Affinage

Showing FKBP1A — FKBP12 is a alias.

FKBP1A

Peptidyl-prolyl cis-trans isomerase FKBP1A · UniProt P62942

Length
108 aa
Mass
12.0 kDa
Annotated
2026-06-09
100 papers in source corpus 42 papers cited in narrative 38 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 8/8 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

FKBP1A (FKBP12) is a small cytoplasmic peptidyl-prolyl isomerase whose dominant biological role is as a high-affinity ligand-binding scaffold and a constitutive regulator of membrane receptor and channel complexes (PMID:7678431, PMID:7518616). Its defining pharmacological property is binding the immunosuppressant FK506 and the macrolide rapamycin within a cavity formed by its five-stranded beta-sheet, alpha-helix and three loops (PMID:7678431); the resulting drug-bound complexes act as composite surfaces that engage second targets. The FKBP12-FK506 complex docks onto calcineurin, displacing its autoinhibitory element through surface residues Asp37, Arg42 and His87 to block phosphatase activity independently of PPIase function (PMID:8524402, PMID:1379588), and FKBP12 is the unique family member required for FK506-mediated T-cell suppression (PMID:12085010). The FKBP12-rapamycin complex instead binds the FRB domain of mTOR/FRAP at a serine-gated pocket (Ser2035), with rapamycin bridging two hydrophobic surfaces to dimerize the proteins (PMID:7518356, PMID:7822316, PMID:8662507, PMID:10089303, PMID:7499212, PMID:7528205); loss of FKBP12 in brain derepresses mTOR-Raptor signaling and S6K phosphorylation (PMID:19081378). Independently of drugs, FKBP12 occupies a Leu-Pro motif adjacent to the activating phosphorylation sites of TGF-beta family type I receptors, holding ligand-free receptors silent until type II receptor-mediated phosphorylation releases it (PMID:8756725, PMID:9233797); this gatekeeper role extends to BMP receptor ALK2, where FKBP12 suppresses ligand-independent and gain-of-function signaling that drives hepcidin expression and FOP-associated mutations (PMID:28864813, PMID:29551750), and to ALK4, where re-association recruits the Smad7-Smurf1 ubiquitination machinery (PMID:16720724). FKBP12 also constitutively and stoichiometrically binds the ryanodine receptors via a hydrophobic cluster in the SPRY1 domain and the critical RyR1 residue Val2461, stabilizing the closed channel state and tuning Ca2+ release and excitation-contraction coupling gain in a PPIase-independent manner (PMID:7531689, PMID:11279144, PMID:12704193, PMID:26245150, PMID:28536302). Genetic ablation reveals physiological consequences across tissues: global loss causes dilated cardiomyopathy with hypertrabeculation/noncompaction and disordered ryanodine receptor Ca2+ release (PMID:9461216), and endocardial-specific loss recapitulates this phenotype by stabilizing activated Notch1 (PMID:23571217). Additional regulatory targets include the IP3R, to which FKBP12 anchors calcineurin (PMID:9346894), the EGFR kinase domain whose autophosphorylation it suppresses (PMID:22103444), MDM2 self-ubiquitination promoting p53 activation (PMID:27617579), and the RIPK1-RIPK3-MLKL necroptotic pathway (PMID:31028177).

Mechanistic history

Synthesis pass · year-by-year structured walk · 16 steps
  1. 1993 High

    Establishing the atomic architecture of FKBP12 and how it captures FK506 and rapamycin defined the structural basis for all of its drug-mediated functions.

    Evidence High-resolution X-ray crystallography of FKBP12-FK506 and FKBP12-rapamycin complexes

    PMID:7678431

    Open questions at the time
    • Structure alone did not establish the cellular target of either drug complex
    • PPIase catalytic mechanism inferred but not functionally dissected
  2. 1994 High

    Identifying that FKBP12 binds type I TGF-beta receptors and, separately, the mTOR target revealed that FKBP12 has both drug-dependent and drug-independent receptor partners.

    Evidence Yeast two-hybrid plus Co-IP for TGF-beta receptors; FKBP12-rapamycin affinity purification of RAFT1/mTOR

    PMID:7518356 PMID:7518616 PMID:7822316

    Open questions at the time
    • Functional consequence of receptor binding not yet defined
    • Binding sites on receptors unmapped
  3. 1995 High

    Mapping the FRB domain and the Ser2035 gating residue on mTOR, and the calcineurin contact residues on FKBP12, defined how the ternary drug complexes select and inhibit their targets.

    Evidence Proteolysis mapping/mutagenesis of mTOR FRB; crystallography plus mutagenesis of FKBP12-FK506-calcineurin; rapamycin-resistance two-hybrid

    PMID:1379588 PMID:7499212 PMID:7528205 PMID:7539137 PMID:8524402

    Open questions at the time
    • Whether PPIase activity contributes to target engagement (later shown dispensable)
    • In vivo selectivity of calcineurin inhibition not yet measured
  4. 1995 High

    Demonstrating stoichiometric FKBP12 binding to RyR1 and PPIase-independent channel modulation established FKBP12 as a constitutive structural regulator of Ca2+ release channels.

    Evidence Exchange binding assays, Ca2+ flux measurements, PPIase-dead mutagenesis on skeletal muscle RyR1

    PMID:7531689

    Open questions at the time
    • Precise RyR1 binding epitope not yet identified
    • Physiological role of channel stabilization untested in vivo
  5. 1996 High

    Defining FKBP12 as a phosphorylation-released gatekeeper of TGF-beta type I receptors and resolving the FKBP12-rapamycin-FRB ternary structure clarified the mechanistic logic of both its receptor-silencing and drug-bridging functions.

    Evidence Co-IP, FKBP12 point mutants, myristylated overexpression assays; 2.7 A ternary complex crystallography

    PMID:10089303 PMID:8662507 PMID:8702774 PMID:8756725

    Open questions at the time
    • Generalization across all type I receptors initially incomplete
    • RyR isoform selectivity mechanism unresolved
  6. 1997 High

    Pinpointing the Leu-Pro receptor motif engaged by the FKBP12 rapamycin pocket explained how it inhibits type I receptor phosphorylation and how rapamycin reverses this, and extended the anchoring role to the IP3R-calcineurin axis.

    Evidence Reciprocal mutagenesis of FKBP12 and TbetaR-I with kinase assays; mutagenesis/Co-IP mapping on IP3R

    PMID:9233797 PMID:9346894

    Open questions at the time
    • IP3R-calcineurin functional output (Co-IP-based, single lab) not quantified
    • Receptor occupancy dynamics in vivo unclear
  7. 1998 High

    Genetic ablation showed FKBP12 is physiologically essential for cardiac development and ryanodine receptor regulation while being dispensable for TGF-beta signaling in vivo, separating its developmental and pharmacological roles.

    Evidence Conditional knockout mice with cardiac phenotyping and Ca2+ release measurements

    PMID:9461216

    Open questions at the time
    • Cell type driving cardiomyopathy not yet localized
    • Molecular link between FKBP12 loss and the developmental defect undefined
  8. 2001 High

    Identifying RyR1 Val2461 as the binding-critical residue and showing FKBP12 loss derepresses TGF-beta receptor signaling toward p21/p38-driven G1 arrest linked structural binding determinants to discrete physiological outputs.

    Evidence RyR1 site-directed mutagenesis with single-channel electrophysiology; FKBP12-/- cells with dominant-negative receptor and p38 epistasis

    PMID:11226255 PMID:11279144

    Open questions at the time
    • How Val2461 substitution alters gating mechanistically not fully resolved
    • Selectivity of p38 versus SMAD branch downstream of receptor over-signaling
  9. 2003 High

    Functional studies established that FKBP12 binding sets skeletal EC coupling gain and that FKBP12.6 dissociation underlies exercise-induced cardiac arrhythmia, connecting channel occupancy to muscle physiology.

    Evidence RyR1 mutant rescue in dyspedic myotubes with voltage-clamp fluorometry; FKBP12.6 knockout mice with exercise challenge and single-channel recordings

    PMID:12704193 PMID:12837242

    Open questions at the time
    • Whether PKA phosphorylation truly dissociates FKBP12.6 was later contested
    • Quantitative contribution of FKBP12 to in vivo EC coupling gain
  10. 2004 High

    A rigorous negative result showed PKA phosphorylation at RyR2 Ser2808 does not dissociate FKBP12.6, refining the model of how phosphorylation and FKBP occupancy interact.

    Evidence Phospho-specific antibodies and Co-IP with recombinant and native RyR2, phosphomimetic mutant

    PMID:14715536

    Open questions at the time
    • Reconciliation with earlier dissociation claims unresolved
    • Alternative regulators of FKBP12.6-RyR2 affinity not defined here
  11. 2008 High

    Brain-specific deletion demonstrated FKBP12 restrains mTOR-Raptor signaling and translation-dependent synaptic plasticity and behavior in vivo, generalizing its negative-regulator role beyond drug-bound contexts.

    Evidence Conditional brain knockout with mTOR-Raptor Co-IP, LTP electrophysiology and behavioral assays

    PMID:19081378

    Open questions at the time
    • Direct biochemical mechanism of mTOR inhibition by endogenous FKBP12 undefined
    • Rapamycin-resistant LTP component not mechanistically resolved
  12. 2013 High

    Cell-type-specific ablation localized the cardiomyopathy to endocardium and identified Notch1 stabilization as the causal mechanism, resolving the long-standing developmental phenotype.

    Evidence Endothelial- versus cardiomyocyte-specific Cre knockout with N1ICD stability assays and Notch inhibition rescue

    PMID:23571217

    Open questions at the time
    • Direct physical mechanism by which FKBP12 destabilizes N1ICD not shown
    • Whether PPIase activity is involved unaddressed
  13. 2015 High

    High-resolution structural work on the RyR SPRY1 domain and cryo-EM of the RyR2-FKBP12.6 complex defined the binding interface and the conformational mechanism of channel stabilization.

    Evidence SPRY1 crystallography with FRET and mutagenesis; cryo-EM of RyR2-FKBP12.6 with atomic modeling

    PMID:26245150 PMID:28536302

    Open questions at the time
    • Resolution insufficient to model side-chain contacts at the interface
    • Link between FKBP occupancy and the P2-domain phosphorylation conformations inferred from structure
  14. 2017 High

    Expanding FKBP12 to BMP receptor ALK2/hepcidin control and to endogenous calcineurin substrate selectivity broadened its gatekeeper and phosphatase-targeting roles into iron homeostasis and neurodegeneration.

    Evidence Pharmacologic and genetic ALK2 binding-deficient mutants with SMAD/hepcidin assays; quantitative phosphoproteomics with a rat PD model

    PMID:28864813 PMID:29229832

    Open questions at the time
    • Whether calcineurin substrate selectivity is direct or via anchoring not fully resolved
    • Therapeutic window of FKBP12-calcineurin disruption undefined
  15. 2019 Medium

    Loss-of-function studies placed FKBP12 within necroptotic RIPK1-RIPK3-MLKL signaling, adding a programmed cell death role to its repertoire.

    Evidence siRNA/shRNA knockdown with TNF-induced necroptosis assays and necrosome western blots

    PMID:31028177

    Open questions at the time
    • Whether FKBP12 directly binds RIPK1/RIPK3 not demonstrated
    • Single lab; mechanism of necrosome regulation incompletely resolved
  16. 2025 High

    Discovery of fully synthetic FKBP12-mTOR molecular glues showed the FKBP12-FRB interface can be re-engineered with non-rapamycin chemotypes, extending its scaffold function to designed proximity inducers.

    Evidence Biochemical screening, ternary complex crystallography and cell-based FKBP12-FRB dimerization assays

    PMID:39916884

    Open questions at the time
    • Downstream functional consequences of synthetic dimerization in vivo untested
    • Selectivity across FKBP family not established

Open questions

Synthesis pass · forward-looking unresolved questions
  • How FKBP12 mechanistically distinguishes and switches among its many partners (receptors, channels, phosphatases, ubiquitin ligases, death-signaling kinases) within a single cell remains unresolved.
  • No unifying model for partner selection or competition
  • Role of PPIase activity in most non-channel functions undefined
  • Direct structural mechanism of Notch1, MDM2 and necrosome regulation lacking

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0098772 molecular function regulator activity 4 GO:0060089 molecular transducer activity 3 GO:0016853 isomerase activity 2 GO:0060090 molecular adaptor activity 2
Localization
GO:0005886 plasma membrane 3 GO:0005829 cytosol 2 GO:0005856 cytoskeleton 1
Pathway
R-HSA-162582 Signal Transduction 5 R-HSA-397014 Muscle contraction 3 R-HSA-1266738 Developmental Biology 2 R-HSA-168256 Immune System 2 R-HSA-5357801 Programmed Cell Death 2
Partners
ACVR1EGFRITPR1MTORPPP3CARYR1RYR2TGFBR1
Complex memberships
FKBP12-FK506-calcineurin complexFKBP12-rapamycin-mTOR/FRB ternary complexRyR1/RyR2-FKBP12 channel complexSmad7-Smurf1-ALK4 complex

Evidence

Reading pass · 38 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1993 Crystal structures of human FKBP12 complexed with FK506 and rapamycin revealed a novel fold (five-stranded beta-sheet wrapping a short alpha-helix) with both ligands binding in a cavity defined by the beta-sheet, alpha-helix and three loops via hydrogen bonds and an unusual carbonyl binding pocket. The structures suggest how peptidyl-prolyl isomerase (PPIase) catalytic activity could operate. X-ray crystallography (high-resolution structures of FKBP12-FK506 and FKBP12-rapamycin complexes) Journal of molecular biology High 7678431
1994 FKBP12 binds the mammalian TOR homolog RAFT1 (mTOR) in a rapamycin-dependent fashion; purified FKBP12-rapamycin complex specifically precipitates the 289-kDa RAFT1/mTOR protein, identifying it as the direct cellular target of the FKBP12-rapamycin complex. Affinity purification (FKBP12-rapamycin affinity matrix), peptide sequencing, cDNA cloning Cell High 7518356 7822316
1995 An 11-kDa FKBP12-rapamycin-binding (FRB) domain within FRAP/mTOR (residues 2025–2114) was identified as the minimal binding domain for the FKBP12-rapamycin complex. Mutagenesis at Ser2035 showed that most substitutions abolish binding, whereas Ser2035Ala retains binding, suggesting steric rather than phosphorylation-based regulation at this site. In vitro transcription/translation, proteolysis mapping, site-directed mutagenesis Proceedings of the National Academy of Sciences of the United States of America High 7539137
1996 Crystal structure of the ternary FKBP12–rapamycin–FRB(FRAP) complex at 2.7 Å revealed that rapamycin simultaneously occupies two different hydrophobic binding pockets on FKBP12 and FRB, mediating protein dimerization with extensive rapamycin-protein interactions but fewer direct protein-protein contacts. X-ray crystallography (2.7 Å resolution ternary complex) Science High 10089303 8662507
1995 Crystal structure of human FKBP12-FK506 bound to calcineurin (CaN) at 3.5 Å resolution revealed the FKBP12-FK506 complex displaces the calcineurin auto-inhibitory element from the active site. Surface residues Asp-37, Arg-42, and His-87 of FKBP12 (identified by mutagenesis) directly participate in calcineurin complex formation; R42K/H87V double mutant reduced calcineurin affinity ~600-fold without affecting PPIase activity or FK506 binding. X-ray crystallography, site-directed mutagenesis, calcineurin inhibition assays Nature High 1379588 8524402
1994 FKBP12 specifically interacts with type I receptors of the TGF-beta family (identified by yeast two-hybrid screen); deletion and point mutation studies confirmed specificity, and excess FK506 competed with type I receptors for FKBP12 binding, suggesting shared/overlapping binding sites. Yeast two-hybrid screen, co-immunoprecipitation, competition binding with FK506 Science High 7518616
1996 FKBP12 acts as a common inhibitor of TGF-beta family type I receptors: it binds to ligand-free type I receptor and is released upon ligand-induced, type II receptor-mediated phosphorylation. Two FKBP12 point mutations (G89P, I90K) abolish its inhibitory activity; overexpression of myristylated FKBP12 specifically inhibits two TGF-beta-activated pathways. Co-immunoprecipitation, overexpression with point mutations, cell-based inhibition assays Cell High 8756725
1997 FKBP12 binds TbetaR-I via the rapamycin/Leu-Pro binding pocket of FKBP12 and a Leu-Pro sequence adjacent to the activating phosphorylation sites of TbetaR-I. FKBP12 does not block TbetaR-I/TbetaR-II association but inhibits TbetaR-I phosphorylation by TbetaR-II; rapamycin reverses this inhibition by blocking FKBP12 binding to TbetaR-I. Mutagenesis of FKBP12 and TbetaR-I binding sites, kinase phosphorylation assays, rapamycin competition The EMBO journal High 9233797
1997 FKBP12 binds the inositol 1,4,5-trisphosphate receptor (IP3R) at residues Leu1400-Pro1401 (a leucyl-prolyl dipeptide epitope resembling FK506) and this interaction enables FKBP12 to anchor calcineurin to the IP3R, presumably to modulate the receptor's phosphorylation status. Mutagenesis mapping, co-immunoprecipitation, peptide competition assays The Journal of biological chemistry Medium 9346894
1998 FKBP12-deficient mice develop severe dilated cardiomyopathy, ventricular septal defects resembling noncompaction of left ventricular myocardium, and altered calcium release activity of both skeletal (RyR1) and cardiac (RyR2) ryanodine receptors; FKBP12 is dispensable for TGF-beta-mediated signaling in vivo. Conditional knockout mice (ES cell technology), physiological Ca2+ release measurements, cardiac phenotyping Nature High 9461216
1995 FKBP12 physically and stoichiometrically binds RyR1 in skeletal muscle (4 FKBP12 per tetrameric RyR1); dissociation of FKBP12 from the RyR complex by FK-590 or rapamycin increases RyR1 open probability and Ca2+ leak. PPIase-deficient FKBP12 mutants can bind and modulate RyR1 normally, indicating RyR1 modulation is independent of PPIase activity. Exchange binding assays, Ca2+ flux measurements, site-directed mutagenesis of FKBP12 PPIase active site The Journal of biological chemistry High 7531689
1996 The cardiac ryanodine receptor (RyR2) selectively binds FKBP12.6 but not FKBP12 from the cardiac sarcoplasmic reticulum, whereas skeletal RyR1 binds both isoforms. This differential selectivity explains the isoform specificity of RyR-FKBP complexes in different muscle types. 35S-labeled FKBP12 and FKBP12.6 binding assays on FKBP-stripped cardiac and skeletal SR vesicles The Journal of biological chemistry High 8702774
2001 Val2461 in RyR1 is a critical residue required for FKBP12 binding; substitution with Gly, Glu, or Ile prevents FKBP12 binding and results in RyR1 channels with increased gating frequency; normal channel function can be restored by adding FKBP12.6 to V2461I mutant channels. Site-directed mutagenesis of RyR1, single-channel electrophysiology, FKBP12 binding assays The Journal of biological chemistry High 11279144
2001 FKBP12 deficiency causes G1 cell cycle arrest via TGF-beta receptor over-signaling, leading to marked upregulation of p21(WAF1/CIP1) through the p38 MAP kinase pathway (not ERK or SMAD); dominant-negative TGF-beta receptor rescues the arrest. FKBP12-/- mouse cells, transfection rescue, dominant-negative TGF-beta receptor, p38 inhibitor, p21 western blotting Proceedings of the National Academy of Sciences of the United States of America High 11226255
2003 FKBP12-deficient mice exhibit exercise-induced cardiac arrhythmias; exercise-induced PKA phosphorylation of RyR2 partially dissociates FKBP12.6 from RyR2, increasing intracellular Ca2+ release; CPVT-associated RyR2 mutations reduce FKBP12.6 affinity and increase channel activity under exercise-simulating conditions. FKBP12.6 knockout mice, single-channel electrophysiology, in vivo exercise challenge, co-immunoprecipitation Cell High 12837242
2004 PKA phosphorylation at Ser2808 of RyR2 does NOT dissociate FKBP12.6 from RyR2; FKBP12.6 binds both the phosphorylated and nonphosphorylated forms; the S2808D phosphomimetic mutant retains FKBP12.6 binding. Complete PKA phosphorylation at Ser2808 disrupts neither recombinant nor native FKBP12.6-RyR2 complex. Site-specific phospho-antibodies, co-immunoprecipitation with recombinant and native RyR2, exogenous PKA phosphorylation Circulation research High 14715536
2005 Cryo-EM difference mapping at 16 Å resolution determined the 3D position and unique orientation of FKBP12 bound to RyR1; the FK506-binding site of FKBP12 faces toward RyR1, explaining how FK506 causes FKBP12 dissociation; Gln3 of FKBP12 was identified as directly participating in the RyR1 interaction. Cryo-electron microscopy, single-particle image processing, atomic model fitting Journal of molecular biology High 16405911
2003 FKBP12 binding to RyR1 enhances the gain of skeletal muscle excitation-contraction (EC) coupling; RyR1 mutations disrupting FKBP12 binding (V2461G, V2461I) reduce voltage-gated Ca2+ release ~50%; co-expression of FKBP12.6 restores normal EC coupling in V2461I myotubes. FKBP12 binding does not affect retrograde coupling. Expression of RyR1 mutants in dyspedic myotubes (RyR1-KO), voltage-clamp fluorometry, caffeine-induced Ca2+ release The Journal of biological chemistry High 12704193
2008 Brain-specific FKBP12 knockout mice show increased basal mTOR phosphorylation, enhanced mTOR-Raptor interactions, increased p70 S6K phosphorylation, enhanced LTP, and enhanced contextual fear memory with autistic/OCD-like perseveration; the LTP enhancement is rapamycin-resistant but anisomycin-sensitive, implicating altered translational control. Conditional knockout mice (brain-specific), co-immunoprecipitation of mTOR-Raptor, electrophysiology (LTP), behavioral assays Neuron High 19081378
2013 Endothelial cell-specific (not cardiomyocyte-specific) ablation of Fkbp1a recapitulates ventricular hypertrabeculation and noncompaction; Fkbp1a is a negative modulator of activated Notch1 (N1ICD) in endocardial cells; N1ICD is upregulated upon Fkbp1a ablation and direct inhibition of Notch signaling reduces hypertrabeculation. Conditional knockout mice (endothelial vs cardiomyocyte-specific Cre), in vivo and in vitro Notch1 activity assays, N1ICD stability measurements Development High 23571217
2006 FKBP12 acts as an adaptor for the Smad7-Smurf1 complex on the activin type I receptor (ALK4): after initial ligand-induced dissociation, FKBP12 re-associates with ALK4 and recruits Smad7. FK506, which dissociates FKBP12 from the receptor, decreases Smad7-Smurf1 interaction and inhibits Smurf1-mediated ubiquitination of the type I receptor. Co-immunoprecipitation, ubiquitination assays, FK506 competition Journal of molecular endocrinology Medium 16720724
2017 FKBP12 preferentially binds the BMP type I receptor ALK2 and inhibits hepcidin expression; sequestration of FKBP12 by rapamycin or tacrolimus activates BMP-SMAD signaling and increases hepcidin both in vitro and in vivo; ALK2 mutants defective in FKBP12 binding show ligand-independent hepcidin activation and gain responsiveness to the non-canonical ligand Activin A. Pharmacologic (rapamycin/tacrolimus treatment), genetic (ALK2 binding-deficient mutants), in vitro and murine hepatocyte models, SMAD signaling assays Blood High 28864813
2017 FKBP12 endogenously regulates calcineurin activity toward a specific subset of substrates and promotes dephosphorylation of proteins contributing to alpha-synuclein toxicity; partial pharmacological disruption of FKBP12-calcineurin interaction with low-dose tacrolimus protects against alpha-synuclein pathology in a rat PD model. Quantitative phosphoproteomics, genetic manipulation of FKBP12-calcineurin interaction, in vivo rat PD model Proceedings of the National Academy of Sciences of the United States of America High 29229832
2019 FKBP12 is essential for necroptosis: it is required for RIPK1 and RIPK3 expression and spontaneous phosphorylation, necrosome formation, and RIPK1-RIPK3-MLKL signaling pathway activation in response to TNF receptor 1 ligation; FKBP12 may target RIPK1 and RIPK3 directly. siRNA/shRNA knockdown, in vitro and in vivo TNF-induced necroptosis assays, western blot for necrosome components Journal of cell science Medium 31028177
2016 FKBP12 interacts with MDM2 and induces MDM2 degradation via disruption of the MDM2/MDM4 interaction and induction of MDM2 self-ubiquitination; FKBP12 preferentially degrades cytoplasmic MDM2; DNA-damage-induced nuclear MDM2 translocates to the cytoplasm where it is targeted by FKBP12, leading to constitutive p53 activation and sensitization of cancer cells to apoptosis. Co-immunoprecipitation, ubiquitination assays, subcellular fractionation, siRNA knockdown, apoptosis assays Oncogene Medium 27617579
2002 FKBP12 is the only FKBP family member required for FK506-mediated T-cell growth inhibition; FK506-induced T-cell suppression is abolished in FKBP12-deficient cells but not FKBP12.6-deficient cells. FKBP12-/- and FKBP12.6-/- mouse T cells, T-cell growth inhibition assay with FK506 Transplantation High 12085010
2012 FKBP12 (not FKBP12.6) is a high-affinity activator of cardiac RyR2, sensitizing the channel to cytosolic Ca2+; FKBP12.6 has very low efficacy on RyR2 but antagonizes FKBP12 effects. Physiological concentrations of FKBP12 (3 µM) increase Ca2+ wave frequency and decrease SR Ca2+ content in cardiac cells. Single-channel bilayer electrophysiology, Ca2+ wave imaging in permeabilized cardiac cells, mathematical modeling PloS one Medium 22363773
2011 FKBP12 inhibits EGF-induced EGFR autophosphorylation at all internal phosphorylation sites by targeting the EGFR kinase domain; altering intracellular FKBP12 levels changes EGFR autophosphorylation level. In vitro kinase assays, siRNA knockdown/overexpression with EGFR phosphorylation readout Biochemistry Medium 22103444
2005 RyR1 S-nitrosylation (but not S-glutathionylation) specifically increases the Kd of FKBP12 binding to RyR1 by four- to five-fold, reducing FKBP12 association with the channel. Radiolabeled [35S]FKBP12 binding assays, redox modification of native RyR1 in triads Antioxidants & redox signaling Medium 15998242
2015 Crystal structures of RyR SPRY1 domain at 1.2–1.5 Å combined with FRET studies and molecular dynamics/mutagenesis identified a hydrophobic cluster within SPRY1 as crucial for FKBP binding; the RyR1 disease mutation N760D disrupts FKBP binding by interfering with SPRY1 folding. X-ray crystallography, FRET, cryo-EM docking, site-directed mutagenesis Nature communications High 26245150
2017 Cryo-EM structure of RyR2-FKBP12.6 complex at 11.8 Å revealed that FKBP12.6 binding rigidifies the HD2 (helical domain 2/Clamp) domain of RyR2, stabilizing the closed state; two RyR2 conformations were identified corresponding to different phosphorylation states of the P2 domain, suggesting phosphorylation lowers the energy barrier to channel opening. Cryo-electron microscopy (11.8 Å resolution), atomic model building Science signaling High 28536302
2021 FKBP12 is expressed along the actin cytoskeleton of podocytes and associates with filamentous actin (F-actin), 14-3-3, and synaptopodin; FKBP12 silencing reduces 14-3-3 expression, F-actin staining, and process formation; tacrolimus restores FKBP12 at F-actin and enhances FKBP12-synaptopodin interaction, ameliorating podocyte injury. RNA silencing, confocal immunofluorescence, co-immunoprecipitation, podocyte morphology assays FASEB journal Medium 34662453
2018 FKBP12 over-expression suppresses basal BMP signaling of thirteen of fourteen FOP/DIPG-associated gain-of-function ALK2 mutants; the PF197-8L (L197) mutant uniquely resists FKBP12 suppression because modeled steric clash between ALK2-L197 and FKBP12-D36 disrupts binding; co-expression of BMP type II receptors or ligand stimulation relieves FKBP12 suppression by disrupting the mutant ALK2–FKBP12 interaction. Overexpression studies, signaling assays (BMP-SMAD), molecular modeling of binding interface Bone Medium 29551750
2025 Fully synthetic FKBP12-mTOR molecular glues were discovered from a FKBP-focused ligand library; crystal structure of the ternary complex revealed the compounds target a similar FRB domain surface as rapamycin but with a radically different interaction pattern; structure-guided optimization yielded compounds inducing FKBP12-FRB complex formation in cells. Biochemical screening, X-ray crystallography of ternary complex, structure-activity relationship optimization, cell-based FKBP12-FRB dimerization assay Chemical science High 39916884
1995 TOR1 and mTOR (as well as TOR2) directly interact with FKBP12-rapamycin complex; a conserved serine residue (Ser1972 in TOR1, corresponding to Ser2035 in mTOR) is required for this interaction; mutations at this serine confer rapamycin resistance by preventing FKBP12-rapamycin binding; FKBP12 prolyl isomerase activity is not required for TOR binding. Yeast two-hybrid (rapamycin-dependent), site-directed mutagenesis, rapamycin-resistance assays The Journal of biological chemistry High 7499212 7528205
1995 FKBP12 undergoes upregulation during nerve regeneration (not degeneration) with a time course paralleling GAP-43 mRNA; FKBP12 is rapidly axonally transported at rates similar to GAP-43 following sciatic nerve crush. In situ hybridization, nerve crush models, axonal transport measurements The Journal of neuroscience Medium 7536825
1995 Immunophilins CyclophilinA and FKBP12 interact with transcription factor YY1 in yeast two-hybrid and in mammalian cells; cyclosporin A and FK506 disrupt these interactions respectively; overexpression of FKBP12 alters YY1-regulated transcription in a promoter-dependent manner. Yeast two-hybrid, co-immunoprecipitation in mammalian cells, transcription reporter assays The Journal of biological chemistry Medium 7541038
2002 FKBP12 modulates the binding of RyR1 to the II-III loop of the dihydropyridine receptor (DHPR): FKBP12 potentiates RyR1 binding to the Thr671-Leu690 domain of DHPR alpha1-subunit with EC50 of 10 nM, and this potentiation is inhibited by rapamycin or FK506. Removal of FKBP12 from RyR1 abolishes the DHPR domain A-induced increase in RyR1 open probability. Surface plasmon resonance, polystyrene bead binding assays, single-channel lipid bilayer electrophysiology Biophysical journal Medium 11751303

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1994 RAFT1: a mammalian protein that binds to FKBP12 in a rapamycin-dependent fashion and is homologous to yeast TORs. Cell 1264 7518356
1993 Atomic structures of the human immunophilin FKBP-12 complexes with FK506 and rapamycin. Journal of molecular biology 1082 7678431
1995 Isolation of a protein target of the FKBP12-rapamycin complex in mammalian cells. The Journal of biological chemistry 735 7822316
1996 Structure of the FKBP12-rapamycin complex interacting with the binding domain of human FRAP. Science (New York, N.Y.) 734 8662507
1995 Crystal structures of human calcineurin and the human FKBP12-FK506-calcineurin complex. Nature 632 8524402
2003 FKBP12.6 deficiency and defective calcium release channel (ryanodine receptor) function linked to exercise-induced sudden cardiac death. Cell 613 12837242
1995 Identification of an 11-kDa FKBP12-rapamycin-binding domain within the 289-kDa FKBP12-rapamycin-associated protein and characterization of a critical serine residue. Proceedings of the National Academy of Sciences of the United States of America 456 7539137
1999 Protein phosphatase 2A interacts with the 70-kDa S6 kinase and is activated by inhibition of FKBP12-rapamycinassociated protein. Proceedings of the National Academy of Sciences of the United States of America 422 10200280
1998 Cardiac defects and altered ryanodine receptor function in mice lacking FKBP12. Nature 350 9461216
1996 The immunophilin FKBP12 functions as a common inhibitor of the TGF beta family type I receptors. Cell 326 8756725
1994 Specific interaction of type I receptors of the TGF-beta family with the immunophilin FKBP-12. Science (New York, N.Y.) 312 7518616
1997 Mechanism of TGFbeta receptor inhibition by FKBP12. The EMBO journal 295 9233797
2000 FKBP12-rapamycin-associated protein (FRAP) autophosphorylates at serine 2481 under translationally repressive conditions. The Journal of biological chemistry 275 10702316
2002 Oestrogen protects FKBP12.6 null mice from cardiac hypertrophy. Nature 245 11907581
1996 Selective binding of FKBP12.6 by the cardiac ryanodine receptor. The Journal of biological chemistry 220 8702774
1995 TOR mutations confer rapamycin resistance by preventing interaction with FKBP12-rapamycin. The Journal of biological chemistry 212 7499212
2002 FKBP12-rapamycin-associated protein associates with mitochondria and senses osmotic stress via mitochondrial dysfunction. Proceedings of the National Academy of Sciences of the United States of America 210 11930000
1997 FKBP12 binds the inositol 1,4,5-trisphosphate receptor at leucine-proline (1400-1401) and anchors calcineurin to this FK506-like domain. The Journal of biological chemistry 189 9346894
2008 Removal of FKBP12 enhances mTOR-Raptor interactions, LTP, memory, and perseverative/repetitive behavior. Neuron 183 19081378
2000 Cytoplasmic-nuclear shuttling of FKBP12-rapamycin-associated protein is involved in rapamycin-sensitive signaling and translation initiation. Proceedings of the National Academy of Sciences of the United States of America 176 11114166
1992 The Hsp56 component of steroid receptor complexes binds to immobilized FK506 and shows homology to FKBP-12 and FKBP-13. The Journal of biological chemistry 169 1371107
2001 FKBP12 binding modulates ryanodine receptor channel gating. The Journal of biological chemistry 142 11279144
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 137 14715536
1999 Rapamycin antifungal action is mediated via conserved complexes with FKBP12 and TOR kinase homologs in Cryptococcus neoformans. Molecular and cellular biology 133 10330150
2003 FKBP12-rapamycin-associated protein or mammalian target of rapamycin (FRAP/mTOR) localization in the endoplasmic reticulum and the Golgi apparatus. The Journal of biological chemistry 129 14578359
1995 Characterization of an exchange reaction between soluble FKBP-12 and the FKBP.ryanodine receptor complex. Modulation by FKBP mutants deficient in peptidyl-prolyl isomerase activity. The Journal of biological chemistry 127 7531689
1997 A nonimmunosuppressant FKBP-12 ligand increases nerve regeneration. Experimental neurology 126 9344552
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 124 11157671
1999 The FKBP12-rapamycin-binding domain is required for FKBP12-rapamycin-associated protein kinase activity and G1 progression. The Journal of biological chemistry 123 9933627
1995 Neuronal regeneration enhances the expression of the immunophilin FKBP-12. The Journal of neuroscience : the official journal of the Society for Neuroscience 121 7536825
2001 FKBP12, the 12-kDa FK506-binding protein, is a physiologic regulator of the cell cycle. Proceedings of the National Academy of Sciences of the United States of America 118 11226255
1999 Refined structure of the FKBP12-rapamycin-FRB ternary complex at 2.2 A resolution. Acta crystallographica. Section D, Biological crystallography 116 10089303
2001 Rapamycin and less immunosuppressive analogs are toxic to Candida albicans and Cryptococcus neoformans via FKBP12-dependent inhibition of TOR. Antimicrobial agents and chemotherapy 114 11600372
1995 FKBP12-rapamycin target TOR2 is a vacuolar protein with an associated phosphatidylinositol-4 kinase activity. The EMBO journal 113 8846782
1994 Interaction between FKBP12-rapamycin and TOR involves a conserved serine residue. The Journal of biological chemistry 111 7528205
2003 Overexpression of the EGFR/FKBP12/HIF-2alpha pathway identified in childhood astrocytomas by angiogenesis gene profiling. Cancer research 110 12702575
1992 Charged surface residues of FKBP12 participate in formation of the FKBP12-FK506-calcineurin complex. The Journal of biological chemistry 105 1379588
2015 BK Polyomavirus Replication in Renal Tubular Epithelial Cells Is Inhibited by Sirolimus, but Activated by Tacrolimus Through a Pathway Involving FKBP-12. American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons 99 26639422
1999 Folding pathway of FKBP12 and characterisation of the transition state. Journal of molecular biology 93 10438630
2005 Effects of S-glutathionylation and S-nitrosylation on calmodulin binding to triads and FKBP12 binding to type 1 calcium release channels. Antioxidants & redox signaling 87 15998242
2019 Harnessing calcineurin-FK506-FKBP12 crystal structures from invasive fungal pathogens to develop antifungal agents. Nature communications 86 31537789
2002 The FKBP12-rapamycin-associated protein (FRAP) is a CLIP-170 kinase. EMBO reports 86 12231510
1995 Cyclophilin A and FKBP12 interact with YY1 and alter its transcriptional activity. The Journal of biological chemistry 86 7541038
1993 Rapamycin-FKBP12 blocks proliferation, induces differentiation, and inhibits cdc2 kinase activity in a myogenic cell line. The Journal of biological chemistry 84 7503980
2005 Structural characterization of the RyR1-FKBP12 interaction. Journal of molecular biology 78 16405911
2013 Fkbp1a controls ventricular myocardium trabeculation and compaction by regulating endocardial Notch1 activity. Development (Cambridge, England) 75 23571217
1995 The rapamycin and FKBP12 target (RAFT) displays phosphatidylinositol 4-kinase activity. The Journal of biological chemistry 71 7673106
2019 LncRNA SNHG15 acts as an oncogene in prostate cancer by regulating miR-338-3p/FKBP1A axis. Gene 67 30981837
2003 FKBP12 binding to RyR1 modulates excitation-contraction coupling in mouse skeletal myotubes. The Journal of biological chemistry 61 12704193
2015 Crystal structures of ryanodine receptor SPRY1 and tandem-repeat domains reveal a critical FKBP12 binding determinant. Nature communications 59 26245150
2009 Structural coupling between FKBP12 and buried water. Proteins 59 18704951
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 58 15271664
2004 The immunophilin FKBP12: a molecular guardian of the TGF-beta family type I receptors. Frontiers in bioscience : a journal and virtual library 57 14766396
2012 FKBP12 activates the cardiac ryanodine receptor Ca2+-release channel and is antagonised by FKBP12.6. PloS one 56 22363773
2017 The immunophilin FKBP12 inhibits hepcidin expression by binding the BMP type I receptor ALK2 in hepatocytes. Blood 55 28864813
2006 FKBP12 functions as an adaptor of the Smad7-Smurf1 complex on activin type I receptor. Journal of molecular endocrinology 54 16720724
2002 Ryanodine receptors, FKBP12, and heart failure. Frontiers in bioscience : a journal and virtual library 53 11897558
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
2004 Over-expression of FK506-binding protein FKBP12.6 alters excitation-contraction coupling in adult rabbit cardiomyocytes. The Journal of physiology 49 14966299
2004 Interaction of FKBP12.6 with the cardiac ryanodine receptor C-terminal domain. The Journal of biological chemistry 49 15591045
2004 Role of FKBP12.6 in hypoxia- and norepinephrine-induced Ca2+ release and contraction in pulmonary artery myocytes. Cell calcium 46 15036951
2002 Neuroprotective and antioxidant properties of FKBP-binding immunophilin ligands are independent on the FKBP12 pathway in human cells. Neuroscience letters 43 12231433
2007 Removal of FKBP12/12.6 from endothelial ryanodine receptors leads to an intracellular calcium leak and endothelial dysfunction. Arteriosclerosis, thrombosis, and vascular biology 42 17478757
2002 FKBP12 is the only FK506 binding protein mediating T-cell inhibition by the immunosuppressant FK506. Transplantation 42 12085010
2017 A cryo-EM-based model of phosphorylation- and FKBP12.6-mediated allosterism of the cardiac ryanodine receptor. Science signaling 40 28536302
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
2004 FKBP12 controls aspartate pathway flux in Saccharomyces cerevisiae to prevent toxic intermediate accumulation. Eukaryotic cell 39 15470257
2016 Tomato FK506 Binding Protein 12KD (FKBP12) Mediates the Interaction between Rapamycin and Target of Rapamycin (TOR). Frontiers in plant science 37 27917191
2008 FKBP12.6 disruption impairs glucose-induced insulin secretion. Biochemical and biophysical research communications 37 18466757
2017 FKBP12 contributes to α-synuclein toxicity by regulating the calcineurin-dependent phosphoproteome. Proceedings of the National Academy of Sciences of the United States of America 36 29229832
2009 A peptidyl-prolyl isomerase, FKBP12, accumulates in Alzheimer neurofibrillary tangles. Neuroscience letters 36 19414059
1998 TGF-beta-signaling with small molecule FKBP12 antagonists that bind myristoylated FKBP12-TGF-beta type I receptor fusion proteins. Chemistry & biology 36 9662508
2003 Energetic and structural analysis of the role of tryptophan 59 in FKBP12. Biochemistry 33 12600203
2002 FKBP12 modulation of the binding of the skeletal ryanodine receptor onto the II-III loop of the dihydropyridine receptor. Biophysical journal 33 11751303
1997 FKBP12 physically and functionally interacts with aspartokinase in Saccharomyces cerevisiae. Molecular and cellular biology 33 9315655
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
2016 FKBP12 enhances sensitivity to chemotherapy-induced cancer cell apoptosis by inhibiting MDM2. Oncogene 32 27617579
2010 A mechanism of ryanodine receptor modulation by FKBP12/12.6, protein kinase A, and K201. Cardiovascular research 32 19661110
2014 Eccentric contractions disrupt FKBP12 content in mouse skeletal muscle. Physiological reports 30 25347864
1997 Functions of FKBP12 and mitochondrial cyclophilin active site residues in vitro and in vivo in Saccharomyces cerevisiae. Molecular biology of the cell 30 9362068
2020 LncRNA AFAP1-AS1 modulates the sensitivity of paclitaxel-resistant prostate cancer cells to paclitaxel via miR-195-5p/FKBP1A axis. Cancer biology & therapy 29 33138677
2019 FKBP12 mediates necroptosis by initiating RIPK1-RIPK3-MLKL signal transduction in response to TNF receptor 1 ligation. Journal of cell science 28 31028177
2018 Effects of FKBP12 and type II BMP receptors on signal transduction by ALK2 activating mutations associated with genetic disorders. Bone 28 29551750
2020 Tacrolimus-induced hypomagnesemia and hypercalciuria requires FKBP12 suggesting a role for calcineurin. Physiological reports 26 31908154
1993 The tyrosine89 residue of yeast FKBP12 is required for rapamycin binding. Gene 26 8325502
2014 Ligands for FKBP12 increase Ca2+ influx and protein synthesis to improve skeletal muscle function. The Journal of biological chemistry 25 25053409
2004 The 12 kDa FK506-binding protein, FKBP12, modulates the Ca(2+)-flux properties of the type-3 ryanodine receptor. Journal of cell science 25 14970260
1994 Streptomyces chrysomallus FKBP-33 is a novel immunophilin consisting of two FK506 binding domains; its gene is transcriptionally coupled to the FKBP-12 gene. The EMBO journal 25 8062824
2021 Tacrolimus ameliorates podocyte injury by restoring FK506 binding protein 12 (FKBP12) at actin cytoskeleton. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 24 34662453
2015 Molecular Docking studies of FKBP12-mTOR inhibitors using binding predictions. Bioinformation 24 26229292
2007 Increased striatal mRNA and protein levels of the immunophilin FKBP-12 in experimental Parkinson's disease and identification of FKBP-12-binding proteins. Journal of proteome research 24 17877381
2025 Discovery of fully synthetic FKBP12-mTOR molecular glues. Chemical science 22 39916884
2013 Expression of budding yeast FKBP12 confers rapamycin susceptibility to the unicellular red alga Cyanidioschyzon merolae. Biochemical and biophysical research communications 22 23973485
2003 Expression of FKBP12 in benign and malignant vascular endothelium: an immunohistochemical study on conventional sections and tissue microarrays. The American journal of surgical pathology 22 12502928
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
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
2015 Characterization of the FKBP12-Encoding Genes in Aspergillus fumigatus. PloS one 19 26366742
2005 Ryanodine receptor binding to FKBP12 is modulated by channel activation state. Journal of cell science 19 16176935
2011 Suppression of EGFR autophosphorylation by FKBP12. Biochemistry 18 22103444
2008 FKBP12 deficiency reduces strength deficits after eccentric contraction-induced muscle injury. Journal of applied physiology (Bethesda, Md. : 1985) 18 18511525

Missed literature

Know a paper Affinage missed for FKBP1A? Flag it for the maintainers and the community.

No submissions yet.