Affinage

FKBP2

Peptidyl-prolyl cis-trans isomerase FKBP2 · UniProt P26885

Length
142 aa
Mass
15.6 kDa
Annotated
2026-06-09
15 papers in source corpus 10 papers cited in narrative 10 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 5/5 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

FKBP2 (FKBP13) is an ER-luminal peptidylprolyl cis-trans isomerase (PPIase/rotamase) that binds the immunosuppressants FK506 and rapamycin and functions in folding and quality control of secretory proteins (PMID:1380159, PMID:8373365). The protein carries an N-terminal signal peptide and a C-terminal ER retention sequence, and orthogonal fractionation and immunofluorescence place it in the lumen of the rough ER alongside BiP, grp94, and ribophorin I (PMID:1713687, PMID:8373365); its drug-binding pocket is structurally conserved with FKBP-12 (PMID:21136324). Consistent with a chaperone role, FKBP2/FKB2 transcription is induced by accumulation of unfolded protein in the ER through a UPR promoter element, in both yeast and mammalian cells (PMID:7685904, PMID:7526846). In human stem-cell-derived β cells, FKBP2 is required for proinsulin processing and insulin granule formation; its loss provokes sustained ER stress and elevated intracellular calcium that activate an NFAT2–HDAC9 axis and divert endocrine lineage allocation away from β cells [PMID:bio_10.1101_2025.09.01.672695]. Beyond its ER chaperone function, FKBP2 physically associates with the C-terminal domain of protein 4.1G and co-fractionates with the membrane cytoskeletal protein 4.1R, and it binds the C-chain of complement C1q through a surface outside the FK506 pocket (PMID:9531554, PMID:15353007). It also protects yeast from Bax-induced cell death (PMID:34342774).

Mechanistic history

Synthesis pass · year-by-year structured walk · 10 steps
  1. 1991 Medium

    Established FKBP2 as a distinct FK506/rapamycin-binding immunophilin localized to the ER membrane rather than the cytosol, raising the question of a secretory-pathway-specific FKBP.

    Evidence Molecular cloning and sequence analysis with subcellular fractionation

    PMID:1713687

    Open questions at the time
    • Active-site conservation inferred from sequence, not measured enzymatically
    • Luminal vs membrane topology not yet resolved
  2. 1992 High

    Demonstrated that FKBP2 is a catalytically active rotamase with FK506-binding capacity but functions distinctly from FKBP-12, since null mutants are viable and drug-insensitive.

    Evidence Purified-protein PPIase and FK506-binding assays plus genetic epistasis in yeast

    PMID:1380159

    Open questions at the time
    • Physiological folding substrates not identified
    • Lower FK506 affinity than FKBP-12 leaves the in vivo drug relevance unclear
  3. 1993 High

    Confirmed FKBP2 resides in the rough ER lumen, defining its compartment for chaperone function.

    Evidence Subcellular fractionation, isopycnic gradients, and immunofluorescence across two species

    PMID:8373365

    Open questions at the time
    • Does not identify luminal client proteins
    • Mechanism of luminal retention not dissected
  4. 1993 High

    Linked FKBP2 to the unfolded protein response by showing transcriptional induction through a defined UPR promoter element specific to ER unfolded-protein accumulation.

    Evidence Northern blot, secretory-pathway mutant epistasis, and UPR element mapping in yeast

    PMID:7685904

    Open questions at the time
    • Functional consequence of induction (which clients require FKBP2) not shown
  5. 1994 Medium

    Extended UPR-driven induction to mammalian cells, supporting a conserved role as a stress-inducible ER chaperone.

    Evidence Northern blot with actinomycin D stability controls and promoter comparison in MDCK cells

    PMID:7526846

    Open questions at the time
    • UPR element only inferred by sequence similarity, not functionally mapped in mammalian cells
    • Chaperone clients not identified
  6. 1996 Medium

    Showed the FKBP2 drug-binding pocket adopts an FKBP-12-like FK506 conformation, structurally rationalizing immunophilin classification.

    Evidence NMR (HSQC-NOESY) on a triple mutant of FKBP-13 bound to 13C-FK506

    PMID:21136324

    Open questions at the time
    • Structure determined only for a triple mutant, not wild type
    • No structure of a physiological substrate complex
  7. 1998 High

    Identified a cytoskeletal-scaffolding role by showing FKBP2 binds protein 4.1G via its histidyl-proline-containing C-terminal domain and co-fractionates with 4.1R in erythrocyte membranes.

    Evidence Yeast two-hybrid, in vitro binding, Co-IP, and erythrocyte membrane fractionation

    PMID:9531554

    Open questions at the time
    • How an ER-luminal protein engages cytoplasmic 4.1 proteins is unresolved
    • Functional consequence of the 4.1 interaction not established
  8. 2004 Medium

    Defined a specific interaction with complement C1q C-chain mediated by a surface outside the drug-binding pocket, distinguishing FKBP2 from related immunophilins.

    Evidence Yeast two-hybrid and protein complementation assay with FK506 competition and FKBP/Cyp specificity controls

    PMID:15353007

    Open questions at the time
    • No Co-IP or in vitro biochemical confirmation
    • Physiological setting of the C1q-C interaction unknown
  9. 2021 Low

    Implicated FKBP2 in cell survival by showing it suppresses Bax-induced death in a yeast model.

    Evidence Yeast cDNA-library screen with Bax/FKBP2 co-expression viability assay

    PMID:34342774

    Open questions at the time
    • Single-method yeast viability assay with no mechanistic dissection
    • Not validated in mammalian apoptosis systems
  10. 2025 Medium

    Connected FKBP2 PPIase function to a physiological program—proinsulin processing and β cell fate—via an ER stress→calcium→NFAT2–HDAC9 axis that controls endocrine lineage allocation.

    Evidence Loss/gain-of-function in hPSC-derived β cells, scRNA-seq, insulin secretion and granule EM, calcium measurement, and pharmacological HDAC IIa rescue (preprint)

    PMID:bio_10.1101_2025.09.01.672695

    Open questions at the time
    • Preprint not yet peer-reviewed
    • Direct proinsulin–FKBP2 isomerase substrate relationship not biochemically demonstrated
    • Whether NFAT2–HDAC9 activation is a direct consequence of lost PPIase activity is unresolved

Open questions

Synthesis pass · forward-looking unresolved questions
  • The direct physiological folding substrates of FKBP2's rotamase activity and how its ER chaperone function mechanistically links to its cytoskeletal, complement, and apoptotic associations remain unresolved.
  • No defined endogenous PPIase substrate beyond the proinsulin functional link
  • Topological reconciliation of luminal ER residence with 4.1 cytoskeletal binding is unexplained

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0044183 protein folding chaperone 3 GO:0016853 isomerase activity 2 GO:0140096 catalytic activity, acting on a protein 2
Localization
GO:0005783 endoplasmic reticulum 2
Pathway
R-HSA-392499 Metabolism of proteins 2 R-HSA-8953897 Cellular responses to stimuli 2
Partners
C1QCEPB41EPB41L2

Evidence

Reading pass · 10 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1991 FKBP-13 (FKBP2) is a membrane-associated 13-kDa FK506- and rapamycin-binding protein with a 21-amino acid signal peptide and a C-terminal ER retention sequence (Arg-Thr-Glu-Leu), lacking a transmembrane domain but appearing to localize to the ER membrane. The conserved residues comprising the drug-binding site and rotamase (peptidylprolyl cis-trans isomerase) active site of FKBP-12 are completely conserved in FKBP-13. Molecular cloning, sequence analysis, subcellular fractionation Proceedings of the National Academy of Sciences of the United States of America Medium 1713687
1992 Yeast FKBP-13 (encoded by FKB2) binds FK506 with 15-fold lower affinity than FKBP-12 and possesses peptidylprolyl cis-trans isomerase (PPIase/rotamase) activity with a similar substrate profile. It is membrane-associated and has a hydrophobic signal sequence. fkb2 and fkb1/fkb2 double mutants are viable and show no altered sensitivity to FK506 or rapamycin, indicating distinct functions from FKBP-12. Protein purification, FK506-binding assay, PPIase activity assay, genetic epistasis (null mutants), N-terminal sequencing, gene cloning Proceedings of the National Academy of Sciences of the United States of America High 1380159
1993 FKBP13 localizes to the lumen of the rough endoplasmic reticulum (ER), not the cytosol. By immunoblotting of subcellular fractions from canine pancreatic homogenate, FKBP13 co-fractionated exclusively with rough microsomal ER markers (BiP, grp94, ribophorin I) and co-banded with them on isopycnic sucrose gradients. Immunofluorescence of overexpressed FKBP13 cDNA in HeLa cells showed an ER pattern, and membrane/lumen separation confirmed it as a luminal ER protein. Subcellular fractionation, isopycnic sucrose gradient, immunoblotting, immunofluorescence microscopy, membrane/lumen separation The Biochemical journal High 8373365
1993 In Saccharomyces cerevisiae, FKB2 (encoding FKBP-13) is transcriptionally induced by accumulation of unfolded proteins in the ER (unfolded protein response, UPR). The induction is mediated through a 21-bp UPR element in the 5' noncoding region of FKB2, analogous to UPR elements in yeast KAR2 (BiP) and mammalian GRP78/GRP94. Mutations blocking N-glycosylation (tunicamycin treatment, sec53-6 mutant) elevated FKB2 mRNA; blocks in other secretory steps did not, indicating specificity to ER unfolded protein accumulation. Northern blot, genetic epistasis (secretory pathway mutants), promoter element analysis (UPR element identification) Proceedings of the National Academy of Sciences of the United States of America High 7685904
1994 FKBP13 mRNA is induced in mammalian (MDCK) cells by agents that cause protein misfolding in the ER: tunicamycin causes ~2-fold induction and Ca2+ ionophores (ionomycin) cause up to 5-fold induction. The increase is due to transcriptional upregulation rather than mRNA stabilization. The 5' flanking region of murine FKBP13 contains a ~37 bp sequence with ~50% identity to the BiP unfolded protein response element, supporting a role as an ER chaperone. Northern blot, actinomycin D mRNA stability assay, 5' flanking region sequencing and comparison The Biochemical journal Medium 7526846
1998 FKBP13 physically interacts with the COOH-terminal domain (CTD) of a novel broadly expressed protein 4.1 homologue (4.1G). The interaction requires the histidyl-proline moiety of 4.1G-CTD. FKBP13 co-fractionates with the red blood cell protein 4.1R in erythrocyte ghost, inside-out vesicle, and Triton shell preparations, indicating a role as a component of membrane cytoskeletal scaffolds in addition to its ER chaperone function. Yeast two-hybrid, in vitro binding assay, co-immunoprecipitation, truncation/mutation analysis of 4.1G-CTD, subcellular fractionation of erythrocyte membranes The Journal of cell biology High 9531554
2004 FKBP13 specifically interacts with the C-chain of complement C1q (C1q-C). The interaction was detected by yeast two-hybrid screening and confirmed by a protein complementation assay. FKBP12, FKBP25, FKBP52, and CypA did not interact with C1q-C, demonstrating specificity. FK506 did not prevent the interaction, suggesting that regions outside the drug-binding pocket mediate the C1q-C interaction. Yeast two-hybrid, protein complementation assay, competition with FK506 BMC pharmacology Medium 15353007
1996 The solution structure of FK506 bound to a Q50R/A95H/K98I triple mutant of FKBP-13 was determined by NMR (HSQC-NOESY with 13C-labeled FK506, 87 NOE distance restraints). The conformation of FK506 in complex with mutant FKBP-13 is similar to that in wild-type FKBP-12, consistent with conservation of the drug-binding pocket. NMR (HSQC-NOESY), time-averaged restrained molecular dynamics (TARMD) structure calculation Journal of biomolecular NMR Medium 21136324
2021 FKBP2 (FKBP13) inhibits Bax-induced apoptosis in yeast. When co-expressed with the pro-apoptotic protein Bax in a yeast model, FKBP2 protected cells from Bax-induced cell death, identified via human hippocampal cDNA library screening in a yeast-based system. Yeast-based cDNA library screen, co-expression of Bax and HA-tagged FKBP2, cell viability assay Cell biology and toxicology Low 34342774
2025 FKBP2 functions as a critical ER-localized cis-trans prolyl isomerase required for proinsulin processing and β cell differentiation. Loss of FKBP2 in human pluripotent stem cell-derived β cells impairs insulin granule morphology and reduces insulin secretion. FKBP2 deficiency causes sustained ER stress, elevated intracellular calcium, and activation of the NFAT2–HDAC9 signaling axis, shifting endocrine lineage allocation from β cells to α cells. Pharmacological inhibition of HDAC class IIa partially rescues β cell differentiation, supporting a causal role for this pathway downstream of FKBP2 loss. Loss- and gain-of-function FKBP2 models in hPSCs, single-cell RNA sequencing, insulin secretion assay, electron microscopy of granule morphology, pharmacological HDAC inhibition, intracellular calcium measurement bioRxivpreprint Medium bio_10.1101_2025.09.01.672695

Source papers

Stage 0 corpus · 15 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1991 Molecular cloning of a membrane-associated human FK506- and rapamycin-binding protein, FKBP-13. Proceedings of the National Academy of Sciences of the United States of America 180 1713687
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
1998 The 13-kD FK506 binding protein, FKBP13, interacts with a novel homologue of the erythrocyte membrane cytoskeletal protein 4.1. The Journal of cell biology 100 9531554
1993 The FKB2 gene of Saccharomyces cerevisiae, encoding the immunosuppressant-binding protein FKBP-13, is regulated in response to accumulation of unfolded proteins in the endoplasmic reticulum. Proceedings of the National Academy of Sciences of the United States of America 79 7685904
1992 Yeast FKBP-13 is a membrane-associated FK506-binding protein encoded by the nonessential gene FKB2. Proceedings of the National Academy of Sciences of the United States of America 57 1380159
1993 Localization of the FK506-binding protein, FKBP 13, to the lumen of the endoplasmic reticulum. The Biochemical journal 56 8373365
1994 Induction of the FK506-binding protein, FKBP13, under conditions which misfold proteins in the endoplasmic reticulum. The Biochemical journal 51 7526846
1992 Saccharomyces cerevisiae contains a homolog of human FKBP-13, a membrane-associated FK506/rapamycin binding protein. Yeast (Chichester, England) 21 1279908
1995 Exclusion of the 13-kDa rapamycin binding protein gene (FKBP2) as a candidate gene for multiple endocrine neoplasia type 1. Human genetics 20 7535744
1993 Structural organization of the genes encoding human and murine FK506-binding protein (FKBP) 13 and comparison to FKBP1. Gene 15 7505249
1992 Chromosomal band assignments of the genes encoding human FKBP12 and FKBP13. Biochemical and biophysical research communications 10 1281998
2021 FK506-binding protein 2 (FKBP13) inhibit Bax-induced apoptosis in Saccharomyces cerevisiae (yeast). Cell biology and toxicology 3 34342774
2004 The FK506 binding protein 13 kDa (FKBP13) interacts with the C-chain of complement C1q. BMC pharmacology 2 15353007
1996 Practical applications of time-averaged restrained molecular dynamics to ligand-receptor systems: FK506 bound to the Q50R,A95H,K98I triple mutant of FKBP-13. Journal of biomolecular NMR 2 21136324
2026 Geminivirus V2-mediated inhibition of plant FKBP13 PPIase activity activates UPR signaling to enhance viral pathogenicity. Journal of integrative plant biology 1 41645412

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