{"gene":"FKBP1B","run_date":"2026-06-09T23:54:43","timeline":{"discoveries":[{"year":1996,"finding":"FKBP12.6 selectively binds to the cardiac ryanodine receptor (RyR2) but not to the skeletal muscle RyR1; only FKBP12.6 (not FKBP12) exchanges with endogenously bound FKBP12.6 or rebinds to FKBP-stripped cardiac sarcoplasmic reticulum, explaining why cardiac CRC is isolated as a complex with FKBP12.6.","method":"35S-labeled FKBP12/12.6 binding assays, cosedimentation with stripped SR membranes","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — direct in vitro reconstitution binding assay with radiolabeled proteins, replicated across multiple muscle types, foundational biochemical characterization","pmids":["8702774"],"is_preprint":false},{"year":2000,"finding":"FKBP12.6 is a component of a macromolecular complex on the sarcoplasmic reticulum comprising RyR2, FKBP12.6, PKA, phosphatases PP1 and PP2A, and the anchoring protein mAKAP, as defined by cosedimentation and co-immunoprecipitation.","method":"Cosedimentation, co-immunoprecipitation","journal":"Cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP and cosedimentation in native cardiac tissue, highly cited and replicated in subsequent work","pmids":["10830164"],"is_preprint":false},{"year":2000,"finding":"PKA phosphorylation of RyR2 dissociates FKBP12.6 from the channel complex and increases RyR2 open probability; in failing human hearts RyR2 is PKA hyperphosphorylated, resulting in FKBP12.6 dissociation and defective channel function.","method":"Co-immunoprecipitation, single-channel recordings, PKA phosphorylation assay, failing human heart tissue","journal":"Cell","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — single lab, Co-IP plus single-channel electrophysiology; findings on PKA-induced dissociation were subsequently disputed by other labs (PMIDs 14715536, 20431056)","pmids":["10830164"],"is_preprint":false},{"year":2000,"finding":"In canine pacing-induced heart failure, the stoichiometric ratio of FKBP12.6 per RyR monomer is significantly decreased (3.6 to 1.6) and FKBP12.6 protein expression is reduced, correlating with a prominent Ca2+ leak through RyR and conformational change in RyR.","method":"[3H]dihydro-FK506 and [3H]ryanodine binding assays, stopped-flow Ca2+ release measurements, Western blot","journal":"Circulation","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — multiple orthogonal biochemical assays (radiolabeled binding, functional Ca2+ release, Western blot) in native failing heart tissue","pmids":["11044432"],"is_preprint":false},{"year":2000,"finding":"In heart failure, the number of FKBP12.6 binding sites (Bmax) on RyR is dramatically decreased (~83%) while affinity (Kd) is unchanged; this loss underlies RyR channel instability and impaired Ca2+ release function.","method":"[3H]dihydro-FK506 binding assay, stopped-flow Ca2+ release, FK506 competition","journal":"Cardiovascular research","confidence":"High","confidence_rationale":"Tier 1 / Strong — quantitative radioligand binding plus functional Ca2+ release assays in native tissue","pmids":["11054478"],"is_preprint":false},{"year":2001,"finding":"Adenoviral overexpression of FKBP12.6 in adult rabbit cardiomyocytes reduces SR Ca2+ leak through RyR2 by ~53%, increases SR Ca2+ load, and increases fractional shortening, demonstrating that FKBP12.6 stabilizes the closed conformation of RyR2.","method":"Adenovirus-mediated gene transfer, fluorometric Ca2+ uptake in permeabilized myocytes, contractility measurements","journal":"Circulation research","confidence":"High","confidence_rationale":"Tier 2 / Moderate — clean gain-of-function with defined phenotypic readout using multiple functional assays","pmids":["11157671"],"is_preprint":false},{"year":2002,"finding":"FKBP12.6 disruption in mice results in cardiac hypertrophy in males but not females; both sexes show dysregulated Ca2+ release (increased Ca2+ spark amplitude and duration), indicating FKBP12.6 modulates cardiac excitation-contraction coupling. Estrogen receptor antagonism with tamoxifen causes hypertrophy in female knockouts.","method":"FKBP12.6 knockout mice, echocardiography, Ca2+ spark imaging (confocal), tamoxifen treatment","journal":"Nature","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic loss-of-function with defined Ca2+ and cardiac phenotype, replicated with pharmacological intervention, multiple methods","pmids":["11907581"],"is_preprint":false},{"year":2002,"finding":"FKBP12.6 binds to RyR2 and regulates type 2 RyRs in tracheal smooth muscle; cyclic ADP-ribose (cADPR) alters spontaneous and receptor-mediated Ca2+ release through FKBP12.6, as these effects are blocked by excess recombinant FKBP12.6 and absent in FKBP12.6-knockout mouse myocytes.","method":"FKBP12.6 knockout mice, intracellular cADPR dialysis, Ca2+ imaging, force measurement in isolated trachealis","journal":"American journal of physiology. Cell physiology","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic KO combined with pharmacological rescue and functional readouts in native smooth muscle","pmids":["14592808"],"is_preprint":false},{"year":2002,"finding":"cADPR activates RyR/Ca2+ release channels from coronary arterial smooth muscle SR through FKBP12.6; removal of FKBP12.6 by FK506 or anti-FKBP12 antibody completely abolishes cADPR-induced channel activation in planar lipid bilayer recordings.","method":"Planar lipid bilayer single-channel recording, FK506 dissociation, anti-FKBP12 antibody blockade, gradient centrifugation","journal":"American journal of physiology. Heart and circulatory physiology","confidence":"High","confidence_rationale":"Tier 1 / Moderate — reconstituted single-channel electrophysiology with biochemical depletion of FKBP12.6, single lab but multiple orthogonal manipulations","pmids":["11893565"],"is_preprint":false},{"year":2002,"finding":"The FKBP12.6 binding site on RyR2 is localized to the NH2-terminal domain (residues 305–1937); deletion analyses show the first 305 residues and C-terminal residues 1937–4967 are not essential, while a fragment containing the first 1937 residues is sufficient for GST-FKBP12.6 binding. The isoleucine-proline dipeptide motif (I2427-P2428) is not the core binding site.","method":"GST pulldown with deletion mutants of RyR2 expressed in HEK293 cells","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — systematic deletion mutagenesis with direct binding assay, comprehensive mapping","pmids":["12446682"],"is_preprint":false},{"year":2003,"finding":"FKBP12.6 co-expressed with human RyR2 in CHO cells is selectively recruited from cytoplasm to ER membranes (sequestration) as RyR2 expression increases; co-expression of FKBP12.6 (but not FKBP12) markedly decreases agonist-induced Ca2+ release and promotes ER Ca2+ superfilling, effects antagonized by rapamycin.","method":"Stable CHO cell lines expressing hRyR2, confocal microscopy, Ca2+ imaging, rapamycin competition","journal":"The Biochemical journal","confidence":"High","confidence_rationale":"Tier 2 / Moderate — live-cell localization linked to functional consequence, comparison with FKBP12 negative control, pharmacological validation","pmids":["12443530"],"is_preprint":false},{"year":2003,"finding":"FKBP12.6 co-expression (but not FKBP12) in CHO cells expressing dysregulated hRyR2 suppresses intracellular Ca2+ flux and restores normal cell viability and proliferation; FKBP12.6's protective effect is independent of resting [Ca2+] or ER Ca2+ load.","method":"Stable CHO cell lines, Ca2+ imaging, cell viability/proliferation assays, ryanodine pharmacology","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — clean gain-of-function with defined phenotypic readouts, single lab","pmids":["12754204"],"is_preprint":false},{"year":2003,"finding":"FKBP12.6 deficiency in mice causes exercise-induced ventricular arrhythmias and sudden cardiac death; RyR2 mutations linked to CPVT reduce FKBP12.6 affinity for RyR2 and increase single-channel activity under simulated exercise conditions.","method":"FKBP12.6 knockout mice, in vivo exercise testing, single-channel recordings in lipid bilayers, radioligand binding","journal":"Cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic KO with defined lethal phenotype, single-channel electrophysiology with disease mutants, multiple orthogonal methods","pmids":["12837242"],"is_preprint":false},{"year":2004,"finding":"PKA phosphorylation of RyR2 at serine-2808 does NOT dissociate FKBP12.6 from RyR2; both phosphorylated and non-phosphorylated forms of RyR2, as well as the S2808D phosphomimetic mutant, retain FKBP12.6 binding. Complete PKA phosphorylation does not disrupt native or recombinant FKBP12.6-RyR2 complex.","method":"Site-specific phosphorylation-state antibodies, Co-IP with recombinant and native RyR2, S2808D mutant binding assay","journal":"Circulation research","confidence":"High","confidence_rationale":"Tier 1 / Moderate — site-directed mutagenesis plus Co-IP with phospho-specific antibodies, directly contradicts earlier claim (PMID 10830164)","pmids":["14715536"],"is_preprint":false},{"year":2004,"finding":"The C-terminal domain of human RyR2 (encompassing pore-forming transmembrane domains) exhibits rapamycin-sensitive, specific binding to FKBP12.6 but not FKBP12 when expressed in mammalian cells, identifying a novel C-terminal FKBP12.6-binding site.","method":"Competition binding assays, mammalian cell expression of RyR2 C-terminal constructs, rapamycin competition","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — binding competition assay plus expression in mammalian cells, single lab; partially conflicts with N-terminal site mapping (PMID 12446682)","pmids":["15591045"],"is_preprint":false},{"year":2004,"finding":"FKBP12.6 overexpression in rat cardiac myocytes decreases Ca2+ spark amplitude, duration, width, and frequency, but enhances global [Ca2+]i transient amplitude and cell shortening, associated with increased SR Ca2+ load.","method":"Adenoviral overexpression, confocal Ca2+ spark imaging with Rhod-2, caffeine-evoked Ca2+ transients","journal":"American journal of physiology. Heart and circulatory physiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct gain-of-function with functional Ca2+ readouts, single lab","pmids":["15271664"],"is_preprint":false},{"year":2004,"finding":"FKBP12.6 overexpression in adult rabbit cardiomyocytes increases peak-systolic [Ca2+], SR Ca2+ content, and synchronicity of SR Ca2+ release without altering L-type Ca2+ current or NCX; Ca2+ spark amplitude, duration, width, and frequency are reduced in permeabilized cells.","method":"Adenoviral overexpression, Fura-2/Fluo-3 Ca2+ imaging, voltage clamp, confocal microscopy","journal":"The Journal of physiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — clean gain-of-function with multiple Ca2+ and electrophysiological readouts, single lab","pmids":["14966299"],"is_preprint":false},{"year":2004,"finding":"FKBP12.6 in pulmonary artery smooth muscle associates with RyR2 but not RyR1, RyR3, or IP3 receptors; FKBP12.6 deficiency enhances hypoxic and norepinephrine-induced Ca2+ release and vasoconstriction in pulmonary arterial smooth muscle cells.","method":"FKBP12.6 knockout mice, Ca2+ imaging, Ca2+-activated current measurements, FK506/rapamycin pharmacology, isolated tissue force measurements","journal":"Cell calcium","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic KO with multiple functional readouts and pharmacological controls, Ca2+ imaging plus force measurements","pmids":["15036951"],"is_preprint":false},{"year":2005,"finding":"Cryo-EM and 3D reconstruction localizes FKBP12.6 binding to the sides of the cytoplasmic region of canine RyR2 adjacent to domain 9 (clamp structures); FKBP12.6 binding alters RyR2 conformation particularly in the transmembrane region and clamp structures.","method":"Cryo-electron microscopy, 3D reconstruction, difference mapping, X-ray structure docking","journal":"Biophysical journal","confidence":"High","confidence_rationale":"Tier 1 / Moderate — cryo-EM structural determination with quantitative difference mapping, single lab","pmids":["16214874"],"is_preprint":false},{"year":2005,"finding":"The central domain of human RyR2 does NOT mediate interaction with FKBP12.6; yeast two-hybrid and in vitro immunoprecipitation with overlapping fragments covering the entire RyR2 failed to reconstitute FKBP12.6 binding, and an alternatively spliced FKBP12.6 variant cannot interact with RyR.","method":"Yeast two-hybrid, in vitro immunoprecipitation, expression of overlapping RyR2 fragments","journal":"Cell biochemistry and biophysics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — two orthogonal methods (Y2H + Co-IP), single lab; negative result is mechanistically informative","pmids":["16049346"],"is_preprint":false},{"year":2005,"finding":"FKBP12.6 (but not FKBP12) coexpression with cardiac DHPR (alpha1CYM) and RyR2 in dyspedic myotubes eliminates spontaneous Ca2+ oscillations and enables robust electrically evoked Ca2+ transients, demonstrating that FKBP12.6 suppresses spontaneous RyR2 activity and is required for ordered CICR. S2808D RyR2 phosphomimetic does not alter FKBP12.6 regulation in this reconstituted system.","method":"Reconstitution in RyR1-null dyspedic myotubes, Ca2+ imaging, electrical stimulation, FKBP12.6 coexpression with RyR2 S2808D mutant","journal":"American journal of physiology. Cell physiology","confidence":"High","confidence_rationale":"Tier 1 / Moderate — molecular reconstitution in null background, multiple functional assays, mutagenesis included","pmids":["16049053"],"is_preprint":false},{"year":2006,"finding":"Key aspartic acid residues on calstabin2/FKBP12.6 (particularly Asp-37) are involved in binding to RyR2 and in PKA phosphorylation-induced dissociation; a D37S mutant calstabin2 binds to the constitutively PKA-phosphorylated RyR2-S2808D mutant and restores normal cardiac function in a mouse model of heart failure.","method":"Site-directed mutagenesis of FKBP12.6, co-immunoprecipitation with RyR2-S2808D, in vivo myocardial infarction model with mutant calstabin2 manipulation","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — mutagenesis plus Co-IP plus in vivo functional rescue, single lab but multiple orthogonal approaches","pmids":["16481613"],"is_preprint":false},{"year":2007,"finding":"FKBP12.6 removal (by FK506 or genetic knockout) does NOT alter the conductance, Ca2+-activation, caffeine-activation, or subconductance state properties of recombinant or native RyR2, and FKBP12.6-null mice do not exhibit enhanced stress-induced ventricular arrhythmias.","method":"Single-channel lipid bilayer recordings, [3H]ryanodine binding, HEK293 SOICR imaging, FKBP12.6-null mouse stress testing","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — reconstituted single-channel recordings plus radioligand binding plus in vivo stress testing, directly contradicts earlier claims (PMID 12837242)","pmids":["17921453"],"is_preprint":false},{"year":2007,"finding":"K201 (JTV519) suppresses spontaneous Ca2+ release and inhibits [3H]ryanodine binding to RyR2 independently of FKBP12.6; FK506-induced dissociation of FKBP12.6 does not affect K201's suppression, and K201 is equally effective on RyR2 expressed with or without FKBP12.6.","method":"Rat ventricular myocytes, HEK293 cells expressing RyR2±FKBP12.6, FK506 pretreatment, [3H]ryanodine binding","journal":"The Biochemical journal","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — radioligand binding plus Ca2+ imaging in multiple cell systems with systematic FKBP12.6 removal controls","pmids":["17313373"],"is_preprint":false},{"year":2008,"finding":"FKBP12.6-deficient mice are highly susceptible to pacing-induced atrial fibrillation (81% vs 7% in WT); atrial myocytes from KO mice show 53% greater SR Ca2+ leak and increased spontaneous Ca2+ release events, both blocked by the RyR antagonist tetracaine.","method":"FKBP12.6-/- mice, intracardiac electrography, Ca2+ imaging in atrial myocytes, tetracaine pharmacology","journal":"Heart rhythm","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic KO with defined electrophysiological and Ca2+ phenotypes plus pharmacological rescue","pmids":["18598963"],"is_preprint":false},{"year":2008,"finding":"FKBP12.6 disruption impairs glucose-induced insulin secretion in pancreatic beta-cells; FKBP12.6-/- islets show markedly impaired glucose-stimulated Ca2+ elevation and insulin secretion (but normal sulfonylurea or KCl response), placing FKBP12.6 downstream of ATP production in the glucose-sensing pathway.","method":"FKBP12.6-/- mice generated by homologous recombination, in vivo glucose tolerance test, isolated islet insulin secretion assay, Ca2+ imaging","journal":"Biochemical and biophysical research communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic KO with specific functional readout, epistatic placement downstream of ATP/independent of KATP channels","pmids":["18466757"],"is_preprint":false},{"year":2009,"finding":"Dissociation of FKBP12.6 from RyR2 does NOT play a significant role in beta-adrenergic-stimulated Ca2+ release; ISO increases Ca2+ spark frequency similarly in both WT and FKBP12.6 KO myocytes, and twitch force is not significantly different. In contrast, cADPR-stimulated Ca2+ spark augmentation occurs only in WT and not KO cells, placing cADPR action through FKBP12.6 dissociation from RyR2.","method":"FKBP12.6 KO mice, Ca2+ spark imaging, papillary muscle force measurements, pharmacological manipulation (thapsigargin, 2D12, cADPR)","journal":"Cardiovascular research","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic KO with multiple functional readouts and epistatic dissection of two pathways (ISO vs cADPR)","pmids":["19578067"],"is_preprint":false},{"year":2009,"finding":"FKBP12.6-/- mice display hyperinsulinemia and enhanced glucose-stimulated insulin secretion due to enhanced glucose-induced islet Ca2+ elevation; deletion also confers resistance to high-fat diet-induced hyperglycemia despite greater weight gain.","method":"FKBP12.6-/- mice, in vivo glucose tolerance test, ex vivo islet insulin secretion, Ca2+ imaging","journal":"FASEB journal","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic KO with in vivo and ex vivo functional readouts, replicates and extends PMID 18466757","pmids":["19805579"],"is_preprint":false},{"year":2000,"finding":"Crystal structure of FKBP12.6 in complex with rapamycin determined at 2.0 Å resolution; FKBP12.6 and FKBP12 structures are nearly identical except for a displacement in the helical region of FKBP12.6 toward the hydrophobic pocket, not predicted by homology modeling.","method":"X-ray crystallography, 2.0 Å resolution","journal":"Acta crystallographica. Section D, Biological crystallography","confidence":"High","confidence_rationale":"Tier 1 / Moderate — atomic resolution crystal structure with functional implication for RyR2 binding specificity, single lab but definitive structural method","pmids":["10713512"],"is_preprint":false},{"year":2010,"finding":"Direct fluorescent binding measurements in permeabilized myocytes show FKBP12.6 binds RyR2 with very high affinity (Kd ~0.7 nM) while FKBP12 has much lower affinity (Kd ~206 nM); only FKBP12.6 (not FKBP12) inhibits basal RyR2 activity; PKA phosphorylation does NOT alter binding kinetics or affinity of either FKBP for RyR2.","method":"Fluorescently labeled FKBP12.6/12 binding in permeabilized myocytes, FRAP, Ca2+ spark measurements, quantitative immunoblot","journal":"Circulation research","confidence":"High","confidence_rationale":"Tier 1 / Strong — direct quantitative binding kinetics in situ (FRAP + steady-state fluorescence), Ca2+ spark functional readout, conclusively addresses PKA controversy","pmids":["20431056"],"is_preprint":false},{"year":2011,"finding":"Genetic inhibition of CaMKII phosphorylation of RyR2 at S2814 (S2814A mutation) prevents AF induction in FKBP12.6-/- mice by suppressing SR Ca2+ leak and DADs, while S2808A mutation does not protect; this epistasis places CaMKII-mediated RyR2-S2814 phosphorylation downstream of FKBP12.6 deficiency in the AF pathway.","method":"FKBP12.6-/-:S2814A double-mutant mice, intracardiac stimulation, Ca2+ spark/wave imaging, NCX current measurement","journal":"Circulation research","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic epistasis with double-mutant mice, multiple functional readouts (electrophysiology + Ca2+ imaging), clear pathway placement","pmids":["22158709"],"is_preprint":false},{"year":2012,"finding":"FKBP12 is a high-affinity activator of RyR2 (sensitizes channel to cytosolic Ca2+), whereas FKBP12.6 has very low efficacy but can antagonize FKBP12 effects on single-channel gating; physiological concentrations of FKBP12 increase Ca2+ wave frequency and decrease SR Ca2+ content in cardiac cells.","method":"Single sheep RyR2 channels in planar phospholipid bilayers, Ca2+ wave measurements in permeabilized rat cardiomyocytes, mathematical modeling","journal":"PloS one","confidence":"High","confidence_rationale":"Tier 1 / Moderate — single-channel electrophysiology reconstitution plus functional Ca2+ imaging in native cells plus modeling, single lab","pmids":["22363773"],"is_preprint":false},{"year":2002,"finding":"VTSIP-associated RyR2 point mutations increase binding to FKBP12.6, while ARVD2-associated mutations decrease it, as measured by a quantitative yeast two-hybrid system; these opposing effects on FKBP12.6 binding correlate with the clinical differences between the two diseases.","method":"Quantitative yeast two-hybrid system with disease-associated RyR2 point mutations","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — yeast two-hybrid is indirect, single method, but systematic analysis of multiple disease mutations","pmids":["12459180"],"is_preprint":false},{"year":2017,"finding":"Cryo-EM structure of rabbit RyR2 in complex with FKBP12.6 at 11.8 Å resolution reveals that FKBP12.6 binding rigidifies the HD2 domain of RyR2 and stabilizes the closed state; two RyR2 conformations in the dataset are proposed to reflect phosphorylation state of the P2 domain.","method":"Cryo-electron microscopy, 3D reconstruction, atomic model building, conformational heterogeneity analysis","journal":"Science signaling","confidence":"High","confidence_rationale":"Tier 1 / Moderate — cryo-EM structure at defined resolution with atomic model, identifies domain-specific conformational effect of FKBP12.6 binding","pmids":["28536302"],"is_preprint":false},{"year":2016,"finding":"Fully active FKBP12.6 (calstabin 2) retains peptidyl-prolyl cis-trans isomerase (PPIase) enzymatic activity; total chemical synthesis followed by refolding produced enzyme with catalytic activity and crystallographic structure (at 2.0 Å) indistinguishable from recombinant wild-type.","method":"Native chemical ligation synthesis, refolding, enzymatic activity assay, X-ray crystallography","journal":"Protein science","confidence":"High","confidence_rationale":"Tier 1 / Moderate — direct in vitro enzymatic assay plus crystal structure, confirms intrinsic PPIase activity","pmids":["27670942"],"is_preprint":false},{"year":2013,"finding":"Sirolimus (rapamycin) bound to FKBP12.6 impairs endothelial barrier function through RyR2-mediated intracellular Ca2+ elevation, protein kinase C-α activation, and disruption of the p120-VE cadherin interaction; siRNA knockdown of FKBP12.6 mimics these effects.","method":"HAEC culture, transendothelial electrical resistance, siRNA knockdown, Ca2+ imaging, PKC-α phosphorylation Western blot, immunostaining, mouse vascular permeability assay","journal":"Arteriosclerosis, thrombosis, and vascular biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — siRNA KD plus pharmacological rescue plus in vivo validation, single lab","pmids":["23887639"],"is_preprint":false},{"year":2017,"finding":"Absence or inhibition of FKBP12.6 increases RyR2 sensitivity to L-type Ca2+ channel triggers (increased spark frequency and LCC-RyR coupling fidelity) without altering LCC open probability; this sensitization is additive with isoproterenol and can lead to chaotic Ca2+ waves and ventricular arrhythmias.","method":"FKBP12.6 KO mice, whole-cell patch clamp with confocal Ca2+ spark imaging, loose-seal patch-clamp LCC-RyR signaling kinetics, FK506/rapamycin pharmacology","journal":"Cardiovascular research","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic KO plus pharmacological confirmation, multiple orthogonal methods including patch clamp and Ca2+ imaging","pmids":["28077437"],"is_preprint":false},{"year":2018,"finding":"FKBP12.6 protects against AngII-induced cardiac hypertrophy by reducing intracellular [Ca2+] and inhibiting calcineurin/NFATc4, CaMKII/MEF-2, AKT/GSK3β/NFATc4, and AKT/mTOR signaling pathways; KO aggravates and cardiac-specific TG overexpression prevents AngII-induced hypertrophy.","method":"FKBP12.6 KO and cardiac-specific TG mice, AngII osmotic pump infusion, echocardiography, Ca2+ imaging, Western blot for signaling pathway components","journal":"Journal of cellular and molecular medicine","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal genetic models (KO and TG) with multiple signaling pathway readouts","pmids":["29682889"],"is_preprint":false},{"year":2020,"finding":"Rieske iron-sulfur protein (RISP)-dependent ROS generation causes dissociation of FKBP12.6 from RyR2 in pulmonary arterial smooth muscle cells during chronic hypoxia, leading to increased RyR2 activity, NF-κB/cyclin D1 activation, cell proliferation, and pulmonary hypertension; SMC-specific RyR2 KO, RISP knockdown, or RyR2/FKBP12.6 complex stabilization by S107 attenuates PH.","method":"SMC-specific RyR2 KO mice, RISP knockdown, FKBP12.6 KO, S107 pharmacological stabilization, co-IP, Ca2+ imaging, NF-κB/cyclin D1 activity assay","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple genetic models plus pharmacological rescue, co-IP defines complex, in vivo PH phenotype","pmids":["32669538"],"is_preprint":false},{"year":2021,"finding":"FKBP12.6 directly binds BMP/TGF-β type I receptors (e.g., ALK2/ACVR1) but not type II receptors; the 2.17 Å crystal structure of the ALK2-FKBP12.6 complex shows FKBP12.6 binding to the GS domain of ALK2 in a manner equivalent to the FKBP12 complex, with ALK2 residues Phe198 and Leu199 inserting into the FK506-binding pocket.","method":"Cellular immunoprecipitation, SEC-MALS (1:1 direct interaction), X-ray crystallography at 2.17 Å","journal":"Biomedicines","confidence":"High","confidence_rationale":"Tier 1 / Moderate — atomic resolution crystal structure plus SEC-MALS quantification of direct binding, single lab","pmids":["33572801"],"is_preprint":false},{"year":2019,"finding":"FKBP12.6 directly binds Glomulin (Glmn) in vitro with higher affinity than FKBP12; the FKBP51-Glmn interaction (as a model for the class) requires two amino acids lining the FK506-binding site and is blocked by FKBP ligands.","method":"In vitro binding assays (FKBP12.6 vs FKBP12 vs FKBP51/52 truncation mutants), FKBP ligand competition","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct in vitro binding quantification, single lab; FKBP51 used as surrogate model for binding pocket characterization","pmids":["31490997"],"is_preprint":false},{"year":2009,"finding":"FKBP12.6 overexpression in rabbit cardiomyocytes decreases inward rectifier current (IK1) amplitude by ~25% in a Ca2+-dependent and FK506-sensitive manner and prolongs action potential duration by ~30%; this effect is independent of calcineurin binding (shown using a calcineurin-binding deficient FKBP12.6 mutant).","method":"Adenoviral overexpression, whole-cell patch clamp, action potential recordings, FKBP12.6 calcineurin-binding mutant","journal":"Pflugers Archiv : European journal of physiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — electrophysiology with mutant controls, single lab, Ca2+-dependent and FK506-reversible effects mechanistically linked","pmids":["19333617"],"is_preprint":false},{"year":2025,"finding":"FKBP12.6 ubiquitination is regulated by NR3C1-mediated repression of Glomulin (GLMN); under stress, activated NR3C1 represses GLMN, preventing FKBP12.6 ubiquitination and degradation, leading to FKBP12.6 accumulation, calcium leakage/overload, and mitochondrial quality control impairment in cardiomyocytes.","method":"ChIP-qPCR, siRNA knockdown of NR3C1 and GLMN, mouse restraint stress models, transmission electron microscopy, Western blot","journal":"International journal of molecular sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP-qPCR plus siRNA with functional readouts, single lab, 2025 paper with 0 citations","pmids":["40943170"],"is_preprint":false},{"year":2026,"finding":"FKBP12.6 directly binds IP3R (inositol 1,4,5-trisphosphate receptor) in bladder detrusor muscle, as shown by co-immunoprecipitation; FKBP12.6 knockout increases bladder sensitivity and detrusor instability, and IP3R/TRPM4 pathway inhibitors rescue the knockout phenotype, indicating FKBP12.6 regulates bladder function through IP3R/TRPM4.","method":"FKBP12.6 KO mice, co-immunoprecipitation, urodynamic testing, void spot assay, pharmacological rescue with 2-APB and 9-PHE","journal":"Current medicinal chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic KO with defined bladder phenotype plus co-IP plus pharmacological rescue, single lab, novel tissue/partner","pmids":["40051354"],"is_preprint":false},{"year":2015,"finding":"miR-34a directly targets the 3'-UTR of FKBP1B mRNA to repress its expression; FKBP1B overexpression attenuates MDI-induced adipogenesis and reduces PPARγ and C/EBPα expression, demonstrating FKBP1B acts as an anti-adipogenic factor downstream of miR-34a.","method":"Luciferase 3'-UTR reporter assay, miR-34a mimic/inhibitor, FKBP1B overexpression in 3T3-L1 preadipocytes, adipogenesis assay","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct 3'-UTR reporter plus gain-of-function with defined phenotype, single lab","pmids":["26471303"],"is_preprint":false},{"year":2014,"finding":"X-ray crystal structures of unligated FKBP12.6 (1.70 and 1.90 Å) reveal conformational flexibility: the Phe59 active-site ring can rotate perpendicular to its typical orientation, and the '80s loop' peptide unit can flip; NMR shows 21 backbone amides undergo slow conformational exchange near the 80s loop.","method":"X-ray crystallography (two crystal forms), NMR backbone amide resonance doubling","journal":"Acta crystallographica. Section D, Biological crystallography","confidence":"High","confidence_rationale":"Tier 1 / Moderate — high-resolution crystal structures plus NMR conformational analysis, single lab but orthogonal methods","pmids":["24598733"],"is_preprint":false},{"year":2012,"finding":"Conditional deletion of the transcription factor CHF1/Hey2 in cardiomyocytes leads to increased FKBP12.6 expression; treatment with FK506 (which inhibits FKBP12.6-RyR2 association) restores contractile function in CHF1/Hey2 KO myocytes, placing FKBP12.6 downstream of CHF1/Hey2 in a pathway regulating cardiac EC coupling.","method":"Conditional KO mice, aortic banding, Ca2+ transients in isolated myocytes, gene expression analysis, FK506 pharmacological rescue","journal":"American journal of physiology. Heart and circulatory physiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic epistasis by KO plus pharmacological rescue, single lab","pmids":["22408025"],"is_preprint":false},{"year":2009,"finding":"FKBP12.6 overexpression conditionally in cardiac myocytes reduces Ca2+ spark frequency by 50% (including under isoproterenol) with unchanged SR Ca2+ load and prevents triggered ventricular tachycardia induced by burst pacing after isoproterenol pretreatment.","method":"Conditional cardiac-specific FKBP12.6 transgenic mice, in vivo electrophysiology, confocal Ca2+ spark imaging, Co-IP of FKBP12.6-RyR2","journal":"Circulation","confidence":"High","confidence_rationale":"Tier 2 / Strong — conditional cardiac-specific transgene with in vivo electrophysiology endpoint and Ca2+ spark mechanistic analysis","pmids":["18378612"],"is_preprint":false}],"current_model":"FKBP12.6 (calstabin2) is a high-affinity (Kd ~0.7 nM), selective binding partner of the cardiac ryanodine receptor RyR2, where it forms part of a macromolecular complex with PKA, PP1, PP2A, and mAKAP on the sarcoplasmic reticulum; by occupying a conformationally sensitive site spanning the RyR2 N-terminal domain (residues 305–1937) and possibly the C-terminal transmembrane region, FKBP12.6 rigidifies the RyR2 HD2/clamp domain and stabilizes the closed channel state, thereby suppressing spontaneous diastolic Ca2+ leak, Ca2+ sparks, and store overload-induced Ca2+ release; its loss or dissociation (triggered by cADPR signaling or CaMKII-dependent S2814 phosphorylation of RyR2, but not necessarily by PKA phosphorylation at S2808) leads to RyR2 hypersensitivity to Ca2+ triggers and underlies arrhythmias, cardiac hypertrophy (suppressed by estrogen), atrial fibrillation, and impaired glucose-stimulated insulin secretion; additionally, FKBP12.6 binds BMP/TGF-β type I receptors (e.g., ALK2 GS domain), Glomulin, and IP3R, and possesses intrinsic peptidyl-prolyl cis-trans isomerase activity, while its stability is regulated by NR3C1/Glomulin-dependent ubiquitination."},"narrative":{"mechanistic_narrative":"FKBP1B (FKBP12.6/calstabin2) is a peptidyl-prolyl cis-trans isomerase that functions as a high-affinity (Kd ~0.7 nM), selective regulatory subunit of the cardiac ryanodine receptor RyR2, stabilizing the channel's closed state to suppress diastolic Ca2+ leak and govern excitation-contraction coupling [PMID:8702774, PMID:20431056, PMID:27670942]. Unlike FKBP12, only FKBP12.6 binds and rebinds RyR2 (not RyR1), and it assembles into an SR macromolecular complex with PKA, the phosphatases PP1 and PP2A, and the anchoring protein mAKAP [PMID:8702774, PMID:10830164]. The interaction maps principally to the RyR2 N-terminal domain (residues 305–1937), with cryo-EM showing that FKBP12.6 docks at the cytoplasmic clamp region and rigidifies the HD2 domain to lock the closed conformation [PMID:12446682, PMID:16214874, PMID:28536302]. Gain- and loss-of-function studies establish the functional consequence directly: FKBP12.6 overexpression reduces Ca2+ spark frequency, raises SR Ca2+ load, and prevents triggered arrhythmias, whereas its loss or dissociation increases RyR2 sensitivity to Ca2+ triggers and SR Ca2+ leak [PMID:11157671, PMID:28077437, PMID:18378612]. Loss of FKBP12.6 in mice produces sex-dependent cardiac hypertrophy, atrial fibrillation, and aberrant Ca2+ release, and the protein further protects against AngII-induced hypertrophy by restraining calcineurin/NFAT, CaMKII/MEF-2, and AKT/mTOR signaling [PMID:11907581, PMID:18598963, PMID:29682889]. Dissociation is driven by cADPR signaling and by CaMKII-dependent phosphorylation of RyR2 at S2814, but not by PKA phosphorylation at S2808, which does not alter FKBP12.6 binding [PMID:14715536, PMID:19578067, PMID:20431056, PMID:22158709]. Beyond RyR2, FKBP12.6 directly binds the IP3 receptor in detrusor muscle, the BMP/TGF-β type I receptor ALK2 via its GS domain, and Glomulin, and it acts in non-cardiac settings including glucose-stimulated insulin secretion, smooth-muscle Ca2+ release, and anti-adipogenesis downstream of miR-34a [PMID:40051354, PMID:33572801, PMID:31490997, PMID:18466757, PMID:15036951, PMID:26471303]. Its abundance is set post-translationally through Glomulin/NR3C1-dependent ubiquitination [PMID:40943170].","teleology":[{"year":1996,"claim":"Established that FKBP12.6, distinct from the closely related FKBP12, is the physiological FKBP partner of the cardiac RyR2, defining its binding selectivity as the basis for isoform-specific channel regulation.","evidence":"radiolabeled FKBP12/12.6 binding and cosedimentation with stripped cardiac SR membranes","pmids":["8702774"],"confidence":"High","gaps":["Did not localize the binding site on RyR2","Did not establish functional consequence of binding"]},{"year":2000,"claim":"Placed FKBP12.6 within an SR macromolecular signaling complex and proposed a regulatory model in which PKA phosphorylation dissociates it to increase channel activity, linking the complex to heart failure.","evidence":"cosedimentation, reciprocal Co-IP, single-channel recordings, and failing human heart tissue","pmids":["10830164"],"confidence":"High","gaps":["The PKA-induced dissociation claim was subsequently disputed","Stoichiometry and phospho-site dependence not resolved here"]},{"year":2000,"claim":"Showed quantitatively that FKBP12.6 loss in failing hearts arises from reduced binding-site occupancy/expression rather than altered affinity, mechanistically connecting FKBP12.6 depletion to pathological Ca2+ leak.","evidence":"[3H]dihydro-FK506 and [3H]ryanodine binding, stopped-flow Ca2+ release, and Western blot in failing canine/native heart tissue","pmids":["11044432","11054478"],"confidence":"High","gaps":["Did not define the trigger for FKBP12.6 loss","Correlative in disease, not causal manipulation"]},{"year":2001,"claim":"Directly demonstrated by gain-of-function that FKBP12.6 stabilizes the closed RyR2 state, reducing SR Ca2+ leak and improving contractility.","evidence":"adenoviral FKBP12.6 overexpression in rabbit cardiomyocytes with Ca2+ leak and contractility readouts","pmids":["11157671"],"confidence":"High","gaps":["Structural basis of stabilization not addressed","Single overexpression context"]},{"year":2002,"claim":"Genetic deletion established FKBP12.6 as a modulator of cardiac EC coupling with sex-dependent hypertrophy and identified it as the effector through which cADPR controls Ca2+ release across cardiac and smooth muscle.","evidence":"FKBP12.6 knockout mice with echocardiography, Ca2+ spark imaging, tamoxifen, and cADPR dialysis in cardiac/tracheal/coronary smooth muscle","pmids":["11907581","14592808","11893565"],"confidence":"High","gaps":["Molecular mechanism of estrogen protection unresolved","Direct cADPR target within the complex not defined"]},{"year":2002,"claim":"Mapped the FKBP12.6 footprint on RyR2 to the N-terminal domain (residues 305–1937) and excluded the I2427-P2428 motif as the core site, providing the first structural localization of the interaction.","evidence":"GST pulldown with RyR2 deletion mutants in HEK293 cells; complementary quantitative Y2H of disease mutants","pmids":["12446682","12459180"],"confidence":"High","gaps":["Did not resolve residue-level contacts","A separate C-terminal site was later proposed, creating an unresolved discrepancy"]},{"year":2003,"claim":"Linked FKBP12.6 deficiency to exercise-induced lethal ventricular arrhythmia and to CPVT mutations that weaken FKBP12.6 binding, framing FKBP12.6 dissociation as an arrhythmogenic mechanism.","evidence":"FKBP12.6 knockout mice with in vivo exercise testing, single-channel recordings of CPVT mutants, and radioligand binding","pmids":["12837242"],"confidence":"High","gaps":["The stress-induced arrhythmia phenotype was later not reproduced in another knockout study","Causal chain from binding loss to arrhythmia incompletely defined"]},{"year":2003,"claim":"Demonstrated in heterologous cells that FKBP12.6 is sequestered to RyR2-bearing ER membranes and suppresses agonist-evoked Ca2+ release independent of resting Ca2+/ER load, establishing a cell-protective regulatory function.","evidence":"stable CHO lines expressing hRyR2 with confocal localization, Ca2+ imaging, rapamycin competition, and viability assays","pmids":["12443530","12754204"],"confidence":"High","gaps":["Heterologous system may not recapitulate native stoichiometry","FKBP12 negative control behavior left mechanism of selectivity open"]},{"year":2004,"claim":"Resolved the PKA-phosphorylation controversy by showing S2808 phosphorylation does not dissociate FKBP12.6, while reconstitution confirmed FKBP12.6 (not FKBP12) suppresses spontaneous RyR2 activity and supports ordered CICR.","evidence":"phospho-specific Co-IP with S2808D mutant; reconstitution in dyspedic myotubes with DHPR/RyR2; competition binding to a C-terminal RyR2 construct","pmids":["14715536","16049053","15591045"],"confidence":"High","gaps":["Reconciliation of N-terminal versus C-terminal binding sites not achieved","Did not identify the true dissociation trigger"]},{"year":2004,"claim":"Reinforced through multiple gain-of-function studies that FKBP12.6 reduces Ca2+ spark parameters while enhancing global Ca2+ transients and SR load, and extended its RyR2-selective role to pulmonary artery smooth muscle Ca2+ signaling.","evidence":"adenoviral overexpression in rat/rabbit cardiomyocytes with Ca2+ imaging and voltage clamp; FKBP12.6 KO with Ca2+/force readouts in pulmonary artery SMC","pmids":["15271664","14966299","15036951"],"confidence":"High","gaps":["Tissue-specific differences in coupling not mechanistically unified","RyR2-selectivity over RyR1/3 and IP3R asserted but contacts undefined"]},{"year":2005,"claim":"Provided structural visualization that FKBP12.6 binds the cytoplasmic clamp region adjacent to domain 9 and alters RyR2 conformation in the transmembrane/clamp domains, connecting binding to gating control.","evidence":"cryo-EM 3D reconstruction and difference mapping of canine RyR2±FKBP12.6; orthogonal Y2H/Co-IP fragment analysis","pmids":["16214874","16049346"],"confidence":"High","gaps":["Low resolution precluded atomic contacts","Conformational mechanism inferred, not dynamically resolved"]},{"year":2006,"claim":"Identified FKBP12.6 residues (notably Asp-37) governing RyR2 binding and engineered a mutant that binds phospho-mimetic RyR2 and rescues failing-heart function, providing a structure-guided therapeutic proof of concept.","evidence":"FKBP12.6 site-directed mutagenesis, Co-IP with RyR2-S2808D, and in vivo myocardial infarction rescue","pmids":["16481613"],"confidence":"High","gaps":["Single lab, dependent on the contested PKA-dissociation framework","Generalizability of mutant rescue not established"]},{"year":2007,"claim":"Challenged the FKBP12.6-RyR2 gating paradigm by reporting that FKBP12.6 removal does not alter RyR2 single-channel properties or confer stress-induced arrhythmia, and that K201's action is FKBP12.6-independent.","evidence":"lipid-bilayer single-channel recordings, [3H]ryanodine binding, HEK293 SOICR imaging, and KO stress testing","pmids":["17921453","17313373"],"confidence":"High","gaps":["Directly contradicts earlier arrhythmia findings, leaving the in vivo role context-dependent","Did not reconcile differing knockout phenotypes"]},{"year":2008,"claim":"Established causal roles for FKBP12.6 in atrial fibrillation susceptibility and in glucose-stimulated insulin secretion, broadening its physiological scope beyond ventricular EC coupling.","evidence":"FKBP12.6-/- mice with intracardiac electrography and tetracaine rescue; in vivo glucose tolerance, islet secretion, and Ca2+ imaging","pmids":["18598963","18466757"],"confidence":"High","gaps":["Beta-cell Ca2+ channel target left to placement downstream of ATP","Atrial leak mechanism not yet tied to a specific phospho-site"]},{"year":2009,"claim":"Dissected the dissociation signals by showing cADPR—but not β-adrenergic/ISO stimulation—augments Ca2+ sparks through FKBP12.6, and demonstrated conditional cardiac FKBP12.6 overexpression prevents triggered ventricular tachycardia; also revealed FKBP12.6 effects on IK1/action potential duration and opposing insulin phenotypes.","evidence":"FKBP12.6 KO Ca2+ spark/force studies, conditional cardiac transgenic in vivo electrophysiology, patch clamp with calcineurin-mutant FKBP12.6, and KO glucose/insulin assays","pmids":["19578067","18378612","19333617","19805579"],"confidence":"High","gaps":["Insulin secretion phenotype differed between knockout studies","Mechanism coupling FKBP12.6 to IK1 not fully defined"]},{"year":2010,"claim":"Provided definitive in situ binding kinetics (Kd ~0.7 nM for FKBP12.6 vs ~206 nM for FKBP12) and conclusively showed PKA phosphorylation does not change FKBP12.6 binding, settling the affinity and phospho-dependence questions.","evidence":"fluorescent binding and FRAP in permeabilized myocytes with Ca2+ spark readouts and quantitative immunoblot","pmids":["20431056"],"confidence":"High","gaps":["Did not address which physiological trigger dissociates FKBP12.6","In situ measurement does not resolve binding-site geometry"]},{"year":2012,"claim":"Clarified the FKBP isoform paradox—FKBP12 activates/sensitizes RyR2 while FKBP12.6 antagonizes this—and placed FKBP12.6 downstream of the CHF1/Hey2 transcriptional program in cardiac EC coupling.","evidence":"single sheep RyR2 bilayer recordings with modeling; conditional CHF1/Hey2 KO with FK506 rescue and expression analysis","pmids":["22363773","22408025"],"confidence":"High","gaps":["Mechanism by which CHF1/Hey2 controls FKBP12.6 transcription not defined","Competition dynamics of FKBP12 vs FKBP12.6 in vivo unresolved"]},{"year":2011,"claim":"Established by genetic epistasis that CaMKII phosphorylation of RyR2 at S2814—not PKA at S2808—mediates the atrial fibrillation arising from FKBP12.6 deficiency, defining the operative dissociation/leak pathway.","evidence":"FKBP12.6-/-:S2814A double-mutant mice with intracardiac stimulation and Ca2+ spark/wave imaging","pmids":["22158709"],"confidence":"High","gaps":["Did not establish whether S2814 phosphorylation directly weakens FKBP12.6 binding","Ventricular versus atrial pathway differences not fully mapped"]},{"year":2017,"claim":"Refined the structural mechanism (HD2-domain rigidification stabilizing the closed state) and demonstrated functionally that FKBP12.6 absence increases LCC-RyR coupling fidelity and spark frequency without changing LCC gating, linking the molecular effect to arrhythmogenic Ca2+ waves.","evidence":"cryo-EM of rabbit RyR2-FKBP12.6 with conformational analysis; KO patch clamp with confocal Ca2+ spark and LCC-RyR coupling kinetics","pmids":["28536302","28077437"],"confidence":"High","gaps":["Resolution insufficient for full atomic phospho-domain modeling","How HD2 rigidification propagates to the pore not mechanistically traced"]},{"year":2016,"claim":"Confirmed that FKBP12.6 retains intrinsic peptidyl-prolyl cis-trans isomerase catalytic activity and characterized its conformational flexibility, distinguishing its enzymatic function from its scaffolding role at RyR2.","evidence":"total chemical synthesis with enzymatic assay and crystallography; high-resolution crystal structures plus NMR conformational exchange analysis","pmids":["27670942","24598733"],"confidence":"High","gaps":["No physiological PPIase substrate identified","Relationship of catalytic activity to channel regulation undefined"]},{"year":2021,"claim":"Expanded the FKBP12.6 interactome beyond RyR2 by structurally defining direct binding to the ALK2 GS domain and to Glomulin, implicating it in TGF-β/BMP receptor regulation and FKBP-ligand-sensitive complexes.","evidence":"Co-IP and SEC-MALS with 2.17 Å ALK2-FKBP12.6 crystal structure; in vitro Glomulin binding versus FKBP12/51/52","pmids":["33572801","31490997"],"confidence":"High","gaps":["Cellular consequences of ALK2 binding for BMP/TGF-β signaling not established","Glomulin interaction not yet linked to a downstream pathway"]},{"year":2020,"claim":"Defined a redox-driven dissociation mechanism in which RISP-dependent ROS during chronic hypoxia releases FKBP12.6 from RyR2 to drive NF-κB/cyclin D1 proliferation and pulmonary hypertension, providing a disease pathway with pharmacological rescue.","evidence":"SMC-specific RyR2 KO, RISP knockdown, FKBP12.6 KO, S107 stabilization, Co-IP, and Ca2+/NF-κB assays","pmids":["32669538"],"confidence":"High","gaps":["Molecular target of ROS on the complex not pinpointed","Generalizability beyond pulmonary vasculature unknown"]},{"year":2018,"claim":"Showed FKBP12.6 restrains pathological cardiac hypertrophy by lowering intracellular Ca2+ and suppressing calcineurin/NFAT, CaMKII/MEF-2, and AKT/mTOR signaling, integrating its channel role into hypertrophic signaling.","evidence":"reciprocal FKBP12.6 KO and cardiac-specific transgenic mice with AngII infusion, echocardiography, Ca2+ imaging, and pathway immunoblots","pmids":["29682889"],"confidence":"High","gaps":["Direct versus Ca2+-indirect contribution to each pathway not separated","Did not test rescue by RyR2 stabilization specifically"]},{"year":2025,"claim":"Identified post-translational control of FKBP12.6 abundance via NR3C1 repression of Glomulin, blocking FKBP12.6 ubiquitination so that stress-driven accumulation impairs mitochondrial quality control.","evidence":"ChIP-qPCR, NR3C1/GLMN siRNA knockdown, restraint-stress mouse models, electron microscopy, and Western blot","pmids":["40943170"],"confidence":"Medium","gaps":["Single recent study with limited independent confirmation","Direct demonstration of Glomulin-mediated FKBP12.6 ubiquitination not shown"]},{"year":2026,"claim":"Extended FKBP12.6 regulation to a second channel class by showing direct IP3R binding in detrusor muscle and a knockout bladder-instability phenotype rescued by IP3R/TRPM4 inhibition.","evidence":"FKBP12.6 KO mice, Co-IP, urodynamic and void-spot testing, and pharmacological rescue with 2-APB/9-PHE","pmids":["40051354"],"confidence":"Medium","gaps":["Single Co-IP without reciprocal structural mapping of the IP3R site","Selectivity versus RyR2 in this tissue not resolved"]},{"year":2015,"claim":"Placed FKBP1B within a miR-34a-regulated anti-adipogenic axis, indicating transcript-level control and a metabolic role distinct from Ca2+ channel regulation.","evidence":"luciferase 3'-UTR reporter, miR-34a mimic/inhibitor, and FKBP1B overexpression in 3T3-L1 adipogenesis assays","pmids":["26471303"],"confidence":"Medium","gaps":["Mechanism by which FKBP1B suppresses PPARγ/C/EBPα undefined","Single cell-line context"]},{"year":null,"claim":"The physiological trigger and structural mechanism that dissociates FKBP12.6 from RyR2 under specific stress states, and how its newly identified partners (IP3R, ALK2, Glomulin) and PPIase activity integrate with channel regulation, remain to be unified.","evidence":"no single study resolves the dissociation trigger across the conflicting cardiac models or links PPIase catalysis to a defined substrate","pmids":[],"confidence":"Low","gaps":["No physiological PPIase substrate identified","N-terminal versus C-terminal RyR2 binding-site discrepancy unresolved","Conflicting knockout arrhythmia phenotypes not reconciled"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0016853","term_label":"isomerase activity","supporting_discovery_ids":[34,45]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[5,29,36,47]},{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[34,39]}],"localization":[{"term_id":"GO:0005783","term_label":"endoplasmic reticulum","supporting_discovery_ids":[10,12]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[10,29]}],"pathway":[{"term_id":"R-HSA-397014","term_label":"Muscle contraction","supporting_discovery_ids":[5,6,36]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[1,30,37]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[12,24,38]}],"complexes":["RyR2-FKBP12.6-PKA-PP1-PP2A-mAKAP SR macromolecular complex"],"partners":["RYR2","ITPR1","ACVR1","GLMN","PRKAR","PPP1CA","AKAP6"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P68106","full_name":"Peptidyl-prolyl cis-trans isomerase FKBP1B","aliases":["12.6 kDa FK506-binding protein","12.6 kDa FKBP","FKBP-12.6","FK506-binding protein 1B","FKBP-1B","Immunophilin FKBP12.6","Rotamase","h-FKBP-12"],"length_aa":108,"mass_kda":11.8,"function":"Has the potential to contribute to the immunosuppressive and toxic effects of FK506 and rapamycin. PPIases accelerate the folding of proteins. It catalyzes the cis-trans isomerization of proline imidic peptide bonds in oligopeptides","subcellular_location":"Cytoplasm; Sarcoplasmic reticulum","url":"https://www.uniprot.org/uniprotkb/P68106/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/FKBP1B","classification":"Not Classified","n_dependent_lines":0,"n_total_lines":1208,"dependency_fraction":0.0},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/FKBP1B","total_profiled":1310},"omim":[{"mim_id":"600620","title":"FK506-BINDING PROTEIN 1B; FKBP1B","url":"https://www.omim.org/entry/600620"},{"mim_id":"180902","title":"RYANODINE RECEPTOR 2; RYR2","url":"https://www.omim.org/entry/180902"},{"mim_id":"114251","title":"CALSEQUESTRIN 2; CASQ2","url":"https://www.omim.org/entry/114251"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Golgi apparatus","reliability":"Approved"},{"location":"Vesicles","reliability":"Approved"},{"location":"Primary cilium","reliability":"Additional"},{"location":"Basal body","reliability":"Additional"},{"location":"Cytosol","reliability":"Additional"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in all","driving_tissues":[{"tissue":"brain","ntpm":73.7}],"url":"https://www.proteinatlas.org/search/FKBP1B"},"hgnc":{"alias_symbol":["OTK4","FKBP12.6","PPIase","FKBP9"],"prev_symbol":["FKBP1L"]},"alphafold":{"accession":"P68106","domains":[{"cath_id":"3.10.50.40","chopping":"2-106","consensus_level":"high","plddt":95.4051,"start":2,"end":106}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P68106","model_url":"https://alphafold.ebi.ac.uk/files/AF-P68106-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P68106-F1-predicted_aligned_error_v6.png","plddt_mean":94.88},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=FKBP1B","jax_strain_url":"https://www.jax.org/strain/search?query=FKBP1B"},"sequence":{"accession":"P68106","fasta_url":"https://rest.uniprot.org/uniprotkb/P68106.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P68106/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P68106"}},"corpus_meta":[{"pmid":"10830164","id":"PMC_10830164","title":"PKA phosphorylation dissociates FKBP12.6 from the calcium release channel (ryanodine receptor): defective regulation in failing hearts.","date":"2000","source":"Cell","url":"https://pubmed.ncbi.nlm.nih.gov/10830164","citation_count":1644,"is_preprint":false},{"pmid":"12837242","id":"PMC_12837242","title":"FKBP12.6 deficiency and defective calcium release channel (ryanodine receptor) function linked to exercise-induced sudden cardiac death.","date":"2003","source":"Cell","url":"https://pubmed.ncbi.nlm.nih.gov/12837242","citation_count":613,"is_preprint":false},{"pmid":"11907581","id":"PMC_11907581","title":"Oestrogen protects FKBP12.6 null mice from cardiac hypertrophy.","date":"2002","source":"Nature","url":"https://pubmed.ncbi.nlm.nih.gov/11907581","citation_count":245,"is_preprint":false},{"pmid":"8702774","id":"PMC_8702774","title":"Selective binding of FKBP12.6 by the cardiac ryanodine receptor.","date":"1996","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/8702774","citation_count":220,"is_preprint":false},{"pmid":"12551874","id":"PMC_12551874","title":"FKBP12.6-mediated stabilization of calcium-release channel (ryanodine receptor) as a novel therapeutic strategy against heart failure.","date":"2003","source":"Circulation","url":"https://pubmed.ncbi.nlm.nih.gov/12551874","citation_count":212,"is_preprint":false},{"pmid":"11044432","id":"PMC_11044432","title":"Altered stoichiometry of FKBP12.6 versus ryanodine receptor as a cause of abnormal Ca(2+) leak through ryanodine receptor in heart failure.","date":"2000","source":"Circulation","url":"https://pubmed.ncbi.nlm.nih.gov/11044432","citation_count":189,"is_preprint":false},{"pmid":"14715536","id":"PMC_14715536","title":"Protein kinase A phosphorylation at serine-2808 of the cardiac Ca2+-release channel (ryanodine receptor) does not dissociate 12.6-kDa FK506-binding protein (FKBP12.6).","date":"2004","source":"Circulation research","url":"https://pubmed.ncbi.nlm.nih.gov/14715536","citation_count":137,"is_preprint":false},{"pmid":"22158709","id":"PMC_22158709","title":"Inhibition of CaMKII phosphorylation of RyR2 prevents induction of atrial fibrillation in FKBP12.6 knockout mice.","date":"2011","source":"Circulation research","url":"https://pubmed.ncbi.nlm.nih.gov/22158709","citation_count":134,"is_preprint":false},{"pmid":"20431056","id":"PMC_20431056","title":"Kinetics of FKBP12.6 binding to ryanodine receptors in permeabilized cardiac myocytes and effects on Ca sparks.","date":"2010","source":"Circulation research","url":"https://pubmed.ncbi.nlm.nih.gov/20431056","citation_count":126,"is_preprint":false},{"pmid":"11157671","id":"PMC_11157671","title":"Overexpression of FK506-binding protein FKBP12.6 in cardiomyocytes reduces ryanodine receptor-mediated Ca(2+) leak from the sarcoplasmic reticulum and increases contractility.","date":"2001","source":"Circulation 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\"35S-labeled FKBP12/12.6 binding assays, cosedimentation with stripped SR membranes\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — direct in vitro reconstitution binding assay with radiolabeled proteins, replicated across multiple muscle types, foundational biochemical characterization\",\n      \"pmids\": [\"8702774\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"FKBP12.6 is a component of a macromolecular complex on the sarcoplasmic reticulum comprising RyR2, FKBP12.6, PKA, phosphatases PP1 and PP2A, and the anchoring protein mAKAP, as defined by cosedimentation and co-immunoprecipitation.\",\n      \"method\": \"Cosedimentation, co-immunoprecipitation\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP and cosedimentation in native cardiac tissue, highly cited and replicated in subsequent work\",\n      \"pmids\": [\"10830164\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"PKA phosphorylation of RyR2 dissociates FKBP12.6 from the channel complex and increases RyR2 open probability; in failing human hearts RyR2 is PKA hyperphosphorylated, resulting in FKBP12.6 dissociation and defective channel function.\",\n      \"method\": \"Co-immunoprecipitation, single-channel recordings, PKA phosphorylation assay, failing human heart tissue\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — single lab, Co-IP plus single-channel electrophysiology; findings on PKA-induced dissociation were subsequently disputed by other labs (PMIDs 14715536, 20431056)\",\n      \"pmids\": [\"10830164\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"In canine pacing-induced heart failure, the stoichiometric ratio of FKBP12.6 per RyR monomer is significantly decreased (3.6 to 1.6) and FKBP12.6 protein expression is reduced, correlating with a prominent Ca2+ leak through RyR and conformational change in RyR.\",\n      \"method\": \"[3H]dihydro-FK506 and [3H]ryanodine binding assays, stopped-flow Ca2+ release measurements, Western blot\",\n      \"journal\": \"Circulation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — multiple orthogonal biochemical assays (radiolabeled binding, functional Ca2+ release, Western blot) in native failing heart tissue\",\n      \"pmids\": [\"11044432\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"In heart failure, the number of FKBP12.6 binding sites (Bmax) on RyR is dramatically decreased (~83%) while affinity (Kd) is unchanged; this loss underlies RyR channel instability and impaired Ca2+ release function.\",\n      \"method\": \"[3H]dihydro-FK506 binding assay, stopped-flow Ca2+ release, FK506 competition\",\n      \"journal\": \"Cardiovascular research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — quantitative radioligand binding plus functional Ca2+ release assays in native tissue\",\n      \"pmids\": [\"11054478\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"Adenoviral overexpression of FKBP12.6 in adult rabbit cardiomyocytes reduces SR Ca2+ leak through RyR2 by ~53%, increases SR Ca2+ load, and increases fractional shortening, demonstrating that FKBP12.6 stabilizes the closed conformation of RyR2.\",\n      \"method\": \"Adenovirus-mediated gene transfer, fluorometric Ca2+ uptake in permeabilized myocytes, contractility measurements\",\n      \"journal\": \"Circulation research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean gain-of-function with defined phenotypic readout using multiple functional assays\",\n      \"pmids\": [\"11157671\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"FKBP12.6 disruption in mice results in cardiac hypertrophy in males but not females; both sexes show dysregulated Ca2+ release (increased Ca2+ spark amplitude and duration), indicating FKBP12.6 modulates cardiac excitation-contraction coupling. Estrogen receptor antagonism with tamoxifen causes hypertrophy in female knockouts.\",\n      \"method\": \"FKBP12.6 knockout mice, echocardiography, Ca2+ spark imaging (confocal), tamoxifen treatment\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic loss-of-function with defined Ca2+ and cardiac phenotype, replicated with pharmacological intervention, multiple methods\",\n      \"pmids\": [\"11907581\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"FKBP12.6 binds to RyR2 and regulates type 2 RyRs in tracheal smooth muscle; cyclic ADP-ribose (cADPR) alters spontaneous and receptor-mediated Ca2+ release through FKBP12.6, as these effects are blocked by excess recombinant FKBP12.6 and absent in FKBP12.6-knockout mouse myocytes.\",\n      \"method\": \"FKBP12.6 knockout mice, intracellular cADPR dialysis, Ca2+ imaging, force measurement in isolated trachealis\",\n      \"journal\": \"American journal of physiology. Cell physiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic KO combined with pharmacological rescue and functional readouts in native smooth muscle\",\n      \"pmids\": [\"14592808\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"cADPR activates RyR/Ca2+ release channels from coronary arterial smooth muscle SR through FKBP12.6; removal of FKBP12.6 by FK506 or anti-FKBP12 antibody completely abolishes cADPR-induced channel activation in planar lipid bilayer recordings.\",\n      \"method\": \"Planar lipid bilayer single-channel recording, FK506 dissociation, anti-FKBP12 antibody blockade, gradient centrifugation\",\n      \"journal\": \"American journal of physiology. Heart and circulatory physiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — reconstituted single-channel electrophysiology with biochemical depletion of FKBP12.6, single lab but multiple orthogonal manipulations\",\n      \"pmids\": [\"11893565\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"The FKBP12.6 binding site on RyR2 is localized to the NH2-terminal domain (residues 305–1937); deletion analyses show the first 305 residues and C-terminal residues 1937–4967 are not essential, while a fragment containing the first 1937 residues is sufficient for GST-FKBP12.6 binding. The isoleucine-proline dipeptide motif (I2427-P2428) is not the core binding site.\",\n      \"method\": \"GST pulldown with deletion mutants of RyR2 expressed in HEK293 cells\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — systematic deletion mutagenesis with direct binding assay, comprehensive mapping\",\n      \"pmids\": [\"12446682\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"FKBP12.6 co-expressed with human RyR2 in CHO cells is selectively recruited from cytoplasm to ER membranes (sequestration) as RyR2 expression increases; co-expression of FKBP12.6 (but not FKBP12) markedly decreases agonist-induced Ca2+ release and promotes ER Ca2+ superfilling, effects antagonized by rapamycin.\",\n      \"method\": \"Stable CHO cell lines expressing hRyR2, confocal microscopy, Ca2+ imaging, rapamycin competition\",\n      \"journal\": \"The Biochemical journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — live-cell localization linked to functional consequence, comparison with FKBP12 negative control, pharmacological validation\",\n      \"pmids\": [\"12443530\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"FKBP12.6 co-expression (but not FKBP12) in CHO cells expressing dysregulated hRyR2 suppresses intracellular Ca2+ flux and restores normal cell viability and proliferation; FKBP12.6's protective effect is independent of resting [Ca2+] or ER Ca2+ load.\",\n      \"method\": \"Stable CHO cell lines, Ca2+ imaging, cell viability/proliferation assays, ryanodine pharmacology\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean gain-of-function with defined phenotypic readouts, single lab\",\n      \"pmids\": [\"12754204\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"FKBP12.6 deficiency in mice causes exercise-induced ventricular arrhythmias and sudden cardiac death; RyR2 mutations linked to CPVT reduce FKBP12.6 affinity for RyR2 and increase single-channel activity under simulated exercise conditions.\",\n      \"method\": \"FKBP12.6 knockout mice, in vivo exercise testing, single-channel recordings in lipid bilayers, radioligand binding\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic KO with defined lethal phenotype, single-channel electrophysiology with disease mutants, multiple orthogonal methods\",\n      \"pmids\": [\"12837242\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"PKA phosphorylation of RyR2 at serine-2808 does NOT dissociate FKBP12.6 from RyR2; both phosphorylated and non-phosphorylated forms of RyR2, as well as the S2808D phosphomimetic mutant, retain FKBP12.6 binding. Complete PKA phosphorylation does not disrupt native or recombinant FKBP12.6-RyR2 complex.\",\n      \"method\": \"Site-specific phosphorylation-state antibodies, Co-IP with recombinant and native RyR2, S2808D mutant binding assay\",\n      \"journal\": \"Circulation research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — site-directed mutagenesis plus Co-IP with phospho-specific antibodies, directly contradicts earlier claim (PMID 10830164)\",\n      \"pmids\": [\"14715536\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"The C-terminal domain of human RyR2 (encompassing pore-forming transmembrane domains) exhibits rapamycin-sensitive, specific binding to FKBP12.6 but not FKBP12 when expressed in mammalian cells, identifying a novel C-terminal FKBP12.6-binding site.\",\n      \"method\": \"Competition binding assays, mammalian cell expression of RyR2 C-terminal constructs, rapamycin competition\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — binding competition assay plus expression in mammalian cells, single lab; partially conflicts with N-terminal site mapping (PMID 12446682)\",\n      \"pmids\": [\"15591045\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"FKBP12.6 overexpression in rat cardiac myocytes decreases Ca2+ spark amplitude, duration, width, and frequency, but enhances global [Ca2+]i transient amplitude and cell shortening, associated with increased SR Ca2+ load.\",\n      \"method\": \"Adenoviral overexpression, confocal Ca2+ spark imaging with Rhod-2, caffeine-evoked Ca2+ transients\",\n      \"journal\": \"American journal of physiology. Heart and circulatory physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct gain-of-function with functional Ca2+ readouts, single lab\",\n      \"pmids\": [\"15271664\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"FKBP12.6 overexpression in adult rabbit cardiomyocytes increases peak-systolic [Ca2+], SR Ca2+ content, and synchronicity of SR Ca2+ release without altering L-type Ca2+ current or NCX; Ca2+ spark amplitude, duration, width, and frequency are reduced in permeabilized cells.\",\n      \"method\": \"Adenoviral overexpression, Fura-2/Fluo-3 Ca2+ imaging, voltage clamp, confocal microscopy\",\n      \"journal\": \"The Journal of physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean gain-of-function with multiple Ca2+ and electrophysiological readouts, single lab\",\n      \"pmids\": [\"14966299\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"FKBP12.6 in pulmonary artery smooth muscle associates with RyR2 but not RyR1, RyR3, or IP3 receptors; FKBP12.6 deficiency enhances hypoxic and norepinephrine-induced Ca2+ release and vasoconstriction in pulmonary arterial smooth muscle cells.\",\n      \"method\": \"FKBP12.6 knockout mice, Ca2+ imaging, Ca2+-activated current measurements, FK506/rapamycin pharmacology, isolated tissue force measurements\",\n      \"journal\": \"Cell calcium\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic KO with multiple functional readouts and pharmacological controls, Ca2+ imaging plus force measurements\",\n      \"pmids\": [\"15036951\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"Cryo-EM and 3D reconstruction localizes FKBP12.6 binding to the sides of the cytoplasmic region of canine RyR2 adjacent to domain 9 (clamp structures); FKBP12.6 binding alters RyR2 conformation particularly in the transmembrane region and clamp structures.\",\n      \"method\": \"Cryo-electron microscopy, 3D reconstruction, difference mapping, X-ray structure docking\",\n      \"journal\": \"Biophysical journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — cryo-EM structural determination with quantitative difference mapping, single lab\",\n      \"pmids\": [\"16214874\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"The central domain of human RyR2 does NOT mediate interaction with FKBP12.6; yeast two-hybrid and in vitro immunoprecipitation with overlapping fragments covering the entire RyR2 failed to reconstitute FKBP12.6 binding, and an alternatively spliced FKBP12.6 variant cannot interact with RyR.\",\n      \"method\": \"Yeast two-hybrid, in vitro immunoprecipitation, expression of overlapping RyR2 fragments\",\n      \"journal\": \"Cell biochemistry and biophysics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — two orthogonal methods (Y2H + Co-IP), single lab; negative result is mechanistically informative\",\n      \"pmids\": [\"16049346\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"FKBP12.6 (but not FKBP12) coexpression with cardiac DHPR (alpha1CYM) and RyR2 in dyspedic myotubes eliminates spontaneous Ca2+ oscillations and enables robust electrically evoked Ca2+ transients, demonstrating that FKBP12.6 suppresses spontaneous RyR2 activity and is required for ordered CICR. S2808D RyR2 phosphomimetic does not alter FKBP12.6 regulation in this reconstituted system.\",\n      \"method\": \"Reconstitution in RyR1-null dyspedic myotubes, Ca2+ imaging, electrical stimulation, FKBP12.6 coexpression with RyR2 S2808D mutant\",\n      \"journal\": \"American journal of physiology. Cell physiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — molecular reconstitution in null background, multiple functional assays, mutagenesis included\",\n      \"pmids\": [\"16049053\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"Key aspartic acid residues on calstabin2/FKBP12.6 (particularly Asp-37) are involved in binding to RyR2 and in PKA phosphorylation-induced dissociation; a D37S mutant calstabin2 binds to the constitutively PKA-phosphorylated RyR2-S2808D mutant and restores normal cardiac function in a mouse model of heart failure.\",\n      \"method\": \"Site-directed mutagenesis of FKBP12.6, co-immunoprecipitation with RyR2-S2808D, in vivo myocardial infarction model with mutant calstabin2 manipulation\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — mutagenesis plus Co-IP plus in vivo functional rescue, single lab but multiple orthogonal approaches\",\n      \"pmids\": [\"16481613\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"FKBP12.6 removal (by FK506 or genetic knockout) does NOT alter the conductance, Ca2+-activation, caffeine-activation, or subconductance state properties of recombinant or native RyR2, and FKBP12.6-null mice do not exhibit enhanced stress-induced ventricular arrhythmias.\",\n      \"method\": \"Single-channel lipid bilayer recordings, [3H]ryanodine binding, HEK293 SOICR imaging, FKBP12.6-null mouse stress testing\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — reconstituted single-channel recordings plus radioligand binding plus in vivo stress testing, directly contradicts earlier claims (PMID 12837242)\",\n      \"pmids\": [\"17921453\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"K201 (JTV519) suppresses spontaneous Ca2+ release and inhibits [3H]ryanodine binding to RyR2 independently of FKBP12.6; FK506-induced dissociation of FKBP12.6 does not affect K201's suppression, and K201 is equally effective on RyR2 expressed with or without FKBP12.6.\",\n      \"method\": \"Rat ventricular myocytes, HEK293 cells expressing RyR2±FKBP12.6, FK506 pretreatment, [3H]ryanodine binding\",\n      \"journal\": \"The Biochemical journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — radioligand binding plus Ca2+ imaging in multiple cell systems with systematic FKBP12.6 removal controls\",\n      \"pmids\": [\"17313373\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"FKBP12.6-deficient mice are highly susceptible to pacing-induced atrial fibrillation (81% vs 7% in WT); atrial myocytes from KO mice show 53% greater SR Ca2+ leak and increased spontaneous Ca2+ release events, both blocked by the RyR antagonist tetracaine.\",\n      \"method\": \"FKBP12.6-/- mice, intracardiac electrography, Ca2+ imaging in atrial myocytes, tetracaine pharmacology\",\n      \"journal\": \"Heart rhythm\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic KO with defined electrophysiological and Ca2+ phenotypes plus pharmacological rescue\",\n      \"pmids\": [\"18598963\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"FKBP12.6 disruption impairs glucose-induced insulin secretion in pancreatic beta-cells; FKBP12.6-/- islets show markedly impaired glucose-stimulated Ca2+ elevation and insulin secretion (but normal sulfonylurea or KCl response), placing FKBP12.6 downstream of ATP production in the glucose-sensing pathway.\",\n      \"method\": \"FKBP12.6-/- mice generated by homologous recombination, in vivo glucose tolerance test, isolated islet insulin secretion assay, Ca2+ imaging\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic KO with specific functional readout, epistatic placement downstream of ATP/independent of KATP channels\",\n      \"pmids\": [\"18466757\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"Dissociation of FKBP12.6 from RyR2 does NOT play a significant role in beta-adrenergic-stimulated Ca2+ release; ISO increases Ca2+ spark frequency similarly in both WT and FKBP12.6 KO myocytes, and twitch force is not significantly different. In contrast, cADPR-stimulated Ca2+ spark augmentation occurs only in WT and not KO cells, placing cADPR action through FKBP12.6 dissociation from RyR2.\",\n      \"method\": \"FKBP12.6 KO mice, Ca2+ spark imaging, papillary muscle force measurements, pharmacological manipulation (thapsigargin, 2D12, cADPR)\",\n      \"journal\": \"Cardiovascular research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic KO with multiple functional readouts and epistatic dissection of two pathways (ISO vs cADPR)\",\n      \"pmids\": [\"19578067\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"FKBP12.6-/- mice display hyperinsulinemia and enhanced glucose-stimulated insulin secretion due to enhanced glucose-induced islet Ca2+ elevation; deletion also confers resistance to high-fat diet-induced hyperglycemia despite greater weight gain.\",\n      \"method\": \"FKBP12.6-/- mice, in vivo glucose tolerance test, ex vivo islet insulin secretion, Ca2+ imaging\",\n      \"journal\": \"FASEB journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic KO with in vivo and ex vivo functional readouts, replicates and extends PMID 18466757\",\n      \"pmids\": [\"19805579\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"Crystal structure of FKBP12.6 in complex with rapamycin determined at 2.0 Å resolution; FKBP12.6 and FKBP12 structures are nearly identical except for a displacement in the helical region of FKBP12.6 toward the hydrophobic pocket, not predicted by homology modeling.\",\n      \"method\": \"X-ray crystallography, 2.0 Å resolution\",\n      \"journal\": \"Acta crystallographica. Section D, Biological crystallography\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — atomic resolution crystal structure with functional implication for RyR2 binding specificity, single lab but definitive structural method\",\n      \"pmids\": [\"10713512\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Direct fluorescent binding measurements in permeabilized myocytes show FKBP12.6 binds RyR2 with very high affinity (Kd ~0.7 nM) while FKBP12 has much lower affinity (Kd ~206 nM); only FKBP12.6 (not FKBP12) inhibits basal RyR2 activity; PKA phosphorylation does NOT alter binding kinetics or affinity of either FKBP for RyR2.\",\n      \"method\": \"Fluorescently labeled FKBP12.6/12 binding in permeabilized myocytes, FRAP, Ca2+ spark measurements, quantitative immunoblot\",\n      \"journal\": \"Circulation research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — direct quantitative binding kinetics in situ (FRAP + steady-state fluorescence), Ca2+ spark functional readout, conclusively addresses PKA controversy\",\n      \"pmids\": [\"20431056\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Genetic inhibition of CaMKII phosphorylation of RyR2 at S2814 (S2814A mutation) prevents AF induction in FKBP12.6-/- mice by suppressing SR Ca2+ leak and DADs, while S2808A mutation does not protect; this epistasis places CaMKII-mediated RyR2-S2814 phosphorylation downstream of FKBP12.6 deficiency in the AF pathway.\",\n      \"method\": \"FKBP12.6-/-:S2814A double-mutant mice, intracardiac stimulation, Ca2+ spark/wave imaging, NCX current measurement\",\n      \"journal\": \"Circulation research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic epistasis with double-mutant mice, multiple functional readouts (electrophysiology + Ca2+ imaging), clear pathway placement\",\n      \"pmids\": [\"22158709\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"FKBP12 is a high-affinity activator of RyR2 (sensitizes channel to cytosolic Ca2+), whereas FKBP12.6 has very low efficacy but can antagonize FKBP12 effects on single-channel gating; physiological concentrations of FKBP12 increase Ca2+ wave frequency and decrease SR Ca2+ content in cardiac cells.\",\n      \"method\": \"Single sheep RyR2 channels in planar phospholipid bilayers, Ca2+ wave measurements in permeabilized rat cardiomyocytes, mathematical modeling\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — single-channel electrophysiology reconstitution plus functional Ca2+ imaging in native cells plus modeling, single lab\",\n      \"pmids\": [\"22363773\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"VTSIP-associated RyR2 point mutations increase binding to FKBP12.6, while ARVD2-associated mutations decrease it, as measured by a quantitative yeast two-hybrid system; these opposing effects on FKBP12.6 binding correlate with the clinical differences between the two diseases.\",\n      \"method\": \"Quantitative yeast two-hybrid system with disease-associated RyR2 point mutations\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — yeast two-hybrid is indirect, single method, but systematic analysis of multiple disease mutations\",\n      \"pmids\": [\"12459180\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Cryo-EM structure of rabbit RyR2 in complex with FKBP12.6 at 11.8 Å resolution reveals that FKBP12.6 binding rigidifies the HD2 domain of RyR2 and stabilizes the closed state; two RyR2 conformations in the dataset are proposed to reflect phosphorylation state of the P2 domain.\",\n      \"method\": \"Cryo-electron microscopy, 3D reconstruction, atomic model building, conformational heterogeneity analysis\",\n      \"journal\": \"Science signaling\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — cryo-EM structure at defined resolution with atomic model, identifies domain-specific conformational effect of FKBP12.6 binding\",\n      \"pmids\": [\"28536302\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Fully active FKBP12.6 (calstabin 2) retains peptidyl-prolyl cis-trans isomerase (PPIase) enzymatic activity; total chemical synthesis followed by refolding produced enzyme with catalytic activity and crystallographic structure (at 2.0 Å) indistinguishable from recombinant wild-type.\",\n      \"method\": \"Native chemical ligation synthesis, refolding, enzymatic activity assay, X-ray crystallography\",\n      \"journal\": \"Protein science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — direct in vitro enzymatic assay plus crystal structure, confirms intrinsic PPIase activity\",\n      \"pmids\": [\"27670942\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Sirolimus (rapamycin) bound to FKBP12.6 impairs endothelial barrier function through RyR2-mediated intracellular Ca2+ elevation, protein kinase C-α activation, and disruption of the p120-VE cadherin interaction; siRNA knockdown of FKBP12.6 mimics these effects.\",\n      \"method\": \"HAEC culture, transendothelial electrical resistance, siRNA knockdown, Ca2+ imaging, PKC-α phosphorylation Western blot, immunostaining, mouse vascular permeability assay\",\n      \"journal\": \"Arteriosclerosis, thrombosis, and vascular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — siRNA KD plus pharmacological rescue plus in vivo validation, single lab\",\n      \"pmids\": [\"23887639\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Absence or inhibition of FKBP12.6 increases RyR2 sensitivity to L-type Ca2+ channel triggers (increased spark frequency and LCC-RyR coupling fidelity) without altering LCC open probability; this sensitization is additive with isoproterenol and can lead to chaotic Ca2+ waves and ventricular arrhythmias.\",\n      \"method\": \"FKBP12.6 KO mice, whole-cell patch clamp with confocal Ca2+ spark imaging, loose-seal patch-clamp LCC-RyR signaling kinetics, FK506/rapamycin pharmacology\",\n      \"journal\": \"Cardiovascular research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic KO plus pharmacological confirmation, multiple orthogonal methods including patch clamp and Ca2+ imaging\",\n      \"pmids\": [\"28077437\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"FKBP12.6 protects against AngII-induced cardiac hypertrophy by reducing intracellular [Ca2+] and inhibiting calcineurin/NFATc4, CaMKII/MEF-2, AKT/GSK3β/NFATc4, and AKT/mTOR signaling pathways; KO aggravates and cardiac-specific TG overexpression prevents AngII-induced hypertrophy.\",\n      \"method\": \"FKBP12.6 KO and cardiac-specific TG mice, AngII osmotic pump infusion, echocardiography, Ca2+ imaging, Western blot for signaling pathway components\",\n      \"journal\": \"Journal of cellular and molecular medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal genetic models (KO and TG) with multiple signaling pathway readouts\",\n      \"pmids\": [\"29682889\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Rieske iron-sulfur protein (RISP)-dependent ROS generation causes dissociation of FKBP12.6 from RyR2 in pulmonary arterial smooth muscle cells during chronic hypoxia, leading to increased RyR2 activity, NF-κB/cyclin D1 activation, cell proliferation, and pulmonary hypertension; SMC-specific RyR2 KO, RISP knockdown, or RyR2/FKBP12.6 complex stabilization by S107 attenuates PH.\",\n      \"method\": \"SMC-specific RyR2 KO mice, RISP knockdown, FKBP12.6 KO, S107 pharmacological stabilization, co-IP, Ca2+ imaging, NF-κB/cyclin D1 activity assay\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple genetic models plus pharmacological rescue, co-IP defines complex, in vivo PH phenotype\",\n      \"pmids\": [\"32669538\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"FKBP12.6 directly binds BMP/TGF-β type I receptors (e.g., ALK2/ACVR1) but not type II receptors; the 2.17 Å crystal structure of the ALK2-FKBP12.6 complex shows FKBP12.6 binding to the GS domain of ALK2 in a manner equivalent to the FKBP12 complex, with ALK2 residues Phe198 and Leu199 inserting into the FK506-binding pocket.\",\n      \"method\": \"Cellular immunoprecipitation, SEC-MALS (1:1 direct interaction), X-ray crystallography at 2.17 Å\",\n      \"journal\": \"Biomedicines\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — atomic resolution crystal structure plus SEC-MALS quantification of direct binding, single lab\",\n      \"pmids\": [\"33572801\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"FKBP12.6 directly binds Glomulin (Glmn) in vitro with higher affinity than FKBP12; the FKBP51-Glmn interaction (as a model for the class) requires two amino acids lining the FK506-binding site and is blocked by FKBP ligands.\",\n      \"method\": \"In vitro binding assays (FKBP12.6 vs FKBP12 vs FKBP51/52 truncation mutants), FKBP ligand competition\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct in vitro binding quantification, single lab; FKBP51 used as surrogate model for binding pocket characterization\",\n      \"pmids\": [\"31490997\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"FKBP12.6 overexpression in rabbit cardiomyocytes decreases inward rectifier current (IK1) amplitude by ~25% in a Ca2+-dependent and FK506-sensitive manner and prolongs action potential duration by ~30%; this effect is independent of calcineurin binding (shown using a calcineurin-binding deficient FKBP12.6 mutant).\",\n      \"method\": \"Adenoviral overexpression, whole-cell patch clamp, action potential recordings, FKBP12.6 calcineurin-binding mutant\",\n      \"journal\": \"Pflugers Archiv : European journal of physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — electrophysiology with mutant controls, single lab, Ca2+-dependent and FK506-reversible effects mechanistically linked\",\n      \"pmids\": [\"19333617\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"FKBP12.6 ubiquitination is regulated by NR3C1-mediated repression of Glomulin (GLMN); under stress, activated NR3C1 represses GLMN, preventing FKBP12.6 ubiquitination and degradation, leading to FKBP12.6 accumulation, calcium leakage/overload, and mitochondrial quality control impairment in cardiomyocytes.\",\n      \"method\": \"ChIP-qPCR, siRNA knockdown of NR3C1 and GLMN, mouse restraint stress models, transmission electron microscopy, Western blot\",\n      \"journal\": \"International journal of molecular sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP-qPCR plus siRNA with functional readouts, single lab, 2025 paper with 0 citations\",\n      \"pmids\": [\"40943170\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"FKBP12.6 directly binds IP3R (inositol 1,4,5-trisphosphate receptor) in bladder detrusor muscle, as shown by co-immunoprecipitation; FKBP12.6 knockout increases bladder sensitivity and detrusor instability, and IP3R/TRPM4 pathway inhibitors rescue the knockout phenotype, indicating FKBP12.6 regulates bladder function through IP3R/TRPM4.\",\n      \"method\": \"FKBP12.6 KO mice, co-immunoprecipitation, urodynamic testing, void spot assay, pharmacological rescue with 2-APB and 9-PHE\",\n      \"journal\": \"Current medicinal chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic KO with defined bladder phenotype plus co-IP plus pharmacological rescue, single lab, novel tissue/partner\",\n      \"pmids\": [\"40051354\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"miR-34a directly targets the 3'-UTR of FKBP1B mRNA to repress its expression; FKBP1B overexpression attenuates MDI-induced adipogenesis and reduces PPARγ and C/EBPα expression, demonstrating FKBP1B acts as an anti-adipogenic factor downstream of miR-34a.\",\n      \"method\": \"Luciferase 3'-UTR reporter assay, miR-34a mimic/inhibitor, FKBP1B overexpression in 3T3-L1 preadipocytes, adipogenesis assay\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct 3'-UTR reporter plus gain-of-function with defined phenotype, single lab\",\n      \"pmids\": [\"26471303\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"X-ray crystal structures of unligated FKBP12.6 (1.70 and 1.90 Å) reveal conformational flexibility: the Phe59 active-site ring can rotate perpendicular to its typical orientation, and the '80s loop' peptide unit can flip; NMR shows 21 backbone amides undergo slow conformational exchange near the 80s loop.\",\n      \"method\": \"X-ray crystallography (two crystal forms), NMR backbone amide resonance doubling\",\n      \"journal\": \"Acta crystallographica. Section D, Biological crystallography\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — high-resolution crystal structures plus NMR conformational analysis, single lab but orthogonal methods\",\n      \"pmids\": [\"24598733\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Conditional deletion of the transcription factor CHF1/Hey2 in cardiomyocytes leads to increased FKBP12.6 expression; treatment with FK506 (which inhibits FKBP12.6-RyR2 association) restores contractile function in CHF1/Hey2 KO myocytes, placing FKBP12.6 downstream of CHF1/Hey2 in a pathway regulating cardiac EC coupling.\",\n      \"method\": \"Conditional KO mice, aortic banding, Ca2+ transients in isolated myocytes, gene expression analysis, FK506 pharmacological rescue\",\n      \"journal\": \"American journal of physiology. Heart and circulatory physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic epistasis by KO plus pharmacological rescue, single lab\",\n      \"pmids\": [\"22408025\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"FKBP12.6 overexpression conditionally in cardiac myocytes reduces Ca2+ spark frequency by 50% (including under isoproterenol) with unchanged SR Ca2+ load and prevents triggered ventricular tachycardia induced by burst pacing after isoproterenol pretreatment.\",\n      \"method\": \"Conditional cardiac-specific FKBP12.6 transgenic mice, in vivo electrophysiology, confocal Ca2+ spark imaging, Co-IP of FKBP12.6-RyR2\",\n      \"journal\": \"Circulation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — conditional cardiac-specific transgene with in vivo electrophysiology endpoint and Ca2+ spark mechanistic analysis\",\n      \"pmids\": [\"18378612\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"FKBP12.6 (calstabin2) is a high-affinity (Kd ~0.7 nM), selective binding partner of the cardiac ryanodine receptor RyR2, where it forms part of a macromolecular complex with PKA, PP1, PP2A, and mAKAP on the sarcoplasmic reticulum; by occupying a conformationally sensitive site spanning the RyR2 N-terminal domain (residues 305–1937) and possibly the C-terminal transmembrane region, FKBP12.6 rigidifies the RyR2 HD2/clamp domain and stabilizes the closed channel state, thereby suppressing spontaneous diastolic Ca2+ leak, Ca2+ sparks, and store overload-induced Ca2+ release; its loss or dissociation (triggered by cADPR signaling or CaMKII-dependent S2814 phosphorylation of RyR2, but not necessarily by PKA phosphorylation at S2808) leads to RyR2 hypersensitivity to Ca2+ triggers and underlies arrhythmias, cardiac hypertrophy (suppressed by estrogen), atrial fibrillation, and impaired glucose-stimulated insulin secretion; additionally, FKBP12.6 binds BMP/TGF-β type I receptors (e.g., ALK2 GS domain), Glomulin, and IP3R, and possesses intrinsic peptidyl-prolyl cis-trans isomerase activity, while its stability is regulated by NR3C1/Glomulin-dependent ubiquitination.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"FKBP1B (FKBP12.6/calstabin2) is a peptidyl-prolyl cis-trans isomerase that functions as a high-affinity (Kd ~0.7 nM), selective regulatory subunit of the cardiac ryanodine receptor RyR2, stabilizing the channel's closed state to suppress diastolic Ca2+ leak and govern excitation-contraction coupling [#0, #29, #34]. Unlike FKBP12, only FKBP12.6 binds and rebinds RyR2 (not RyR1), and it assembles into an SR macromolecular complex with PKA, the phosphatases PP1 and PP2A, and the anchoring protein mAKAP [#0, #1]. The interaction maps principally to the RyR2 N-terminal domain (residues 305–1937), with cryo-EM showing that FKBP12.6 docks at the cytoplasmic clamp region and rigidifies the HD2 domain to lock the closed conformation [#9, #18, #33]. Gain- and loss-of-function studies establish the functional consequence directly: FKBP12.6 overexpression reduces Ca2+ spark frequency, raises SR Ca2+ load, and prevents triggered arrhythmias, whereas its loss or dissociation increases RyR2 sensitivity to Ca2+ triggers and SR Ca2+ leak [#5, #36, #47]. Loss of FKBP12.6 in mice produces sex-dependent cardiac hypertrophy, atrial fibrillation, and aberrant Ca2+ release, and the protein further protects against AngII-induced hypertrophy by restraining calcineurin/NFAT, CaMKII/MEF-2, and AKT/mTOR signaling [#6, #24, #37]. Dissociation is driven by cADPR signaling and by CaMKII-dependent phosphorylation of RyR2 at S2814, but not by PKA phosphorylation at S2808, which does not alter FKBP12.6 binding [#13, #26, #29, #30]. Beyond RyR2, FKBP12.6 directly binds the IP3 receptor in detrusor muscle, the BMP/TGF-β type I receptor ALK2 via its GS domain, and Glomulin, and it acts in non-cardiac settings including glucose-stimulated insulin secretion, smooth-muscle Ca2+ release, and anti-adipogenesis downstream of miR-34a [#43, #39, #40, #25, #17, #44]. Its abundance is set post-translationally through Glomulin/NR3C1-dependent ubiquitination [#42].\",\n  \"teleology\": [\n    {\n      \"year\": 1996,\n      \"claim\": \"Established that FKBP12.6, distinct from the closely related FKBP12, is the physiological FKBP partner of the cardiac RyR2, defining its binding selectivity as the basis for isoform-specific channel regulation.\",\n      \"evidence\": \"radiolabeled FKBP12/12.6 binding and cosedimentation with stripped cardiac SR membranes\",\n      \"pmids\": [\"8702774\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not localize the binding site on RyR2\", \"Did not establish functional consequence of binding\"]\n    },\n    {\n      \"year\": 2000,\n      \"claim\": \"Placed FKBP12.6 within an SR macromolecular signaling complex and proposed a regulatory model in which PKA phosphorylation dissociates it to increase channel activity, linking the complex to heart failure.\",\n      \"evidence\": \"cosedimentation, reciprocal Co-IP, single-channel recordings, and failing human heart tissue\",\n      \"pmids\": [\"10830164\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"The PKA-induced dissociation claim was subsequently disputed\", \"Stoichiometry and phospho-site dependence not resolved here\"]\n    },\n    {\n      \"year\": 2000,\n      \"claim\": \"Showed quantitatively that FKBP12.6 loss in failing hearts arises from reduced binding-site occupancy/expression rather than altered affinity, mechanistically connecting FKBP12.6 depletion to pathological Ca2+ leak.\",\n      \"evidence\": \"[3H]dihydro-FK506 and [3H]ryanodine binding, stopped-flow Ca2+ release, and Western blot in failing canine/native heart tissue\",\n      \"pmids\": [\"11044432\", \"11054478\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not define the trigger for FKBP12.6 loss\", \"Correlative in disease, not causal manipulation\"]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"Directly demonstrated by gain-of-function that FKBP12.6 stabilizes the closed RyR2 state, reducing SR Ca2+ leak and improving contractility.\",\n      \"evidence\": \"adenoviral FKBP12.6 overexpression in rabbit cardiomyocytes with Ca2+ leak and contractility readouts\",\n      \"pmids\": [\"11157671\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of stabilization not addressed\", \"Single overexpression context\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Genetic deletion established FKBP12.6 as a modulator of cardiac EC coupling with sex-dependent hypertrophy and identified it as the effector through which cADPR controls Ca2+ release across cardiac and smooth muscle.\",\n      \"evidence\": \"FKBP12.6 knockout mice with echocardiography, Ca2+ spark imaging, tamoxifen, and cADPR dialysis in cardiac/tracheal/coronary smooth muscle\",\n      \"pmids\": [\"11907581\", \"14592808\", \"11893565\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular mechanism of estrogen protection unresolved\", \"Direct cADPR target within the complex not defined\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Mapped the FKBP12.6 footprint on RyR2 to the N-terminal domain (residues 305–1937) and excluded the I2427-P2428 motif as the core site, providing the first structural localization of the interaction.\",\n      \"evidence\": \"GST pulldown with RyR2 deletion mutants in HEK293 cells; complementary quantitative Y2H of disease mutants\",\n      \"pmids\": [\"12446682\", \"12459180\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not resolve residue-level contacts\", \"A separate C-terminal site was later proposed, creating an unresolved discrepancy\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Linked FKBP12.6 deficiency to exercise-induced lethal ventricular arrhythmia and to CPVT mutations that weaken FKBP12.6 binding, framing FKBP12.6 dissociation as an arrhythmogenic mechanism.\",\n      \"evidence\": \"FKBP12.6 knockout mice with in vivo exercise testing, single-channel recordings of CPVT mutants, and radioligand binding\",\n      \"pmids\": [\"12837242\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"The stress-induced arrhythmia phenotype was later not reproduced in another knockout study\", \"Causal chain from binding loss to arrhythmia incompletely defined\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Demonstrated in heterologous cells that FKBP12.6 is sequestered to RyR2-bearing ER membranes and suppresses agonist-evoked Ca2+ release independent of resting Ca2+/ER load, establishing a cell-protective regulatory function.\",\n      \"evidence\": \"stable CHO lines expressing hRyR2 with confocal localization, Ca2+ imaging, rapamycin competition, and viability assays\",\n      \"pmids\": [\"12443530\", \"12754204\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Heterologous system may not recapitulate native stoichiometry\", \"FKBP12 negative control behavior left mechanism of selectivity open\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Resolved the PKA-phosphorylation controversy by showing S2808 phosphorylation does not dissociate FKBP12.6, while reconstitution confirmed FKBP12.6 (not FKBP12) suppresses spontaneous RyR2 activity and supports ordered CICR.\",\n      \"evidence\": \"phospho-specific Co-IP with S2808D mutant; reconstitution in dyspedic myotubes with DHPR/RyR2; competition binding to a C-terminal RyR2 construct\",\n      \"pmids\": [\"14715536\", \"16049053\", \"15591045\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Reconciliation of N-terminal versus C-terminal binding sites not achieved\", \"Did not identify the true dissociation trigger\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Reinforced through multiple gain-of-function studies that FKBP12.6 reduces Ca2+ spark parameters while enhancing global Ca2+ transients and SR load, and extended its RyR2-selective role to pulmonary artery smooth muscle Ca2+ signaling.\",\n      \"evidence\": \"adenoviral overexpression in rat/rabbit cardiomyocytes with Ca2+ imaging and voltage clamp; FKBP12.6 KO with Ca2+/force readouts in pulmonary artery SMC\",\n      \"pmids\": [\"15271664\", \"14966299\", \"15036951\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Tissue-specific differences in coupling not mechanistically unified\", \"RyR2-selectivity over RyR1/3 and IP3R asserted but contacts undefined\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Provided structural visualization that FKBP12.6 binds the cytoplasmic clamp region adjacent to domain 9 and alters RyR2 conformation in the transmembrane/clamp domains, connecting binding to gating control.\",\n      \"evidence\": \"cryo-EM 3D reconstruction and difference mapping of canine RyR2±FKBP12.6; orthogonal Y2H/Co-IP fragment analysis\",\n      \"pmids\": [\"16214874\", \"16049346\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Low resolution precluded atomic contacts\", \"Conformational mechanism inferred, not dynamically resolved\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Identified FKBP12.6 residues (notably Asp-37) governing RyR2 binding and engineered a mutant that binds phospho-mimetic RyR2 and rescues failing-heart function, providing a structure-guided therapeutic proof of concept.\",\n      \"evidence\": \"FKBP12.6 site-directed mutagenesis, Co-IP with RyR2-S2808D, and in vivo myocardial infarction rescue\",\n      \"pmids\": [\"16481613\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Single lab, dependent on the contested PKA-dissociation framework\", \"Generalizability of mutant rescue not established\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Challenged the FKBP12.6-RyR2 gating paradigm by reporting that FKBP12.6 removal does not alter RyR2 single-channel properties or confer stress-induced arrhythmia, and that K201's action is FKBP12.6-independent.\",\n      \"evidence\": \"lipid-bilayer single-channel recordings, [3H]ryanodine binding, HEK293 SOICR imaging, and KO stress testing\",\n      \"pmids\": [\"17921453\", \"17313373\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Directly contradicts earlier arrhythmia findings, leaving the in vivo role context-dependent\", \"Did not reconcile differing knockout phenotypes\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Established causal roles for FKBP12.6 in atrial fibrillation susceptibility and in glucose-stimulated insulin secretion, broadening its physiological scope beyond ventricular EC coupling.\",\n      \"evidence\": \"FKBP12.6-/- mice with intracardiac electrography and tetracaine rescue; in vivo glucose tolerance, islet secretion, and Ca2+ imaging\",\n      \"pmids\": [\"18598963\", \"18466757\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Beta-cell Ca2+ channel target left to placement downstream of ATP\", \"Atrial leak mechanism not yet tied to a specific phospho-site\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Dissected the dissociation signals by showing cADPR—but not β-adrenergic/ISO stimulation—augments Ca2+ sparks through FKBP12.6, and demonstrated conditional cardiac FKBP12.6 overexpression prevents triggered ventricular tachycardia; also revealed FKBP12.6 effects on IK1/action potential duration and opposing insulin phenotypes.\",\n      \"evidence\": \"FKBP12.6 KO Ca2+ spark/force studies, conditional cardiac transgenic in vivo electrophysiology, patch clamp with calcineurin-mutant FKBP12.6, and KO glucose/insulin assays\",\n      \"pmids\": [\"19578067\", \"18378612\", \"19333617\", \"19805579\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Insulin secretion phenotype differed between knockout studies\", \"Mechanism coupling FKBP12.6 to IK1 not fully defined\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Provided definitive in situ binding kinetics (Kd ~0.7 nM for FKBP12.6 vs ~206 nM for FKBP12) and conclusively showed PKA phosphorylation does not change FKBP12.6 binding, settling the affinity and phospho-dependence questions.\",\n      \"evidence\": \"fluorescent binding and FRAP in permeabilized myocytes with Ca2+ spark readouts and quantitative immunoblot\",\n      \"pmids\": [\"20431056\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not address which physiological trigger dissociates FKBP12.6\", \"In situ measurement does not resolve binding-site geometry\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Clarified the FKBP isoform paradox—FKBP12 activates/sensitizes RyR2 while FKBP12.6 antagonizes this—and placed FKBP12.6 downstream of the CHF1/Hey2 transcriptional program in cardiac EC coupling.\",\n      \"evidence\": \"single sheep RyR2 bilayer recordings with modeling; conditional CHF1/Hey2 KO with FK506 rescue and expression analysis\",\n      \"pmids\": [\"22363773\", \"22408025\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism by which CHF1/Hey2 controls FKBP12.6 transcription not defined\", \"Competition dynamics of FKBP12 vs FKBP12.6 in vivo unresolved\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Established by genetic epistasis that CaMKII phosphorylation of RyR2 at S2814—not PKA at S2808—mediates the atrial fibrillation arising from FKBP12.6 deficiency, defining the operative dissociation/leak pathway.\",\n      \"evidence\": \"FKBP12.6-/-:S2814A double-mutant mice with intracardiac stimulation and Ca2+ spark/wave imaging\",\n      \"pmids\": [\"22158709\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not establish whether S2814 phosphorylation directly weakens FKBP12.6 binding\", \"Ventricular versus atrial pathway differences not fully mapped\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Refined the structural mechanism (HD2-domain rigidification stabilizing the closed state) and demonstrated functionally that FKBP12.6 absence increases LCC-RyR coupling fidelity and spark frequency without changing LCC gating, linking the molecular effect to arrhythmogenic Ca2+ waves.\",\n      \"evidence\": \"cryo-EM of rabbit RyR2-FKBP12.6 with conformational analysis; KO patch clamp with confocal Ca2+ spark and LCC-RyR coupling kinetics\",\n      \"pmids\": [\"28536302\", \"28077437\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Resolution insufficient for full atomic phospho-domain modeling\", \"How HD2 rigidification propagates to the pore not mechanistically traced\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Confirmed that FKBP12.6 retains intrinsic peptidyl-prolyl cis-trans isomerase catalytic activity and characterized its conformational flexibility, distinguishing its enzymatic function from its scaffolding role at RyR2.\",\n      \"evidence\": \"total chemical synthesis with enzymatic assay and crystallography; high-resolution crystal structures plus NMR conformational exchange analysis\",\n      \"pmids\": [\"27670942\", \"24598733\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No physiological PPIase substrate identified\", \"Relationship of catalytic activity to channel regulation undefined\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Expanded the FKBP12.6 interactome beyond RyR2 by structurally defining direct binding to the ALK2 GS domain and to Glomulin, implicating it in TGF-β/BMP receptor regulation and FKBP-ligand-sensitive complexes.\",\n      \"evidence\": \"Co-IP and SEC-MALS with 2.17 Å ALK2-FKBP12.6 crystal structure; in vitro Glomulin binding versus FKBP12/51/52\",\n      \"pmids\": [\"33572801\", \"31490997\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Cellular consequences of ALK2 binding for BMP/TGF-β signaling not established\", \"Glomulin interaction not yet linked to a downstream pathway\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Defined a redox-driven dissociation mechanism in which RISP-dependent ROS during chronic hypoxia releases FKBP12.6 from RyR2 to drive NF-κB/cyclin D1 proliferation and pulmonary hypertension, providing a disease pathway with pharmacological rescue.\",\n      \"evidence\": \"SMC-specific RyR2 KO, RISP knockdown, FKBP12.6 KO, S107 stabilization, Co-IP, and Ca2+/NF-κB assays\",\n      \"pmids\": [\"32669538\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular target of ROS on the complex not pinpointed\", \"Generalizability beyond pulmonary vasculature unknown\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Showed FKBP12.6 restrains pathological cardiac hypertrophy by lowering intracellular Ca2+ and suppressing calcineurin/NFAT, CaMKII/MEF-2, and AKT/mTOR signaling, integrating its channel role into hypertrophic signaling.\",\n      \"evidence\": \"reciprocal FKBP12.6 KO and cardiac-specific transgenic mice with AngII infusion, echocardiography, Ca2+ imaging, and pathway immunoblots\",\n      \"pmids\": [\"29682889\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct versus Ca2+-indirect contribution to each pathway not separated\", \"Did not test rescue by RyR2 stabilization specifically\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Identified post-translational control of FKBP12.6 abundance via NR3C1 repression of Glomulin, blocking FKBP12.6 ubiquitination so that stress-driven accumulation impairs mitochondrial quality control.\",\n      \"evidence\": \"ChIP-qPCR, NR3C1/GLMN siRNA knockdown, restraint-stress mouse models, electron microscopy, and Western blot\",\n      \"pmids\": [\"40943170\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single recent study with limited independent confirmation\", \"Direct demonstration of Glomulin-mediated FKBP12.6 ubiquitination not shown\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Extended FKBP12.6 regulation to a second channel class by showing direct IP3R binding in detrusor muscle and a knockout bladder-instability phenotype rescued by IP3R/TRPM4 inhibition.\",\n      \"evidence\": \"FKBP12.6 KO mice, Co-IP, urodynamic and void-spot testing, and pharmacological rescue with 2-APB/9-PHE\",\n      \"pmids\": [\"40051354\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single Co-IP without reciprocal structural mapping of the IP3R site\", \"Selectivity versus RyR2 in this tissue not resolved\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Placed FKBP1B within a miR-34a-regulated anti-adipogenic axis, indicating transcript-level control and a metabolic role distinct from Ca2+ channel regulation.\",\n      \"evidence\": \"luciferase 3'-UTR reporter, miR-34a mimic/inhibitor, and FKBP1B overexpression in 3T3-L1 adipogenesis assays\",\n      \"pmids\": [\"26471303\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism by which FKBP1B suppresses PPARγ/C/EBPα undefined\", \"Single cell-line context\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The physiological trigger and structural mechanism that dissociates FKBP12.6 from RyR2 under specific stress states, and how its newly identified partners (IP3R, ALK2, Glomulin) and PPIase activity integrate with channel regulation, remain to be unified.\",\n      \"evidence\": \"no single study resolves the dissociation trigger across the conflicting cardiac models or links PPIase catalysis to a defined substrate\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No physiological PPIase substrate identified\", \"N-terminal versus C-terminal RyR2 binding-site discrepancy unresolved\", \"Conflicting knockout arrhythmia phenotypes not reconciled\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0016853\", \"supporting_discovery_ids\": [34, 45]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [5, 29, 36, 47]},\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [34, 39]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005783\", \"supporting_discovery_ids\": [10, 12]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [10, 29]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-397014\", \"supporting_discovery_ids\": [5, 6, 36]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [1, 30, 37]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [12, 24, 38]}\n    ],\n    \"complexes\": [\n      \"RyR2-FKBP12.6-PKA-PP1-PP2A-mAKAP SR macromolecular complex\"\n    ],\n    \"partners\": [\n      \"RYR2\",\n      \"ITPR1\",\n      \"ACVR1\",\n      \"GLMN\",\n      \"PRKAR\",\n      \"PPP1CA\",\n      \"AKAP6\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":8,"faith_total":8,"faith_pct":100.0}}