interaction with glucocerebrosidase not shown\", \"Generality across other ER clients untested\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Genetic knockout in mice and an HSP47-mutation study confirmed FKBP65's in vivo requirement for telopeptide crosslinking and placed FKBP65 and HSP47 in a common procollagen-maturation pathway.\",\n      \"evidence\": \"Fkbp10-/- MEFs and calvarial collagen MS; SERPINH1 patient cells with HSP47-FKBP65 co-IP and localization\",\n      \"pmids\": [\"24777781\", \"25510505\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Stoichiometry and organization of the FKBP65-HSP47 complex unresolved in 2014\", \"Whether HSP47 stabilizes FKBP65 generally or only in disease unclear\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Separation-of-function reconstitution and complex-detection assays established that FKBP65 PPIase activity positively modulates LH2 within an HSP47-FKBP65-BiP complex, defining the molecular mechanism for collagen crosslinking and translating it into bone quality and tendon phenotypes.\",\n      \"evidence\": \"Fkbp10-null MEF reconstitution with WT vs PPIase-mutant FKBP65, crosslink MS, co-IP/PCA/co-IF; OI patient cell LH2 assays; conditional osteoblast KO with \\u03bcCT/Raman/SAXS/mechanics\",\n      \"pmids\": [\"28378777\", \"28177155\", \"28206698\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct enzymatic mechanism by which PPIase activity enhances LH2 not resolved\", \"Whether FKBP65 acts on LH2 itself or on the collagen substrate near LH2 unclear\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Knockdown in scar fibroblasts linked FKBP10 to myofibroblast transition via TGF-\\u03b2/Smad signaling, extending its role into fibrosis regulation.\",\n      \"evidence\": \"siRNA in hypertrophic scar fibroblasts with \\u03b1-SMA/ECM/Smad readouts and in vivo scar model\",\n      \"pmids\": [\"28774593\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct molecular link between FKBP10 and Smad pathway not defined here\", \"Whether effect is PPIase-dependent untested\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Collagen VI rescue experiments showed FKBP10 controls fibroblast adhesion and migration chiefly through collagen VI synthesis, adding another matrix substrate.\",\n      \"evidence\": \"siRNA, IF, proximity ligation assay, scratch/time-lapse migration, collagen VI coating rescue\",\n      \"pmids\": [\"29673351\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct FKBP10-collagen VI biochemical interaction not quantified\", \"Whether collagen VI handling requires PPIase activity untested\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Ribosome association and ribosome profiling revealed a PPIase-dependent role for FKBP10 in translational elongation at proline codons, a function distinct from its ER chaperone activity.\",\n      \"evidence\": \"Gain/loss-of-function in lung cancer cells, ribosome co-IP, ribosome profiling, PPIase-domain dependency\",\n      \"pmids\": [\"32187554\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Topological reconciliation with ER-luminal localization unaddressed\", \"Direct ribosomal contact site not mapped\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Tendon-specific deletion connected FKBP65 loss to ectopic Hedgehog-driven chondrogenesis, and glioma studies tied FKBP10-HSP47 binding to AKT-CREB-PCNA proliferative signaling.\",\n      \"evidence\": \"Tendon/ligament conditional KO with crosslink MS, Gli1 IHC, genetic Hh rescue, gait analysis; glioma GST pulldown/co-IP and pathway analysis with xenograft\",\n      \"pmids\": [\"34161280\", \"33557829\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism linking collagen crosslinking loss to Hh activation not fully defined\", \"Whether the glioma proliferative effect requires PPIase activity untested\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Direct LDHA binding and an fkbp10a zebrafish knockout extended FKBP10 mechanisms into metabolic reprogramming and confirmed conserved control of collagen lysyl hydroxylation with a Bmpr1aa modifier.\",\n      \"evidence\": \"Co-IP of FKBP10-LDHA, Y10 phosphorylation and histone lactylation assays, PPIase dependency in ccRCC; zebrafish KO with crosslink MS, EM, and modifier mapping\",\n      \"pmids\": [\"38233415\", \"39566080\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether FKBP10 directly catalyzes a step in LDHA activation unresolved\", \"How a luminal chaperone accesses cytosolic LDHA unexplained\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Prelamin A binding, VPS4A/RAS engagement, and HSP47/SMAD3 regulation defined further FKBP10 functions in tumor invasion and fibrosis across bladder cancer, hepatic stellate cells, and muscle contracture.\",\n      \"evidence\": \"Co-IP of FKBP10-prelamin A with fractionation and invasion assays; LC-MS/MS and co-IP of VPS4A with in vivo AAV knockdown; co-IP of HSP47 with SMAD3/autophagy readouts and epistasis rescue\",\n      \"pmids\": [\"39781460\", \"42102670\", \"40316212\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether these interactions require PPIase activity not uniformly tested\", \"Cross-context unification of these partner interactions unresolved\", \"Subcellular site of prelamin A and VPS4A interactions unclear\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How a single ER-luminal isomerase mechanistically supports such diverse functions \\u2014 LH2-dependent collagen crosslinking, ribosomal translation elongation, LDHA activation, and prelamin A handling \\u2014 and whether the non-ER activities reflect distinct localization pools remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structural model of FKBP65 engaging LH2 or collagen telopeptides\", \"Topological basis for cytosolic/ribosomal and nuclear-associated functions unexplained\", \"Whether cancer-context partners are direct catalytic substrates untested\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0016853\", \"supporting_discovery_ids\": [0, 1, 17, 22, 25]},\n      {\"term_id\": \"GO:0044183\", \"supporting_discovery_ids\": [6, 2, 8]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [17, 18]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005788\", \"supporting_discovery_ids\": [4, 2]},\n      {\"term_id\": \"GO:0005783\", \"supporting_discovery_ids\": [4, 15]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1474244\", \"supporting_discovery_ids\": [11, 12, 17, 19]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [0, 6, 7]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [10, 12, 23]}\n    ],\n    \"complexes\": [\n      \"HSP47-FKBP65-BiP ER chaperone complex\"\n    ],\n    \"partners\": [\n      \"SERPINH1\",\n      \"HSPA5\",\n      \"PLOD2\",\n      \"LDHA\",\n      \"LMNA\",\n      \"VPS4A\",\n      \"RAF1\",\n      \"HSP90\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}