Affinage

FKBP3

Peptidyl-prolyl cis-trans isomerase FKBP3 · UniProt Q00688

Length
224 aa
Mass
25.2 kDa
Annotated
2026-04-28
29 papers in source corpus 21 papers cited in narrative 21 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

FKBP25 (encoded by FKBP3) is a nuclear immunophilin that integrates peptidylprolyl cis-trans isomerase (PPIase) activity with nucleic acid binding to regulate ribosome biogenesis, chromatin dynamics, DNA repair, and mitotic spindle integrity. Its N-terminal Basic Tilted Helix Bundle (BTHB) domain selectively binds double-stranded RNA, which is required for nucleolar localization and association with pre-60S ribosomal subunits and ribosome biogenesis factors, while both the BTHB and C-terminal FKBP domains cooperate to bind DNA (PMID:29036638, PMID:26762975). The catalytic FKBP domain directly binds microtubules to promote polymerization and spindle stability—with PKC phosphorylation releasing chromatin association during mitosis—and PPIase activity is required for promoting homologous recombination at DNA double-strand breaks (PMID:29361176, PMID:30620620). FKBP25 also modulates signaling and transcription by stabilizing MDM2 auto-ubiquitylation to activate p53, recruiting HDAC1/2 via YY1 to repress target loci including the HIV-1 LTR, driving HDAC2 expression through Sp1 stabilization, and forming a rapamycin-induced ternary complex with the mTOR FRB domain (PMID:19166840, PMID:34281390, PMID:28839465, PMID:27610411).

Mechanistic history

Synthesis pass · year-by-year structured walk · 11 steps
  1. 1992 High

    Identification of FKBP25 as a nuclear immunophilin with PPIase activity and preferential rapamycin binding established that the FKBP family extends to the nucleus with distinct pharmacological properties.

    Evidence Molecular cloning with recombinant PPIase assay and inhibitor IC50 determination

    PMID:1375932

    Open questions at the time
    • No in vivo substrates for PPIase activity identified
    • Nuclear localization signals predicted but not functionally validated
  2. 1993 Medium

    Demonstration that FKBP25 is predominantly nuclear and binds DNA via its unique N-terminal domain distinguished it from cytoplasmic FKBPs and suggested a chromatin-regulatory function.

    Evidence Cell fractionation of Jurkat cells, DNA-binding assay, CD spectroscopy

    PMID:8422914

    Open questions at the time
    • DNA-binding specificity (sequence or structure preference) not defined
    • No mutagenesis to confirm N-terminal domain necessity
  3. 2009 Medium

    Discovery that FKBP25 stimulates MDM2 auto-ubiquitylation and degradation, thereby activating p53, revealed FKBP25 as a regulator of the p53 tumor-suppressor pathway.

    Evidence Reciprocal co-immunoprecipitation, siRNA knockdown, ubiquitylation assay

    PMID:19166840

    Open questions at the time
    • Whether PPIase catalytic activity is required for MDM2 interaction not tested
    • In vivo relevance to tumor suppression not established
    • Earlier observation that p53 represses FKBP25 transcription (PMID:10557083) suggests a feedback loop whose mechanism is undefined
  4. 2014 High

    Proteomic and structural studies collectively revealed that FKBP25 associates with pre-60S ribosomal subunits in an RNA-dependent manner and that its N-terminal domain adopts a novel BTHB fold, reframing the protein as a ribosome biogenesis factor with a structurally unique nucleic acid-binding module.

    Evidence Mass spectrometry interactome, sucrose gradient fractionation, NMR/X-ray crystallography of BTHB domain, RNA/salt dissociation experiments

    PMID:24667607 PMID:24840943 PMID:24998444

    Open questions at the time
    • Direct substrates of PPIase activity during ribosome maturation unknown
    • Whether BTHB binds RNA or DNA in vivo was unresolved at this point
  5. 2016 High

    Full-length NMR structure showed both BTHB and FKBP domains cooperate for DNA binding via major- and minor-groove contacts, and the crystal structure of a rapamycin-bridged FRB–FKBP25 ternary complex established a structural basis for rapamycin-dependent mTOR engagement.

    Evidence NMR solution structure with mutagenesis validation of DNA contacts; 1.67-Å crystal structure of FRB–rapamycin–FKBP25 plus proximity labeling

    PMID:26762975 PMID:27610411

    Open questions at the time
    • Physiological significance of FKBP25–mTOR interaction without exogenous rapamycin unclear
    • Genomic targets of FKBP25 DNA binding not mapped
  6. 2017 High

    The BTHB domain was shown to be a dsRNA-specific binder whose RNA-binding activity directs nucleolar localization and mediates nearly all protein interactions, resolving the question of whether the N-terminus primarily engages DNA or RNA in vivo.

    Evidence NMR, EMSA and fluorescence RNA-binding assays, mutagenesis, nucleolar imaging, proteomic interaction mapping

    PMID:29036638

    Open questions at the time
    • Specific dsRNA targets in the nucleolus not identified
    • Relative contribution of DNA- versus RNA-binding to chromatin functions unresolved
  7. 2017 Medium

    FKBP25 was shown to promote NSCLC cell proliferation through a Sp1/HDAC2/p27 axis, where it stabilizes Sp1 to drive HDAC2 transcription and epigenetically silence the cell-cycle inhibitor p27.

    Evidence siRNA/overexpression, ChIP, luciferase reporter, ubiquitination assay, xenograft model

    PMID:28839465

    Open questions at the time
    • Whether PPIase activity is required for Sp1 stabilization not tested
    • Generalizability beyond NSCLC cell lines unclear
  8. 2018 High

    The catalytic FKBP domain was found to directly bind microtubules and promote polymerization, while PKC phosphorylation releases FKBP25 from chromatin during mitosis, establishing a dual nuclear/cytoskeletal role regulated by cell-cycle-dependent phosphorylation.

    Evidence In vitro MT binding/polymerization, live cell spindle imaging, PKC phosphorylation assay, chromosome instability quantification upon depletion

    PMID:29361176

    Open questions at the time
    • Identity of PKC isoform(s) responsible not determined
    • Structural basis for FKBP domain–tubulin interaction unknown
  9. 2019 High

    PPIase catalytic activity was directly demonstrated to be required for promoting homologous recombination and Rad51 focus formation at DSBs, establishing an enzymatic role in the DNA damage response.

    Evidence DSB repair reporter assays, Rad51 foci imaging, catalytic-dead mutant rescue experiments

    PMID:30620620

    Open questions at the time
    • Direct proline-isomerization substrate in the HR pathway not identified
    • Rapamycin's HR-inhibitory effect was only partially mTOR-independent, leaving the mechanism unclear
  10. 2021 Medium

    FKBP25 was shown to recruit HDAC1/2 to the HIV-1 LTR via YY1 interaction, maintaining viral latency, while oocyte studies confirmed spindle and kinetochore-microtubule functions with identification of S163 as a regulatory phosphosite, and ESD was found to stabilize cytoplasmic FKBP25 to suppress mTORC1.

    Evidence CRISPR KO in latent HIV-1 cells with ChIP (PMID:34281390); siRNA in mouse oocytes with aneuploidy quantification and S163A mutagenesis (PMID:33553183); yeast two-hybrid/Co-IP with mTORC1 substrate phosphorylation readout (PMID:34875997)

    PMID:33553183 PMID:34281390 PMID:34875997

    Open questions at the time
    • Whether FKBP25 isomerase activity is needed for YY1-HDAC recruitment unknown
    • How ESD-mediated stabilization relates to nuclear FKBP25 functions unaddressed
    • Direct FKBP25 phosphosite(s) for PKC versus the S163 site relationship not clarified
  11. 2023 Medium

    FKBP25 was linked to Wnt/β-catenin signaling through stabilization of PARK7/DJ-1, with FOXO3 acting as a transcriptional repressor of FKBP3, expanding its regulatory network.

    Evidence Co-IP, ubiquitination assay, ChIP of FOXO3 at FKBP3 promoter, Wnt reporter, xenograft model

    PMID:37987202

    Open questions at the time
    • Whether PPIase activity mediates PARK7 stabilization untested
    • Relationship of PARK7-Wnt axis to FKBP25's nuclear and ribosomal functions unclear

Open questions

Synthesis pass · forward-looking unresolved questions
  • The direct in vivo substrates of FKBP25 PPIase activity across its diverse functions (HR repair, ribosome biogenesis, chromatin regulation, microtubule dynamics) remain unidentified, and the relative physiological importance of its DNA- versus dsRNA-binding modes is unresolved.
  • No proline-isomerization substrate identified in any pathway
  • Genome-wide binding profiles (ChIP-seq/CLIP-seq) not reported
  • No genetic mouse model phenotype characterized

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0098772 molecular function regulator activity 3 GO:0140096 catalytic activity, acting on a protein 3 GO:0003677 DNA binding 2 GO:0003723 RNA binding 1 GO:0008092 cytoskeletal protein binding 1
Localization
GO:0005634 nucleus 4 GO:0005730 nucleolus 2 GO:0005856 cytoskeleton 2 GO:0005829 cytosol 1
Pathway
R-HSA-162582 Signal Transduction 2 R-HSA-1640170 Cell Cycle 2 R-HSA-392499 Metabolism of proteins 2 R-HSA-4839726 Chromatin organization 2 R-HSA-73894 DNA Repair 1
Partners
ESDHDAC1HDAC2MDM2NCLPARK7TRPC6YY1
Complex memberships
FRB-rapamycin-FKBP25 ternary complexYY1-FKBP25-HDAC1/2 repressor complexpre-60S ribosomal subunit

Evidence

Reading pass · 21 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1992 FKBP25 (FKBP3) was cloned and shown to have peptidylprolyl cis-trans isomerase (PPIase) activity, with higher affinity for rapamycin (IC50 = 50 nM) than FK506 (IC50 = 400 nM). The C-terminal 97 amino acids share identity with FKBP12 and FKBP13, and the sequence contains putative nuclear localization signals. Molecular cloning, recombinant protein expression, in vitro PPIase activity assay with inhibitor titration The Journal of biological chemistry High 1375932
1993 FKBP25 is predominantly nuclear in T-lymphoma Jurkat cells and has the ability to bind DNA; the FKBP25/DNA complex is dissociated by high salt. The N-terminal domain is predicted to form an amphipathic helix-loop-helix that may account for DNA binding, while FKBP12 (lacking this N-terminal region) does not bind DNA. Cell fractionation, Western blotting, DNA-binding assay, CD spectroscopy FEBS letters Medium 8422914
1999 FKBP25 (FKBP3) expression is transcriptionally repressed following p53 induction in both human and murine cell lines after DNA damage. Differential gene expression screening, Northern/Western blot after p53 induction by DNA damage stimuli Oncogene Medium 10557083
2009 FKBP25 interacts with MDM2, stimulates MDM2 auto-ubiquitylation and proteasomal degradation, leading to p53 activation. siRNA-mediated depletion of FKBP25 increases MDM2 levels and reduces p53 and p21 levels. Co-immunoprecipitation, siRNA knockdown, ubiquitylation assay, Western blotting FEBS letters Medium 19166840
2014 FKBP25 interacts with nucleolin in an rRNA-dependent manner and associates with the immature pre-60S ribosomal subunit in nuclear extract but not with mature ribosomes, implicating FKBP25 in ribosome biogenesis. The proteomic analysis also identified interactions with ribosomal proteins, ribosomal processing factors, and chromatin modifiers. Proteomic characterization (mass spectrometry), co-immunoprecipitation, sucrose gradient fractionation RNA (New York, N.Y.) High 24840943
2014 The N-terminal domain of FKBP25 (residues 1-73) adopts a novel Basic Tilted Helix Bundle (BTHB) fold with a positively charged surface patch. This domain is proposed to mediate DNA binding, and YY1 can bind to this region, potentially regulating DNA binding. NMR/X-ray crystallography structural determination, sequence conservation analysis, binding assay with YY1 Biochemical and biophysical research communications Medium 24667607
2014 Endogenous FKBP25 associates with core histones of the nucleosome, spliceosomal complex components, and ribosomal subunits. FKBP25 is detected on polyribosomes, and its association is released by added RNA or 0.5 M NaCl, indicating RNA-dependent binding. Rapamycin/FK506 treatment causes residual release, suggesting some interactions also involve the PPIase cavity. Anti-FKBP25 immunoprecipitation, proteomics, polyribosome fractionation, RNA/salt dissociation experiments Biochemical and biophysical research communications Medium 24998444
2016 The NMR solution structure of full-length human FKBP25 reveals that the N-terminal helix-loop-helix (HLH) domain and C-terminal FKBD interact with each other. Both domains contribute to DNA binding: the HLH domain makes major-groove contacts, while the basic FKBD loop cooperates with adjacent minor-groove interactions. Mutational studies validated this model. NMR solution structure determination, mutational studies, DNA-binding assays Nucleic acids research High 26762975
2016 Crystal structure of the ternary complex FRB-rapamycin-FKBP25 was determined at 1.67-Å resolution, revealing rapamycin-induced physical interaction between FKBP25 and the FRB domain of mTOR. Conformational changes in FRB create a methionine-rich hole and covalent metalloid coordination at C2085 of FRB was observed. Proximity biotin-labeling (pBirA), immunoprecipitation, immunofluorescence, X-ray crystallography (1.67 Å) ACS central science High 27610411
2013 Mutagenesis of the FKBP25 catalytic domain distinguishes domain-destabilizing mutations from 'surgical' mutations that ablate PPIase activity while maintaining domain fold, providing tools to differentiate catalytic versus non-catalytic functions. Site-directed mutagenesis, in vitro PPIase activity assay, domain folding assessment Biochemical Society transactions Medium 23697935
2017 FKBP25 promotes cell proliferation in non-small cell lung cancer through a Sp1/HDAC2/p27 axis: FKBP3 inhibits ubiquitination of the transcription factor Sp1, stabilizing it to drive HDAC2 promoter activity; HDAC2 then modulates histone H3K4 acetylation at the p27 promoter to suppress p27 expression. siRNA knockdown, overexpression, ChIP, luciferase reporter assay, ubiquitination assay, xenograft in vivo model Theranostics Medium 28839465
2017 The N-terminal BTHB domain of FKBP25 specifically binds double-stranded RNA (dsRNA) over single-stranded RNA or DNA. This RNA-binding activity is required for FKBP25 nucleolar localization and for the vast majority of its protein interactions including those with 60S pre-ribosome and early ribosome biogenesis factors. The BTHB and FKBP domains have independent mobility, suggesting the N-terminus anchors to dsRNA while the catalytic domain interacts with neighboring proteins. NMR spectroscopy, RNA binding assays (EMSA and fluorescence), mutagenesis, nucleolar localization imaging, proteomic interaction mapping Nucleic acids research High 29036638
2018 FKBP25 directly binds microtubules via its catalytic FKBP domain to promote microtubule polymerization and stabilize the MT network. FKBP25 associates with the mitotic spindle and regulates entry into mitosis. Depletion leads to increased chromosome instability. Additionally, Protein Kinase C phosphorylates FKBP25 to disrupt its chromatin association during mitosis while maintaining spindle interaction. In vitro microtubule binding and polymerization assay, live cell imaging, knockdown with chromosome instability readout, PKC phosphorylation assay, domain mapping Nucleic acids research High 29361176
2019 FKBP25 promotes homologous recombination (HR) and suppresses single-strand annealing (SSA) in DNA double-strand break repair. Depletion reduces Rad51 repair foci after etoposide and ionizing radiation. The PPIase catalytic activity of FKBP25 is required for this HR-promoting function. Rapamycin impairs HR at least partly independently of mTOR. siRNA knockdown, DSB repair reporter assays, Rad51 foci imaging, rapamycin treatment, catalytic mutant rescue experiments Biochemistry and cell biology High 30620620
2015 FKBP25 interacts with TRPC6 and regulates non-capacitative calcium entry (NCCE) in platelets and HEK-293 cells. FK506 modifies the association pattern between FKBP25 and TRPC channels. siRNA silencing of FKBP25 inhibits OAG-evoked NCCE, and FKBP25 is found at the plasma membrane by biotinylation experiments. Co-immunoprecipitation, siRNA knockdown, calcium flux assay, biotinylation/surface protein isolation, TRPC6-/- mouse platelets Biochimica et biophysica acta Medium 26239116
2021 FKBP3 promotes HIV-1 latency by binding to YY1 (indirect association with the HIV-1 LTR) and recruiting HDAC1/2 to the viral LTR, inducing histone deacetylation. FKBP3 knockout in latently infected cell lines promotes latent HIV-1 activation. CRISPR knockout in latent HIV-1 cell lines, co-immunoprecipitation (FKBP3-YY1), ChIP (HDAC1/2 at LTR), latent HIV-1 reactivation assays, primary latent cell model mBio Medium 34281390
2021 ESD (esterase D) interacts with FKBP25 via the FKBP25 N-terminus (1-90 aa), reduces K48-linked polyubiquitination of FKBP25 thereby stabilizing cytoplasmic FKBP25, and promotes FKBP25 binding to mTORC1, suppressing mTORC1 activity and inducing autophagy. Yeast two-hybrid, co-immunoprecipitation, ubiquitination assay (K48 linkage-specific), mTORC1 substrate phosphorylation (P70S6K, 4EBP1), autophagy assay Cellular & molecular biology letters Medium 34875997
2018 FKBP25 translocates to the nucleus under ischemic (OGD) or peroxynitrite stress conditions in endothelial cells, where it interacts with 60S ribosomal protein L7a. FKBP25 overexpression protects endothelial cells against OGD injury. Western blot, immunofluorescence, co-immunoprecipitation, FRET, overexpression rescue assay Cellular physiology and biochemistry Low 29969783
2021 FKBP25 depletion in mouse oocytes causes abnormal spindle assembly, chromosome misalignment, and defective kinetochore-microtubule attachment, leading to elevated aneuploidy. Serine 163 is identified as a major phosphorylation site modulating FKBP25 function in meiotic maturation. siRNA knockdown in mouse oocytes, immunofluorescence (spindle/chromosome), aneuploidy quantification, site-directed mutagenesis (S163A) Frontiers in cell and developmental biology Medium 33553183
2023 FKBP3 interacts with PARK7 (DJ-1); FKBP3 knockdown enhances PARK7 ubiquitination and degradation. FKBP3 activates the Wnt/β-catenin signaling pathway through PARK7. FOXO3 binds the FKBP3 promoter to suppress its transcription. Co-immunoprecipitation, ubiquitination assay, ChIP (FOXO3 at FKBP3 promoter), Wnt/β-catenin pathway reporters, xenograft model Journal of cellular and molecular medicine Medium 37987202
2023 FKBP25 knockdown in C2C12 myoblasts increases cell viability/accumulation and migration independent of tubulin dynamics, demonstrating a role in myoblast behavior distinct from its previously described microtubule-regulatory function. Doxycycline-inducible shRNA knockdown, cell viability assay, migration assay, tubulin dynamics analysis The FEBS journal Low 37345229

Source papers

Stage 0 corpus · 29 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1999 Down-regulation of the stathmin/Op18 and FKBP25 genes following p53 induction. Oncogene 110 10557083
1992 Molecular cloning of a 25-kDa high affinity rapamycin binding protein, FKBP25. The Journal of biological chemistry 77 1375932
2009 FKBP25, a novel regulator of the p53 pathway, induces the degradation of MDM2 and activation of p53. FEBS letters 58 19166840
2017 FKBP3 Promotes Proliferation of Non-Small Cell Lung Cancer Cells through Regulating Sp1/HDAC2/p27. Theranostics 54 28839465
2016 Proximity-Directed Labeling Reveals a New Rapamycin-Induced Heterodimer of FKBP25 and FRB in Live Cells. ACS central science 46 27610411
1993 On the localization of FKBP25 in T-lymphocytes. FEBS letters 43 8422914
2019 Melatonin Regulates Breast Cancer Progression by the lnc010561/miR-30/FKBP3 Axis. Molecular therapy. Nucleic acids 32 31955008
2019 FKBP3 mediates oxaliplatin resistance in colorectal cancer cells by regulating HDAC2 expression. Oncology reports 27 31524278
2016 Structural basis of nucleic acid recognition by FK506-binding protein 25 (FKBP25), a nuclear immunophilin. Nucleic acids research 26 26762975
2014 The prolyl isomerase, FKBP25, interacts with RNA-engaged nucleolin and the pre-60S ribosomal subunit. RNA (New York, N.Y.) 24 24840943
2018 The prolyl isomerase FKBP25 regulates microtubule polymerization impacting cell cycle progression and genomic stability. Nucleic acids research 17 29361176
2014 Rapamycin-binding FKBP25 associates with diverse proteins that form large intracellular entities. Biochemical and biophysical research communications 14 24998444
2017 The basic tilted helix bundle domain of the prolyl isomerase FKBP25 is a novel double-stranded RNA binding module. Nucleic acids research 13 29036638
2014 Basic Tilted Helix Bundle - a new protein fold in human FKBP25/FKBP3 and HectD1. Biochemical and biophysical research communications 13 24667607
2000 Mammalian FKBP-25 and its associated proteins. Archives of biochemistry and biophysics 13 10900128
2013 Resolving the functions of peptidylprolyl isomerases: insights from the mutagenesis of the nuclear FKBP25 enzyme. Biochemical Society transactions 12 23697935
1996 Cloning and high expression of rabbit FKBP25 in cornea. Japanese journal of ophthalmology 10 8876379
2021 Esterase D stabilizes FKBP25 to suppress mTORC1. Cellular & molecular biology letters 9 34875997
2015 FKBP25 and FKBP38 regulate non-capacitative calcium entry through TRPC6. Biochimica et biophysica acta 9 26239116
2019 FKBP25 participates in DNA double-strand break repair. Biochemistry and cell biology = Biochimie et biologie cellulaire 8 30620620
2021 FKBP3 Induces Human Immunodeficiency Virus Type 1 Latency by Recruiting Histone Deacetylase 1/2 to the Viral Long Terminal Repeat. mBio 7 34281390
2023 Knockdown of FKBP3 suppresses nasopharyngeal carcinoma cell growth, invasion and migration, deactivated NF-κB/IL-6 signaling pathway through inhibiting histone deacetylase 2 expression. The Chinese journal of physiology 6 37082996
2018 Elucidation of the FKBP25-60S Ribosomal Protein L7a Stress Response Signaling During Ischemic Injury. Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology 6 29969783
2005 Molecular cloning and expression pattern of the Fkbp25 gene during cerebral cortical neurogenesis. Gene expression patterns : GEP 6 15908283
2002 Cloning and identification of a novel cDNA which may be associated with FKBP25. Biochemical genetics 5 12392168
2023 FKBP3 aggravates the malignant phenotype of diffuse large B-cell lymphoma by PARK7-mediated activation of Wnt/β-catenin signalling. Journal of cellular and molecular medicine 4 37987202
2021 FKBP25 Regulates Meiotic Apparatus During Mouse Oocyte Maturation. Frontiers in cell and developmental biology 4 33553183
2023 FKBP25 regulates myoblast viability and migration and is differentially expressed in in vivo models of muscle adaptation. The FEBS journal 1 37345229
2023 [Procine recombinant NK-lysin inhibits hepatocellular carcinoma metastasis by downregulating FKBP3 and inhibiting oxidative phosphorylation and glycolysis: a proteomic analysis]. Nan fang yi ke da xue xue bao = Journal of Southern Medical University 0 37488794