Affinage

FKBP1B

Peptidyl-prolyl cis-trans isomerase FKBP1B · UniProt P68106

Round 2 corrected
Length
108 aa
Mass
11.8 kDa
Annotated
2026-04-28
129 papers in source corpus 44 papers cited in narrative 43 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

FKBP1B encodes calstabin 2 (FKBP12.6), a peptidyl-prolyl cis-trans isomerase that functions as a critical stabilizer of the cardiac ryanodine receptor RyR2 in a macromolecular sarcoplasmic reticulum complex containing PKA, PP1, PP2A, and mAKAP (PMID:7592869, PMID:10830164). Bound FKBP12.6 rigidifies the RyR2 HD2 clamp domain, stabilizes the channel closed state, reduces spontaneous Ca²⁺ spark frequency, and facilitates termination of store-overload-induced Ca²⁺ release; its dissociation—triggered by oxidative modification of RyR2 cysteines, CaMKII phosphorylation at Ser-2814, or cADPR binding—increases RyR2 open probability and diastolic SR Ca²⁺ leak (PMID:28536302, PMID:22158709, PMID:17200109, PMID:9013543). Loss of FKBP12.6 in mice causes exercise-induced ventricular tachycardia, atrial fibrillation, sex-dependent cardiac hypertrophy, enhanced hypoxia-driven pulmonary vasoconstriction and pulmonary hypertension, and impaired glucose-stimulated insulin secretion in pancreatic β-cells (PMID:12837242, PMID:18598963, PMID:11907581, PMID:32669538, PMID:18466757). Beyond the heart, FKBP12.6 mediates cADPR-dependent Ca²⁺ release through RyR2 in airway and vascular smooth muscle, and when complexed with rapamycin it can engage mTOR or disrupt endothelial barrier function via PKCα-dependent VE-cadherin uncoupling (PMID:14592808, PMID:11893565, PMID:23887639).

Mechanistic history

Synthesis pass · year-by-year structured walk · 19 steps
  1. 1994 High

    Identification of FKBP1B as a novel FKBP12-related gene with intrinsic PPIase activity established that mammals encode a second immunophilin closely related to FKBP12 but with distinct tissue expression.

    Evidence cDNA cloning from human tissue, recombinant PPIase assay, RT-PCR tissue survey

    PMID:7513996

    Open questions at the time
    • No binding partner or physiological substrate identified
    • Functional distinction from FKBP12 unknown
  2. 1995 High

    Demonstration that FKBP12.6 selectively associates with cardiac RyR2 (not RyR1) and mediates calcineurin inhibition via FK506 resolved the question of isoform specificity and linked FKBP12.6 to cardiac Ca²⁺ regulation.

    Evidence Co-immunoprecipitation with native cardiac SR, rapamycin-mTOR binding assay, calcineurin inhibition in Jurkat cells

    PMID:7592869

    Open questions at the time
    • Functional consequence of RyR2 binding on channel gating not yet determined
    • In vivo relevance unestablished
  3. 1996 High

    Selective FKBP12.6-RyR2 binding was confirmed by isoform exchange experiments showing only FKBP12.6 can compete for the cardiac RyR binding site, establishing the molecular basis for tissue-specific FKBP-RyR pairing.

    Evidence Radiolabeled FKBP12/12.6 competition assays with cardiac and skeletal SR vesicles

    PMID:8702774

    Open questions at the time
    • Structural basis for selectivity unknown
    • Stoichiometry of binding not quantified
  4. 1997 High

    Discovery that cADPR binds FKBP12.6 on the RyR and dissociates it to trigger Ca²⁺ release from islet microsomes revealed FKBP12.6 as the intracellular cADPR-responsive element in non-cardiac tissues.

    Evidence Radioligand binding with [³H]cADPR, Ca²⁺ flux from pancreatic islet microsomes, immunoprecipitation after cADPR treatment

    PMID:9013543

    Open questions at the time
    • Whether cADPR binds FKBP12.6 directly or acts through RyR conformational change debated
    • In vivo metabolic consequences unknown
  5. 2000 High

    Three concurrent advances defined FKBP12.6's structural and functional role: the crystal structure revealed a displaced helix conferring RyR2 selectivity; a macromolecular SR complex (RyR2–FKBP12.6–PKA–PP1–PP2A–mAKAP) was delineated; and PKA hyperphosphorylation in failing human hearts was shown to dissociate FKBP12.6, causing Ca²⁺ leak.

    Evidence X-ray crystallography at 2.0 Å; co-IP/cosedimentation and single-channel bilayer recordings on human failing heart tissue; stoichiometric binding assays in canine HF model

    PMID:10713512 PMID:10830164 PMID:11044432

    Open questions at the time
    • Whether PKA phosphorylation at Ser-2808 is the sole dissociation trigger contested
    • Cryo-EM localization of FKBP12.6 on RyR2 not yet available
  6. 2001 High

    Adenoviral FKBP12.6 overexpression in cardiomyocytes provided the first direct gain-of-function evidence that FKBP12.6 stabilizes RyR2 closure, reduces Ca²⁺ leak, and enhances excitation-contraction coupling.

    Evidence Adenoviral gene transfer in rabbit cardiomyocytes, Fura-2 Ca²⁺ imaging, SR leak assay, caffeine contracture

    PMID:11157671

    Open questions at the time
    • In vivo cardiac-specific overexpression not yet tested
    • Effect on arrhythmia susceptibility unknown
  7. 2002 High

    Generation of FKBP12.6-knockout mice established in vivo causality: male knockouts develop cardiac hypertrophy with dysregulated Ca²⁺ sparks, female knockouts are protected by estrogen, and tracheal smooth muscle loses cADPR-induced Ca²⁺ release, demonstrating tissue-wide dependence on FKBP12.6 for RyR2 regulation.

    Evidence FKBP12.6⁻/⁻ mouse model, confocal Ca²⁺ spark imaging, echocardiography, tamoxifen intervention, isometric force measurements in tracheal smooth muscle

    PMID:11907581 PMID:14592808

    Open questions at the time
    • Mechanism of estrogen-dependent protection unclear
    • Whether phenotype is exclusively RyR2-dependent not formally excluded
  8. 2002 High

    Mapping the FKBP12.6-binding site to the RyR2 N-terminal region (residues 305–1937) overturned the prior model of a central isoleucine-proline motif and showed binding is conformation-dependent.

    Evidence GST-FKBP12.6 pulldown with systematic RyR2 deletion/point mutants in HEK293 cells

    PMID:12446682

    Open questions at the time
    • Atomic contacts not resolved
    • Additional C-terminal binding site later proposed (PMID:15591045) but relationship between sites unclear
  9. 2003 High

    FKBP12.6-knockout mice exhibit exercise-induced ventricular arrhythmias and sudden cardiac death, and CPVT-linked RyR2 mutations reduce FKBP12.6 affinity, directly linking FKBP12.6 dissociation to arrhythmogenesis.

    Evidence Treadmill exercise in FKBP12.6⁻/⁻ mice, single-channel bilayer recordings, co-IP with CPVT mutant RyR2

    PMID:12837242

    Open questions at the time
    • Later studies (PMID:17921453) failed to reproduce stress-induced arrhythmias in an independent FKBP12.6-null line, creating unresolved controversy
    • Mechanism by which CPVT mutations alter FKBP12.6 affinity not structurally defined
  10. 2004 High

    The PKA-dissociation model was challenged by the finding that phosphorylation at Ser-2808 does not dissociate FKBP12.6, while separate work showed FKBP12.6 overexpression reduces Ca²⁺ spark frequency and increases coordinated Ca²⁺ transients, refining understanding of FKBP12.6's role in E-C coupling.

    Evidence Site-directed mutagenesis with phospho-specific antibodies and co-IP (PMID:14715536); adenoviral overexpression with confocal spark imaging in rat cardiomyocytes (PMID:15271664)

    PMID:14715536 PMID:15271664

    Open questions at the time
    • Whether CaMKII phosphorylation at Ser-2814 (rather than PKA at Ser-2808) is the relevant dissociation trigger not yet tested
    • Ser-2808 controversy unresolved between labs
  11. 2005 High

    Cryo-EM localized FKBP12.6 to the cytoplasmic clamp region of RyR2, and mutagenesis identified Asp-37 as a critical FKBP12.6 residue for RyR2 binding; a charge-neutralized D37S mutant can bind phosphorylated RyR2, and the drug JTV519 rescues cardiac function only in the presence of FKBP12.6.

    Evidence Cryo-EM 3-D reconstruction with difference mapping; D37S mutagenesis, co-IP, murine MI model with JTV519

    PMID:15972811 PMID:16214874 PMID:16481613

    Open questions at the time
    • Resolution insufficient for atomic contact mapping
    • JTV519 mechanism of action on FKBP12.6–RyR2 not fully defined
  12. 2007 High

    Oxidative stress was shown to reduce FKBP12.6 binding through RyR2 cysteine residues (not FKBP12.6 cysteines), establishing redox regulation as a distinct dissociation mechanism, though a contemporaneous study found no effect of FKBP12.6 removal on RyR2 gating, highlighting ongoing controversy.

    Evidence Co-IP/cosedimentation of [³⁵S]FKBP12.6 under oxidizing/reducing conditions with cysteine-null mutant (PMID:17200109); single-channel bilayer recordings and stress arrhythmia protocol in independent FKBP12.6⁻/⁻ line (PMID:17921453)

    PMID:17200109 PMID:17921453

    Open questions at the time
    • Identity of specific RyR2 cysteines mediating FKBP12.6 dissociation unknown
    • Reason for discrepant arrhythmia phenotypes across FKBP12.6-null lines unresolved
  13. 2008 High

    FKBP12.6 was connected to two new pathophysiological contexts: atrial fibrillation (81% AF inducibility in knockouts via SR Ca²⁺ leak) and glucose-stimulated insulin secretion (impaired GSIS in knockout islets), broadening the gene's functional scope beyond ventricular arrhythmia.

    Evidence Intracardiac stimulation and Ca²⁺ imaging in FKBP12.6⁻/⁻ atrial myocytes; glucose tolerance tests and perifusion insulin secretion in FKBP12.6⁻/⁻ mice

    PMID:18466757 PMID:18598963

    Open questions at the time
    • Whether FKBP12.6 loss phenocopies human AF genetics unknown
    • Relative contributions of cADPR-RyR2 vs. other pathways in β-cell Ca²⁺ signaling not fully delineated
  14. 2009 High

    Quantitative in-cell measurements established FKBP12.6's binding affinity for RyR2 at ~0.7 nM with ~10–20% occupancy of RyR2 channels, and demonstrated that cADPR (but not β-adrenergic stimulation) requires FKBP12.6 for Ca²⁺ spark augmentation, while a separate study showed FKBP12.6 knockout enhances rather than impairs GSIS.

    Evidence FRAP kinetics of fluorescent FKBP12.6 in permeabilized myocytes, quantitative immunoblots (PMID:20431056); cADPR/ISO pharmacology in KO myocytes (PMID:19578067); in vivo/in vitro GSIS in KO mice (PMID:19805579)

    PMID:19578067 PMID:19805579 PMID:20431056

    Open questions at the time
    • Conflicting reports on GSIS direction (impaired vs. enhanced) in FKBP12.6 KO mice unresolved
    • PKA-independence of FKBP12.6 dissociation contradicts earlier Marks lab findings
  15. 2011 High

    Genetic epistasis in double-mutant mice resolved the phosphorylation controversy for AF: CaMKII phosphorylation at RyR2-Ser2814 (not PKA at Ser-2808) is the downstream event causing SR Ca²⁺ leak and AF in FKBP12.6-deficient hearts.

    Evidence FKBP12.6⁻/⁻ × S2814A or S2808A RyR2 knock-in mice, pacing-induced AF, Ca²⁺ spark imaging, DAD recordings

    PMID:22158709

    Open questions at the time
    • Whether this applies to ventricular arrhythmias and heart failure models not tested in same genetic framework
    • Upstream mechanism by which FKBP12.6 loss activates CaMKII unclear
  16. 2012 High

    A dual-regulation model was established: FKBP12 activates RyR2 by sensitizing it to Ca²⁺, while FKBP12.6 antagonizes this activation through competitive binding, revealing that the balance of FKBP isoforms tunes RyR2 gating.

    Evidence Single-channel bilayer recordings with purified FKBP isoforms, mathematical modelling, Ca²⁺ wave imaging in permeabilized cells

    PMID:22363773

    Open questions at the time
    • In vivo relevance of isoform competition not validated
    • Relative abundance of FKBP12 vs. FKBP12.6 at RyR2 in different tissues poorly quantified
  17. 2016 Medium

    FKBP12.6 was shown to facilitate SOICR termination by raising the termination threshold, and CPVT mutant RyR2 channels retain FKBP binding but lose FKBP-mediated regulation, identifying a novel disease mechanism for catecholaminergic polymorphic VT.

    Evidence Single-cell Ca²⁺ imaging in HEK293 cells expressing WT or CPVT mutant RyR2, SOICR threshold measurements

    PMID:27154203

    Open questions at the time
    • Mechanism by which CPVT mutations uncouple FKBP12.6 binding from channel regulation structurally undefined
    • Single heterologous cell system
  18. 2017 High

    High-resolution cryo-EM of the RyR2–FKBP12.6 complex revealed that FKBP12.6 rigidifies the HD2 clamp domain of RyR2 in the closed state, providing the structural mechanism for channel stabilization, while concurrent electrophysiology showed FKBP12.6 loss increases LCC-RyR2 coupling fidelity.

    Evidence Single-particle cryo-EM at 11.8 Å with conformational heterogeneity analysis (PMID:28536302); whole-cell patch clamp combined with confocal Ca²⁺ imaging in FKBP12.6-KO myocytes (PMID:28077437)

    PMID:28077437 PMID:28536302

    Open questions at the time
    • Atomic-resolution structure of the FKBP12.6–RyR2 interface not achieved
    • Mechanism linking HD2 rigidity to pore closure at atomic level unresolved
  19. 2020 High

    RISP-dependent mitochondrial ROS was identified as the physiological trigger for FKBP12.6 dissociation from RyR2 in pulmonary artery smooth muscle, activating NF-κB/cyclin D1-driven proliferation and pulmonary hypertension, while the FKBP12.6-RyR2 stabilizer S107 was protective.

    Evidence SMC-specific RyR2 KO, RISP knockdown, FKBP12.6 KO mice, S107 treatment, chronic hypoxia PH model, Ca²⁺ imaging, pathway analysis

    PMID:32669538

    Open questions at the time
    • Specific RyR2 cysteines targeted by RISP-ROS not identified
    • Whether S107 has clinical utility in pulmonary hypertension untested in humans

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include: the atomic-resolution structure of the FKBP12.6–RyR2 interface; reconciliation of contradictory FKBP12.6-null arrhythmia phenotypes across independent knockout lines; the precise identity of RyR2 cysteines mediating redox-dependent FKBP12.6 dissociation; and whether pharmacological stabilization of the FKBP12.6–RyR2 complex is therapeutically viable in arrhythmia, heart failure, and pulmonary hypertension.
  • Atomic-resolution interface structure lacking
  • Contradictory KO arrhythmia phenotypes unresolved
  • Human genetic evidence directly linking FKBP1B variants to disease absent

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0098772 molecular function regulator activity 9 GO:0140096 catalytic activity, acting on a protein 3
Localization
GO:0005783 endoplasmic reticulum 5
Pathway
R-HSA-382551 Transport of small molecules 9
Partners
MTORPPP3CAPRKAR2ARYR2TGFBR1
Complex memberships
RyR2–FKBP12.6–PKA–PP1–PP2A–mAKAP macromolecular complex

Evidence

Reading pass · 43 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1995 FKBP12.6 (encoded by FKBP1B) was cloned from human tissue; the recombinant protein exhibits peptidyl-prolyl cis-trans isomerase (PPIase) activity and selectively associates with the cardiac ryanodine receptor isoform RyR2 (not RyR1) in cardiac muscle sarcoplasmic reticulum. Upon binding rapamycin, FKBP12.6 forms a complex with mTOR, and in transfected Jurkat cells it mediates calcineurin inhibition by FK506. cDNA cloning, recombinant protein expression, co-immunoprecipitation with native cardiac SR, calcineurin inhibition assay, mTOR binding assay The Journal of biological chemistry High 7592869
1996 FKBP12.6 selectively binds to cardiac RyR2 but not skeletal RyR1; only FKBP12.6 (not FKBP12) can exchange with endogenously bound FKBP12.6 on cardiac SR, explaining why the cardiac CRC is isolated as a complex with FKBP12.6 whereas skeletal muscle CRC associates with FKBP12. FK506 dissociates FKBP12.6 from cardiac SR. 35S-labeled FKBP isoform binding/competition assays with native cardiac and skeletal SR vesicles; cosedimentation The Journal of biological chemistry High 8702774
1997 Cyclic ADP-ribose (cADPR) binds directly to FKBP12.6 on the ryanodine receptor in pancreatic islet microsomes; this binding dissociates FKBP12.6 from the RyR, thereby releasing Ca2+ from the ER. Microsomes depleted of FKBP12.6 by cADPR treatment no longer respond to cADPR for Ca2+ release, establishing FKBP12.6 as the cADPR receptor on the islet RyR. Radioligand binding ([3H]FK506, [3H]cADPR), Ca2+ flux assay from islet microsomes, immunoprecipitation of FKBP12.6 after cADPR treatment The Journal of biological chemistry High 9013543
2000 PKA phosphorylation of RyR2 dissociates FKBP12.6 from the channel and increases channel open probability. A macromolecular complex on the SR comprising RyR2, FKBP12.6, PKA, protein phosphatases PP1 and PP2A, and the anchoring protein mAKAP was defined. In failing human hearts, RyR2 is PKA-hyperphosphorylated, causing defective channel regulation due to FKBP12.6 dissociation. Cosedimentation, co-immunoprecipitation, single-channel lipid bilayer recordings, phosphorylation assays on human failing heart tissue Cell High 10830164
2000 In pacing-induced canine heart failure, the stoichiometry of FKBP12.6 bound per RyR2 monomer decreases from ~1:1 to ~0.4:1; this partial loss of RyR2-bound FKBP12.6 correlates with conformational changes in RyR2 and a prominent spontaneous Ca2+ leak from the SR. FKBP12.6 protein expression is significantly reduced in failing SR. [3H]dihydro-FK506 and [3H]ryanodine binding assays, stopped-flow Ca2+ release measurements, Western blotting of SR fractions Circulation High 11044432
2000 Crystal structure of FKBP12.6 in complex with rapamycin determined at 2.0 Å resolution. The structures of FKBP12.6 and FKBP12 are nearly identical except for a displacement in the helical region of FKBP12.6 toward the hydrophobic pocket, a feature not predicted by homology modelling and which likely underlies RyR2-binding specificity. X-ray crystallography at 2.0 Å resolution Acta crystallographica. Section D, Biological crystallography High 10713512
2001 Adenovirus-mediated overexpression of FKBP12.6 in adult rabbit cardiomyocytes reduces Ca2+ leak through RyR2 by 53%, increases SR Ca2+ load, and increases fractional shortening by 21%, demonstrating that FKBP12.6 stabilizes the closed conformation of RyR2 and enhances excitation-contraction coupling. Adenoviral gene transfer, Fura-2 Ca2+ imaging, SR Ca2+ uptake/leak assay in permeabilized myocytes, caffeine contracture measurements Circulation research High 11157671
2001 FKBP12.6 binding characteristics of cardiac microsomes are widely conserved across vertebrates; most species (human, rabbit, rat, mouse, chicken, frog, fish) contain both FKBP12 and FKBP12.6 associated with RyR2, with dog being the exception (only FKBP12.6). [3H]FK506 and [3H]dihydro-FK506 binding and exchange assays on isolated cardiac microsomes from eight vertebrate species Biochemical and biophysical research communications Medium 11237759
2002 Disruption of the FKBP12.6 gene in male mice causes cardiac hypertrophy with dysregulated Ca2+ sparks (increased amplitude and duration) and increased Ca2+-induced Ca2+ release gain. Female knockout mice develop the same Ca2+ dysregulation but are protected from hypertrophy by oestrogen; tamoxifen treatment of female knockouts induces hypertrophy, placing FKBP12.6-mediated Ca2+ regulation upstream of an oestrogen-sensitive hypertrophic pathway. Gene knockout mouse model, confocal Ca2+ spark imaging, echocardiography, tamoxifen pharmacological intervention Nature High 11907581
2002 FKBP12.6 associates with RyR2 (not RyR1, RyR3, or IP3Rs) in tracheal smooth muscle; cADPR-induced Ca2+ release and spontaneous Ca2+ release in tracheal myocytes are mediated through FKBP12.6, as they are blocked by excess recombinant FKBP12.6 and absent in FKBP12.6-knockout myocytes. Force development is impaired in FKBP12.6-null tracheal smooth muscle. Co-immunoprecipitation, intracellular dialysis of cADPR, Ca2+ imaging, isometric force measurements in FKBP12.6-knockout mouse tissue American journal of physiology. Cell physiology High 14592808
2002 The FKBP12.6-binding site on RyR2 is located within the N-terminal region (residues 305–1937) rather than the previously proposed central domain isoleucine-proline motif. The first 1937 N-terminal residues are sufficient for GST-FKBP12.6 binding, and binding is conformation-dependent; co-expression of overlapping fragments that restore channel function does not restore FKBP12.6 binding. GST-FKBP12.6 pulldown assays with systematic deletion/point mutants of RyR2 expressed in HEK293 cells The Journal of biological chemistry High 12446682
2002 FKBP12.6 cADPR-mediated activation of RyR2 Ca2+ release channels in arterial smooth muscle (bovine coronary artery) requires intact FKBP12.6 on the receptor: FK506 removal of FKBP12.6 blocks cADPR-induced channel activation, and anti-FKBP12 antibody abolishes both FK506- and cADPR-induced RyR activation in planar lipid bilayer recordings. Planar lipid bilayer single-channel recording, FK506 treatment, anti-FKBP12 antibody blockade, gradient centrifugation depletion American journal of physiology. Heart and circulatory physiology High 11893565
2003 FKBP12.6 knockout mice consistently exhibit exercise-induced ventricular arrhythmias causing sudden cardiac death. RyR2 mutations linked to CPVT reduce FKBP12.6 affinity for RyR2 and increase single-channel open probability under exercise-simulating conditions, establishing that FKBP12.6 dissociation from RyR2 is arrhythmogenic. FKBP12.6-/- mouse model, treadmill exercise, single-channel bilayer recordings, coimmunoprecipitation, [3H]ryanodine binding Cell High 12837242
2003 FKBP12.6 expressed in CHO cells co-localizes with RyR2 at ER membranes (sequestered from cytoplasm as RyR2 levels increase), suppresses agonist-induced Ca2+ release, and causes ER Ca2+ superfilling, demonstrating in situ that FKBP12.6 (but not FKBP12) specifically modulates hRyR2 channel functionality. Rapamycin reverses the FKBP12.6 effect. Stable CHO cell lines expressing graded hRyR2 levels, confocal microscopy, Ca2+ flux measurements, rapamycin pharmacology The Biochemical journal High 12443530
2003 Co-expression of FKBP12.6 (but not FKBP12) with dysregulated RyR2 in CHO cells suppresses intracellular Ca2+ flux, restores normal cell viability and proliferation, demonstrating that FKBP12.6 prevents RyR2-mediated cellular toxicity through specific RyR2 channel stabilization. Stable CHO(hRyR2) cell lines, Ca2+ flux measurements, cell viability/proliferation assays, co-expression of FKBP isoforms The Journal of biological chemistry Medium 12754204
2004 PKA phosphorylation at serine-2808 of RyR2 does not dissociate FKBP12.6 from RyR2; site-specific phospho-antibodies show FKBP12.6 binds equally to both phosphorylated and non-phosphorylated Ser-2808 forms, and the phosphomimetic S2808D mutant retains FKBP12.6 binding, challenging the PKA-dissociation model. Site-directed mutagenesis, site-specific phospho-antibodies, co-immunoprecipitation of recombinant and native RyR2, exogenous PKA phosphorylation Circulation research High 14715536
2004 FKBP12.6 overexpression in rat cardiac myocytes decreases the occurrence, amplitude, duration, and width of spontaneous Ca2+ sparks but increases global [Ca2+]i transient amplitude and SR Ca2+ load, demonstrating that FKBP12.6 reduces local stochastic RyR2 openings while enhancing coordinated Ca2+ release during excitation-contraction coupling. Adenoviral overexpression, confocal Ca2+ spark imaging (Rhod-2), field stimulation, caffeine application in rat cardiomyocytes American journal of physiology. Heart and circulatory physiology High 15271664
2004 A novel C-terminal FKBP12.6-binding site exists on RyR2 proximal to the pore-forming transmembrane domains; a large C-terminal RyR2 construct shows rapamycin-sensitive binding specifically to FKBP12.6 but not FKBP12, whereas short C-terminal fragments can displace FKBP12.6 from native RyR2 in competition assays. Competition binding assays with native RyR2, mammalian cell expression of C-terminal constructs, GST-pulldown, rapamycin competition The Journal of biological chemistry Medium 15591045
2004 Hypoxia- and norepinephrine-induced Ca2+ release and pulmonary artery vasoconstriction are significantly enhanced in FKBP12.6-knockout pulmonary artery smooth muscle cells, showing that FKBP12.6 suppresses hypoxic and neurotransmitter-driven RyR2 activation in pulmonary vascular smooth muscle. FKBP12.6 knockout mouse PASMCs, Ca2+ imaging, Cl- and K+ current recordings, isometric force measurements, FK506/rapamycin pharmacology Cell calcium High 15036951
2005 Cryo-EM 3-D reconstruction localizes FKBP12.6 binding on open-state RyR2 to the sides of the cytoplasmic region adjacent to domain 9 (part of the clamp structures). The conformation of FKBP12.6-bound RyR2 differs substantially from FKBP12.6-depleted RyR2 especially in the transmembrane region and clamp structures, providing structural basis for FKBP12.6-mediated channel stabilization. Cryoelectron microscopy, 3-D reconstruction, quantitative difference mapping, X-ray structure docking Biophysical journal High 16214874
2005 FKBP12.6 central domain of RyR2 does not support FKBP12/12.6 interaction in yeast two-hybrid or immunoprecipitation assays; a distinct alternatively spliced variant of FKBP12.6 cannot interact with RyR. An interaction of FKBP12.6 with the cytoplasmic domain of TGF-β receptor type I was confirmed as a positive control, supporting specificity. Yeast two-hybrid, in vitro immunoprecipitation with overlapping RyR2 fragments, alternative splice variant analysis Cell biochemistry and biophysics Medium 16049346
2005 FKBP12.6 (calstabin2) Asp-37 is a key negatively charged residue involved in RyR2 binding; a D37S mutant calstabin2 with neutralized charge binds to constitutively PKA-phosphorylated RyR2-S2808D. Restoring calstabin2 stoichiometry at RyR2 by JTV519 treatment or genetic manipulation rescued cardiac function in a mouse myocardial infarction model, and the rescue was absent in calstabin2-/- mice. Site-directed mutagenesis of calstabin2, co-immunoprecipitation, murine MI model with JTV519 treatment, echocardiography Proceedings of the National Academy of Sciences of the United States of America High 15972811 16481613
2007 Removal of FKBP12.6 (by FK506 treatment or in FKBP12.6-null mice) does not alter conductance, Ca2+- or caffeine-activation properties of RyR2 in lipid bilayer recordings, does not change store-overload-induced Ca2+ release propensity in HEK293 cells, and FKBP12.6-null mice do not exhibit enhanced stress-induced ventricular arrhythmias, in contrast to earlier reports. Single-channel lipid bilayer recordings, [3H]ryanodine binding, HEK293 Ca2+ imaging, FKBP12.6-null mouse stress arrhythmia protocol The Journal of biological chemistry Medium 17921453
2007 Oxidizing agents (H2O2, diamide) reduce FKBP12.6 binding to RyR2 through cysteine residues on the ryanodine receptor (not on FKBP12.6 itself, as a cysteine-null FKBP12.6 mutant retains redox-sensitive interaction). H2O2 effect is state-dependent (requires open state), whereas diamide is state-independent, establishing redox regulation of the RyR2-FKBP12.6 interaction. Co-immunoprecipitation and cosedimentation of [35S]FKBP12.6 with native cardiac SR under oxidizing/reducing conditions, cysteine-null FKBP12.6 mutant The Journal of biological chemistry High 17200109
2008 FKBP12.6-deficient mice have increased susceptibility to atrial fibrillation (AF), inducible in 81% vs. 7% of wild-type mice. SR Ca2+ leak in FKBP12.6-/- atrial myocytes is 53% larger and spontaneous SR Ca2+ release events are increased; both AF and spontaneous releases are blocked by the RyR2 antagonist tetracaine, establishing that FKBP12.6-dependent SR Ca2+ leak drives AF initiation. FKBP12.6-/- mouse electrophysiology, intracardiac stimulation, Ca2+ imaging in atrial myocytes, tetracaine pharmacology Heart rhythm High 18598963
2008 FKBP12.6 disruption in pancreatic beta-cells impairs glucose-induced insulin secretion downstream of ATP production independently of KATP channels. FKBP12.6-/- mice show glucose intolerance and insufficient insulin secretion after glucose challenge, while sulfonylurea- or KCl-induced secretion is unaffected, placing FKBP12.6-mediated cADPR/RyR Ca2+ signalling in the pathway of glucose-stimulated insulin secretion. FKBP12.6-/- mouse model (homologous recombination), glucose tolerance tests, perifusion insulin secretion assays, islet Ca2+ measurements Biochemical and biophysical research communications High 18466757
2008 Cardiac-specific conditional FKBP12.6 overexpression in mice prevents isoproterenol-triggered ventricular tachycardia; Ca2+ spark frequency is reduced 50% (persisting under isoproterenol), SR Ca2+ load is unchanged, L-type Ca2+ current density decreases 15%, and Na+/Ca2+ exchanger protein is reduced 18%, demonstrating that enhanced FKBP12.6-RyR2 binding prevents diastolic SR Ca2+ leak and triggered arrhythmias. Conditional cardiac-specific transgenic mouse, burst pacing arrhythmia protocol, confocal Ca2+ spark imaging, voltage clamp, Western blotting Circulation High 18378612
2009 In cardiac myocytes, FKBP12.6 binds RyR2 with very high affinity (Kd ~0.7 nM) and only FKBP12.6 (not FKBP12) inhibits resting RyR2 activity. PKA-dependent phosphorylation of RyR2 does not alter binding kinetics or affinity of either FKBP isoform. Quantitative immunoblots show endogenous [FKBP12.6] is ≤150 nM and virtually all FKBP12.6 is RyR2-bound, occupying ~10-20% of RyR2 channels. Fluorescently labeled FKBP in permeabilized myocytes, FRAP kinetics, Ca2+ spark imaging, quantitative immunoblots Circulation research High 20431056
2009 FKBP12.6 dissociation from RyR2 does not significantly contribute to beta-adrenergic-stimulated Ca2+ release in cardiomyocytes (ISO increases Ca2+ sparks equally in WT and FKBP12.6-KO), but DOES mediate cADPR-induced Ca2+ spark increases (cADPR effect is absent in FKBP12.6-KO myocytes). Twitch force is not significantly different between WT and KO papillary muscles. FKBP12.6-KO mouse cardiomyocytes, Ca2+ spark imaging, isoproterenol and cADPR pharmacology, papillary muscle force measurements, Western blotting Cardiovascular research High 19578067
2009 FKBP12.6-knockout mice show fed hyperinsulinemia, enhanced glucose-stimulated insulin secretion (GSIS) and islet Ca2+ elevation, and resistance to high-fat diet-induced hyperglycaemia, demonstrating that FKBP12.6 normally restrains RyR-mediated Ca2+ release during glucose stimulation to limit insulin secretion. FKBP12.6-/- mouse model, glucose and insulin tolerance tests, in vivo and in vitro GSIS, islet Ca2+ imaging, high-fat diet challenge FASEB journal High 19805579
2011 CaMKII phosphorylation of RyR2 at Ser-2814 (not Ser-2808) is the downstream target responsible for SR Ca2+ leak, delayed afterdepolarizations, and AF in FKBP12.6-/- mice; S2814A knock-in into FKBP12.6-/- background reduces Ca2+ spark frequency, SR Ca2+ leak, and AF susceptibility, while S2808A does not protect. Double-mutant mouse models (FKBP12.6-/- × S2814A or S2808A RyR2 knock-in), pacing-induced AF, Ca2+ spark imaging in atrial myocytes, DAD recordings Circulation research High 22158709
2012 FKBP12 is a high-affinity activator of RyR2 (sensitises channel to cytosolic Ca2+), whereas FKBP12.6 has very low intrinsic efficacy but antagonises FKBP12-mediated RyR2 activation. Physiological FKBP12 concentrations (3 µM) increase Ca2+ wave frequency and decrease SR Ca2+ content; FKBP12.6 opposes these effects, establishing a dual regulatory model of RyR2 by competing FKBP isoforms. Single-channel bilayer recordings with purified FKBP isoforms, mathematical modelling, Ca2+ wave imaging in permeabilized cardiac cells PloS one High 22363773
2013 Sirolimus (rapamycin)-FKBP12.6 complex impairs endothelial barrier function by activating protein kinase C-α, which disrupts the p120-VE-cadherin interaction; siRNA knockdown of FKBP12.6 phenocopies sirolimus, and ryanodine pretreatment prevents the sirolimus-induced Ca2+ increase and barrier disruption. Transendothelial electrical resistance, siRNA knockdown, Ca2+ imaging, PKC-α phosphorylation assays, Evans blue permeability in vivo, p120-VE-cadherin co-immunostaining Arteriosclerosis, thrombosis, and vascular biology Medium 23887639
2015 miR-34a directly targets the 3'-UTR of FKBP1B mRNA; FKBP1B expression decreases during adipogenesis in parallel with miR-34a increase; FKBP1B overexpression attenuates MDI-induced adipogenesis and suppresses PPARγ/C/EBPα expression, identifying FKBP1B as a negative regulator of adipogenic differentiation downstream of miR-34a. 3'-UTR luciferase reporter assay, miR-34a inhibitor/mimic transfection, FKBP1B overexpression in 3T3-L1 preadipocytes, adipogenesis assays Biochemical and biophysical research communications Medium 26471303
2016 Total chemical synthesis and refolding of calstabin 2 (FKBP12.6) yields a catalytically active PPIase enzyme whose crystal structure confirms correct fold; N-terminal exotic amino acid substitutions do not alter catalytic activity, establishing structure-function relationships in the isomerase domain. Native chemical ligation synthesis, protein refolding, PPIase activity assay, X-ray crystallography Protein science High 27670942
2017 Cryo-EM structure of rabbit RyR2 in complex with FKBP12.6 in the closed state at 11.8 Å reveals two phosphorylation-related RyR2 conformations; FKBP12.6 binding rigidifies the HD2 domain of RyR2, stabilising the closed state. The more flexible conformation likely corresponds to a phosphorylated P2 domain that requires less energy to open. Single-particle cryo-EM, atomic model building, heterogeneity analysis of conformational states Science signaling High 28536302
2017 Absence or pharmacological removal of FKBP12.6 from cardiomyocytes increases LCC-RyR2 coupling fidelity and accelerates LCC-to-spark signalling kinetics without changing L-type Ca2+ channel open probability; synergistic destabilisation by FKBP12.6 dysfunction and catecholaminergic signalling produces chaotic Ca2+ waves and ventricular arrhythmias. Whole-cell patch clamp combined with confocal Ca2+ imaging in FKBP12.6-KO and FK506/rapamycin-treated myocytes, loose-seal patch-clamp LCC sparklet-spark coupling Cardiovascular research High 28077437
2018 FKBP12.6 protects against angiotensin II-induced cardiac hypertrophy in vivo; FKBP12.6-/- mice show aggravated AngII-induced hypertrophy while cardiac-specific FKBP12.6-TG mice are protected. The mechanism involves FKBP12.6 reducing intracellular [Ca2+]i and thereby inhibiting calcineurin/NFATc4, CaMKII/MEF-2, AKT/GSK3β/NFATc4, and AKT/mTOR signalling pathways. FKBP12.6-/- and cardiac-specific FKBP12.6 TG mouse models, AngII osmotic pump infusion, echocardiography, Ca2+ imaging in H9c2 cells, Western blotting of signalling pathways Journal of cellular and molecular medicine Medium 29682889
2020 Rieske iron-sulfur protein (RISP)-dependent ROS generation in pulmonary artery smooth muscle cells dissociates FKBP12.6 from RyR2, increasing RyR channel activity and Ca2+ release, which activates NF-κB/cyclin D1 signalling to promote PASMC proliferation and pulmonary hypertension. FKBP12.6 KO or FK506 exacerbates hypoxia-induced PH, while the RyR2/FKBP12.6 stabiliser S107 is protective. SMC-specific RyR2 KO and RISP knockdown mice, FKBP12.6 KO mice, S107 drug treatment, chronic hypoxia model, Ca2+ imaging, NF-κB/cyclin D1 pathway analysis, cell proliferation assays Nature communications High 32669538
1994 Molecular cloning of human FKBP1B (designated OTK4): the protein shares 88% amino acid identity with FKBP12 and recombinant OTK4 expressed in E. coli exhibits peptidyl-prolyl cis-trans isomerase (PPIase) activity. Two alternatively spliced transcripts are ubiquitously expressed in human tissues. cDNA library screening, recombinant protein expression, PPIase enzymatic activity assay, RT-PCR tissue expression Biochemical and biophysical research communications High 7513996
2005 Genomic structure of human FKBP1B (FKBP12.6 gene) spans ~16 kb with 4 exons and 3 introns on chromosome 2p21-23. Reporter gene and EMSA analyses identify that Sp3 transcription factor drives FKBP12.6 promoter activity via a consensus Sp-family element at -58 to -24. Fluorescence in situ hybridisation, reporter gene assays, electrophoretic mobility shift assays, promoter deletion analysis Gene Medium 16122887
2010 FKBP12.6 bound to RyR1 and RyR2 adopts the same orientation as determined by FRET between site-specifically labelled FKBP12.6 and RyR-bound calmodulin. Fluorescent labelling at position 41 of FKBP12.6 reduces RyR1 affinity 10-fold; position 32 reduces maximal inhibition of [3H]ryanodine binding by half, delineating surface residues important for RyR binding versus inhibition. Site-directed single-cysteine labelling of FKBP12.6, FRET measurements, [3H]ryanodine binding inhibition assays The Journal of biological chemistry High 20404344
2016 FKBP12.6 and FKBP12 facilitate termination of store overload-induced Ca2+ release (SOICR) in wild-type RyR2 by raising the SOICR termination threshold without changing the activation threshold; an arrhythmogenic RyR2 CPVT mutant retains FKBP association but FKBPs are unable to regulate the mutant channel, representing a novel mechanism of CPVT arrhythmia. Single-cell Ca2+ imaging in HEK293 cells expressing WT or CPVT mutant RyR2, FKBP overexpression, SOICR threshold measurements The Biochemical journal Medium 27154203

Source papers

Stage 0 corpus · 129 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2000 PKA phosphorylation dissociates FKBP12.6 from the calcium release channel (ryanodine receptor): defective regulation in failing hearts. Cell 1638 10830164
2002 Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences. Proceedings of the National Academy of Sciences of the United States of America 1479 12477932
2014 A proteome-scale map of the human interactome network. Cell 977 25416956
2020 A reference map of the human binary protein interactome. Nature 849 32296183
2011 Phylogenetic-based propagation of functional annotations within the Gene Ontology consortium. Briefings in bioinformatics 656 21873635
2003 FKBP12.6 deficiency and defective calcium release channel (ryanodine receptor) function linked to exercise-induced sudden cardiac death. Cell 610 12837242
2004 The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC). Genome research 438 15489334
2015 Panorama of ancient metazoan macromolecular complexes. Nature 407 26344197
2014 Structure of a mammalian ryanodine receptor. Nature 331 25470061
2002 Oestrogen protects FKBP12.6 null mice from cardiac hypertrophy. Nature 243 11907581
1996 Selective binding of FKBP12.6 by the cardiac ryanodine receptor. The Journal of biological chemistry 220 8702774
2003 FKBP12.6-mediated stabilization of calcium-release channel (ryanodine receptor) as a novel therapeutic strategy against heart failure. Circulation 212 12551874
2000 Altered stoichiometry of FKBP12.6 versus ryanodine receptor as a cause of abnormal Ca(2+) leak through ryanodine receptor in heart failure. Circulation 187 11044432
1997 Cyclic ADP-ribose binds to FK506-binding protein 12.6 to release Ca2+ from islet microsomes. The Journal of biological chemistry 172 9013543
1995 A novel FK506 binding protein can mediate the immunosuppressive effects of FK506 and is associated with the cardiac ryanodine receptor. The Journal of biological chemistry 163 7592869
2001 Receptor accessory folding helper enzymes: the functional role of peptidyl prolyl cis/trans isomerases. FEBS letters 152 11322937
2005 Enhancing calstabin binding to ryanodine receptors improves cardiac and skeletal muscle function in heart failure. Proceedings of the National Academy of Sciences of the United States of America 148 15972811
2004 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). Circulation research 136 14715536
2011 Inhibition of CaMKII phosphorylation of RyR2 prevents induction of atrial fibrillation in FKBP12.6 knockout mice. Circulation research 131 22158709
2010 Kinetics of FKBP12.6 binding to ryanodine receptors in permeabilized cardiac myocytes and effects on Ca sparks. Circulation research 124 20431056
2001 Overexpression of FK506-binding protein FKBP12.6 in cardiomyocytes reduces ryanodine receptor-mediated Ca(2+) leak from the sarcoplasmic reticulum and increases contractility. Circulation research 122 11157671
2008 Intracellular calcium leak due to FKBP12.6 deficiency in mice facilitates the inducibility of atrial fibrillation. Heart rhythm 109 18598963
2003 FKBP12.6 and cADPR regulation of Ca2+ release in smooth muscle cells. American journal of physiology. Cell physiology 105 14592808
2002 Propranolol prevents the development of heart failure by restoring FKBP12.6-mediated stabilization of ryanodine receptor. Circulation 104 11901051
2005 Ng-MIP, a surface-exposed lipoprotein of Neisseria gonorrhoeae, has a peptidyl-prolyl cis/trans isomerase (PPIase) activity and is involved in persistence in macrophages. Molecular microbiology 102 16238618
2001 FKBP binding characteristics of cardiac microsomes from diverse vertebrates. Biochemical and biophysical research communications 98 11237759
1992 PPIase catalysis by human FK506-binding protein proceeds through a conformational twist mechanism. The Journal of biological chemistry 98 1371117
2018 A Phytophthora capsici RXLR Effector Targets and Inhibits a Plant PPIase to Suppress Endoplasmic Reticulum-Mediated Immunity. Molecular plant 95 29864524
2002 Role of FKBP12.6 in cADPR-induced activation of reconstituted ryanodine receptors from arterial smooth muscle. American journal of physiology. Heart and circulatory physiology 93 11893565
2007 Removal of FKBP12.6 does not alter the conductance and activation of the cardiac ryanodine receptor or the susceptibility to stress-induced ventricular arrhythmias. The Journal of biological chemistry 86 17921453
2002 Localization of the 12.6-kDa FK506-binding protein (FKBP12.6) binding site to the NH2-terminal domain of the cardiac Ca2+ release channel (ryanodine receptor). The Journal of biological chemistry 80 12446682
2000 Altered interaction of FKBP12.6 with ryanodine receptor as a cause of abnormal Ca(2+) release in heart failure. Cardiovascular research 79 11054478
2007 K201 (JTV519) suppresses spontaneous Ca2+ release and [3H]ryanodine binding to RyR2 irrespective of FKBP12.6 association. The Biochemical journal 75 17313373
2006 Analysis of calstabin2 (FKBP12.6)-ryanodine receptor interactions: rescue of heart failure by calstabin2 in mice. Proceedings of the National Academy of Sciences of the United States of America 73 16481613
2018 Structure and pro-toxic mechanism of the human Hsp90/PPIase/Tau complex. Nature communications 72 30382094
2009 Genome-wide association studies in an isolated founder population from the Pacific Island of Kosrae. PLoS genetics 68 19197348
2007 Redox sensitivity of the ryanodine receptor interaction with FK506-binding protein. The Journal of biological chemistry 60 17200109
2004 FKBP12.6 overexpression decreases Ca2+ spark amplitude but enhances [Ca2+]i transient in rat cardiac myocytes. American journal of physiology. Heart and circulatory physiology 56 15271664
2001 The conserved sites for the FK506-binding proteins in ryanodine receptors and inositol 1,4,5-trisphosphate receptors are structurally and functionally different. The Journal of biological chemistry 56 11598113
2012 FKBP12 activates the cardiac ryanodine receptor Ca2+-release channel and is antagonised by FKBP12.6. PloS one 55 22363773
2011 Structural characterization of the PPIase domain of FKBP51, a cochaperone of human Hsp90. Acta crystallographica. Section D, Biological crystallography 54 21636895
2008 Conditional FKBP12.6 overexpression in mouse cardiac myocytes prevents triggered ventricular tachycardia through specific alterations in excitation-contraction coupling. Circulation 53 18378612
2013 Sirolimus-FKBP12.6 impairs endothelial barrier function through protein kinase C-α activation and disruption of the p120-vascular endothelial cadherin interaction. Arteriosclerosis, thrombosis, and vascular biology 52 23887639
2016 High-Throughput Screens to Discover Small-Molecule Modulators of Ryanodine Receptor Calcium Release Channels. SLAS discovery : advancing life sciences R & D 50 27760856
2009 FRET-based mapping of calmodulin bound to the RyR1 Ca2+ release channel. Proceedings of the National Academy of Sciences of the United States of America 50 19332786
2004 Interaction of FKBP12.6 with the cardiac ryanodine receptor C-terminal domain. The Journal of biological chemistry 49 15591045
2004 Over-expression of FK506-binding protein FKBP12.6 alters excitation-contraction coupling in adult rabbit cardiomyocytes. The Journal of physiology 48 14966299
2002 The Escherichia coli FKBP-type PPIase SlyD is required for the stabilization of the E lysis protein of bacteriophage phi X174. Molecular microbiology 47 12100551
2004 Role of FKBP12.6 in hypoxia- and norepinephrine-induced Ca2+ release and contraction in pulmonary artery myocytes. Cell calcium 46 15036951
2005 Three-dimensional visualization of FKBP12.6 binding to an open conformation of cardiac ryanodine receptor. Biophysical journal 45 16214874
1996 A novel plant peptidyl-prolyl-cis-trans-isomerase (PPIase): cDNA cloning, structural analysis, enzymatic activity and expression. Plant molecular biology 44 8980498
2010 Mapping the ryanodine receptor FK506-binding protein subunit using fluorescence resonance energy transfer. The Journal of biological chemistry 43 20404344
2006 Crystal structure of the PP2A phosphatase activator: implications for its PP2A-specific PPIase activity. Molecular cell 41 16885030
2017 A cryo-EM-based model of phosphorylation- and FKBP12.6-mediated allosterism of the cardiac ryanodine receptor. Science signaling 40 28536302
2009 Solution structure of the parvulin-type PPIase domain of Staphylococcus aureus PrsA--implications for the catalytic mechanism of parvulins. BMC structural biology 40 19309529
2009 Dissociation of FKBP12.6 from ryanodine receptor type 2 is regulated by cyclic ADP-ribose but not beta-adrenergic stimulation in mouse cardiomyocytes. Cardiovascular research 40 19578067
2002 The binding of the RyR2 calcium channel to its gating protein FKBP12.6 is oppositely affected by ARVD2 and VTSIP mutations. Biochemical and biophysical research communications 40 12459180
2000 Structure of FKBP12.6 in complex with rapamycin. Acta crystallographica. Section D, Biological crystallography 40 10713512
2011 Localization of the dantrolene-binding sequence near the FK506-binding protein-binding site in the three-dimensional structure of the ryanodine receptor. The Journal of biological chemistry 39 21262961
2008 FKBP12.6 disruption impairs glucose-induced insulin secretion. Biochemical and biophysical research communications 36 18466757
2006 A novel endothelin receptor antagonist CPU0213 improves diabetic cardiac insufficiency attributed to up-regulation of the expression of FKBP12.6, SERCA2a, and PLB in rats. Journal of cardiovascular pharmacology 36 16810072
2003 Association of EDNRA, but not WNK4 or FKBP1B, polymorphisms with essential hypertension. Clinical genetics 35 14616768
2013 PPIase independent chaperone-like function of recombinant human Cyclophilin A during arginine kinase refolding. FEBS letters 34 23376614
2012 In cardiomyocytes, binding of unzipping peptide activates ryanodine receptor 2 and reciprocally inhibits calmodulin binding. Circulation research 33 23233753
2020 Rieske iron-sulfur protein induces FKBP12.6/RyR2 complex remodeling and subsequent pulmonary hypertension through NF-κB/cyclin D1 pathway. Nature communications 32 32669538
2003 In situ modulation of the human cardiac ryanodine receptor (hRyR2) by FKBP12.6. The Biochemical journal 32 12443530
2018 Gears-In-Motion: The Interplay of WW and PPIase Domains in Pin1. Frontiers in oncology 31 30460195
2012 Identification of RNA targets for the nuclear multidomain cyclophilin atCyp59 and their effect on PPIase activity. Nucleic acids research 31 23248006
2019 Dexmedetomidine protects H9c2 cardiomyocytes against oxygen-glucose deprivation/reoxygenation-induced intracellular calcium overload and apoptosis through regulating FKBP12.6/RyR2 signaling. Drug design, development and therapy 27 31564830
2003 The PPIase active site of Legionella pneumophila Mip protein is involved in the infection of eukaryotic host cells. Biological chemistry 27 12674506
2008 Human CyP33 binds specifically to mRNA and binding stimulates PPIase activity of hCyP33. FEBS letters 26 18258190
2003 Dysregulated ryanodine receptors mediate cellular toxicity: restoration of normal phenotype by FKBP12.6. The Journal of biological chemistry 26 12754204
2020 FKBP9 promotes the malignant behavior of glioblastoma cells and confers resistance to endoplasmic reticulum stress inducers. Journal of experimental & clinical cancer research : CR 25 32111229
2019 The Role of SurA PPIase Domains in Preventing Aggregation of the Outer-Membrane Proteins tOmpA and OmpT. Journal of molecular biology 24 30716334
2014 The C113D mutation in human Pin1 causes allosteric structural changes in the phosphate binding pocket of the PPIase domain through the tug of war in the dual-histidine motif. Biochemistry 24 25100325
2007 Down-regulation of FKBP12.6 and SERCA2a contributes to acute heart failure in septic shock and is related to an up-regulated endothelin signalling pathway. The Journal of pharmacy and pharmacology 23 17637193
2004 Interaction of the BMPR-IA tumor suppressor with a developmentally relevant splicing factor. Biochemical and biophysical research communications 23 15351706
2008 Endothelin receptor antagonist CPU0213 and vitamin E reverse downregulation of FKBP12.6 and SERCA2a: a role of hyperphosphorylation of PKCepsilon. European journal of pharmacology 21 18611397
2008 Total triterpene acids, active ingredients from Fructus Corni, attenuate diabetic cardiomyopathy by normalizing ET pathway and expression of FKBP12.6 and SERCA2a in streptozotocin-rats. The Journal of pharmacy and pharmacology 21 19000375
2005 A novel mutation in FKBP12.6 binding region of the human cardiac ryanodine receptor gene (R2401H) in a Japanese patient with catecholaminergic polymorphic ventricular tachycardia. International journal of cardiology 21 15749201
2015 Bcl-2 and FKBP12 bind to IP3 and ryanodine receptors at overlapping sites: the complexity of protein-protein interactions for channel regulation. Biochemical Society transactions 20 26009182
2007 Reversal of isoproterenol-induced downregulation of phospholamban and FKBP12.6 by CPU0213-mediated antagonism of endothelin receptors. Acta pharmacologica Sinica 20 17959025
2006 NMR solution structure and characterization of substrate binding site of the PPIase domain of PrsA protein from Bacillus subtilis. FEBS letters 20 16516208
1994 Molecular cloning and expression of a novel human gene that is highly homologous to human FK506-binding protein 12kDa (hFKBP-12) and characterization of two alternatively spliced transcripts. Biochemical and biophysical research communications 20 7513996
2012 NMR assignments of the FKBP-type PPIase domain of the human aryl-hydrocarbon receptor-interacting protein (AIP). Biomolecular NMR assignments 19 22287093
2010 PPIase domain of trigger factor acts as auxiliary chaperone site to assist the folding of protein substrates bound to the crevice of trigger factor. The international journal of biochemistry & cell biology 19 20096367
1994 The gene encoding the periplasmic cyclophilin homologue, PPIase A, in Escherichia coli, is expressed from four promoters, three of which are activated by the cAMP-CRP complex and negatively regulated by the CytR repressor. Molecular microbiology 19 7715459
2015 Vaccine potential of bacterial macrophage infectivity potentiator (MIP)-like peptidyl prolyl cis/trans isomerase (PPIase) proteins. Expert review of vaccines 18 26468663
2007 Abrupt changes in FKBP12.6 and SERCA2a expression contribute to sudden occurrence of ventricular fibrillation on reperfusion and are prevented by CPU86017. Acta pharmacologica Sinica 18 17506935
2005 Central domain of the human cardiac muscle ryanodine receptor does not mediate interaction with FKBP12.6. Cell biochemistry and biophysics 18 16049346
2016 FKBPs facilitate the termination of spontaneous Ca2+ release in wild-type RyR2 but not CPVT mutant RyR2. The Biochemical journal 17 27154203
2015 Allosteric Breakage of the Hydrogen Bond within the Dual-Histidine Motif in the Active Site of Human Pin1 PPIase. Biochemistry 17 26226559
2011 PPIase activities and interaction partners of FK506-binding proteins in the wheat thylakoid. Physiologia plantarum 17 21848652
2010 Limitations of FKBP12.6-directed treatment strategies for maladaptive cardiac remodeling and heart failure. Journal of molecular and cellular cardiology 17 20797399
2008 A cavity with an appropriate size is the basis of the PPIase activity. Protein engineering, design & selection : PEDS 17 18175776
2021 The HBV Core Protein and Core Particle Both Bind to the PPiase Par14 and Par17 to Enhance Their Stabilities and HBV Replication. Frontiers in microbiology 16 34970249
2013 Identification and characterization of peptides that bind the PPIase domain of Parvulin17. Journal of peptide science : an official publication of the European Peptide Society 16 23596087
2012 PpiA, a surface PPIase of the cyclophilin family in Lactococcus lactis. PloS one 16 22442694
2008 Downregulated FKBP12.6 expression and upregulated endothelin signaling contribute to elevated diastolic calcium and arrhythmogenesis in rat cardiomyopathy produced by l-thyroxin. International journal of cardiology 16 18684528
2017 Sensitized signalling between L-type Ca2+ channels and ryanodine receptors in the absence or inhibition of FKBP12.6 in cardiomyocytes. Cardiovascular research 15 28077437
2009 FKBP12.6-knockout mice display hyperinsulinemia and resistance to high-fat diet-induced hyperglycemia. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 15 19805579
2015 Shikonin inhibits adipogenic differentiation via regulation of mir-34a-FKBP1B. Biochemical and biophysical research communications 14 26471303
2010 Trigger factor lacking the PPIase domain can enhance the folding of eukaryotic multi-domain proteins in Escherichia coli. FEBS letters 14 20659464
2007 The binding of FKBP23 to BiP modulates BiP's ATPase activity with its PPIase activity. Biochemical and biophysical research communications 14 17223077
2005 Genomic organization, chromosomal localization, and promoter of human gene for FK506-binding protein 12.6. Gene 14 16122887
2020 Susceptibility to Ventricular Arrhythmias Resulting from Mutations in FKBP1B, PXDNL, and SCN9A Evaluated in hiPSC Cardiomyocytes. Stem cells international 13 32952569
2015 The ryanodine receptor provides high throughput Ca2+-release but is precisely regulated by networks of associated proteins: a focus on proteins relevant to phosphorylation. Biochemical Society transactions 13 26009186
2011 Isoproterenol-induced FKBP12.6/12 downregulation is modulated by ETA and ETB receptors and reversed by argirhein, a derivative of rhein. Acta pharmacologica Sinica 13 21293474
2018 FKBP12.6 protects heart from AngII-induced hypertrophy through inhibiting Ca2+ /calmodulin-mediated signalling pathways in vivo and in vitro. Journal of cellular and molecular medicine 12 29682889
2016 The OsCYP19-4 Gene Is Expressed as Multiple Alternatively Spliced Transcripts Encoding Isoforms with Distinct Cellular Localizations and PPIase Activities under Cold Stress. International journal of molecular sciences 12 27447607
2013 Comparative differential proteomic profiles of nonfailing and failing hearts after in vivo thoracic aortic constriction in mice overexpressing FKBP12.6. Physiological reports 12 24303125
2012 Transcription factor CHF1/Hey2 regulates EC coupling and heart failure in mice through regulation of FKBP12.6. American journal of physiology. Heart and circulatory physiology 11 22408025
2012 Impact of hypoxia, simulated ischemia and reperfusion in HL-1 cells on the expression of FKBP12/FKBP12.6 and intracellular calcium dynamics. Biochemical and biophysical research communications 11 22618235
2020 Multicopy Suppressor Analysis of Strains Lacking Cytoplasmic Peptidyl-Prolyl cis/trans Isomerases Identifies Three New PPIase Activities in Escherichia coli That Includes the DksA Transcription Factor. International journal of molecular sciences 10 32823955
2016 Total chemical synthesis, refolding, and crystallographic structure of fully active immunophilin calstabin 2 (FKBP12.6). Protein science : a publication of the Protein Society 10 27670942
2015 Helicobacter pylori FKBP-type PPIase promotes gastric epithelial cell proliferation and anchorage-independent growth through activation of ERK-mediated mitogenic signaling pathway. FEMS microbiology letters 10 25687921
2011 Sildenafil and FDP-Sr attenuate diabetic cardiomyopathy by suppressing abnormal expression of myocardial CASQ2, FKBP12.6, and SERCA2a in rats. Acta pharmacologica Sinica 10 21441944
2009 FKBP12.6 binding of ryanodine receptors carrying mutations associated with arrhythmogenic cardiac disease. The Biochemical journal 10 19226252
2009 Stress-induced cardiac insufficiency relating to abnormal leptin and FKBP12.6 is ameliorated by CPU0213, an endothelin receptor antagonist, which is not affected by the CYP3A suppressing effect of erythromycin. The Journal of pharmacy and pharmacology 10 19405994
2005 Reconstitution of local Ca2+ signaling between cardiac L-type Ca2+ channels and ryanodine receptors: insights into regulation by FKBP12.6. American journal of physiology. Cell physiology 10 16049053
2023 Assessing Trans-Inhibition of OATP1B1 and OATP1B3 by Calcineurin and/or PPIase Inhibitors and Global Identification of OATP1B1/3-Associated Proteins. Pharmaceutics 9 38258074
2015 Inhibition of the mevalonate pathway ameliorates anoxia-induced down-regulation of FKBP12.6 and intracellular calcium handling dysfunction in H9c2 cells. Journal of molecular and cellular cardiology 9 25636197
2012 Role of polar and nonpolar residues at the active site for PPIase activity of FKBP22 from Shewanella sp. SIB1. The FEBS journal 9 22244380
2011 Transgenic analysis of the role of FKBP12.6 in cardiac function and intracellular calcium release. Assay and drug development technologies 9 22087651
2001 Identification and genetic mapping of the mouse Fkbp9 gene encoding a new member of FK506-binding protein family. Molecules and cells 9 11710534
2015 PPIase is associated with the diversity of conotoxins from cone snail venom glands. Biochimie 8 25769415
2013 ATP interacts with the CPVT mutation-associated central domain of the cardiac ryanodine receptor. Biochimica et biophysica acta 6 23747301
2012 A negative screen for mutations in calstabin 1 and 2 genes in patients with dilated cardiomyopathy. Journal of negative results in biomedicine 4 22236651
2004 Evidence of association between FKBP1B and thyroid autoimmune disorders in a large Tunisian family. Autoimmunity 3 15497458