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Gene Review

Fkbp1a  -  FK506 binding protein 1a

Rattus norvegicus

Synonyms: 12 kDa FK506-binding protein, 12 kDa FKBP, FK506-binding protein 1A, FKBP-12, FKBP-1A, ...
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Disease relevance of Fkbp1a

  • Protein expressions of nNOS and FKBP 12 were observed in major pelvic ganglion, cavernous nerve and nerve terminals within the rat penis as well as mRNA expression of FKBP 12 observed in the rat major pelvic ganglion neuronal cell bodies to a minimal extent at baseline conditions [1].
  • It was shown for the first time that neuroprotection by FK506 also included the suppression of the cerebral peptidyl-prolyl cis/trans isomerase activity of FKBP in vivo whereas the expression levels of FKBP12, 52 and 65 following ischemia changed slightly and FK506 treatment does not suppress the expression patterns [2].
  • The present results suggest that GPI-1046 significantly decreased infarct volume and provided neuroprotective effect on rats after transient focal cerebral ischemia by inhibiting the increase of rotamase activity and of the number of FKBP12-, FKBP52-, caspase-8-, cytochrome c-, and caspase-3-positive cells in the ischemic area [3].
  • RT-PCR, immunolocalisation and Western blotting studies were employed to identify and characterise FKBP12 in rat primary osteoblasts and osteoblast-like osteosarcoma ROS 17/2.8 cells [4].
  • In the present study, we show that the potent FKBP-12 inhibitor V-10,367, which lacks the structural components of FK506 required for calcineurin inhibition, increases neurite outgrowth in SH-SY5Y neuroblastoma cells and speeds nerve regeneration in the rat sciatic nerve crush model [5].

High impact information on Fkbp1a

  • We report that a protein complex containing 245 kDa and 35 kDa components, designated rapamycin and FKBP12 targets 1 and 2 (RAFT1 and RAFT2), interacts with FKBP12 in a rapamycin-dependent manner [6].
  • The cellular function of FKBP12, a ubiquitously expressed 12,000-dalton proline isomerase, has been unknown [7].
  • By coexpressing the RyR and FKBP12 in insect cells, we have demonstrated that FKBP12 modulates channel gating by increasing channels with full conductance levels (by > 400%), decreasing open probability after caffeine activation (from 0.63 +/- 0.09 to 0.04 +/- 0.02), and increasing mean open time (from 4.4 +/- 0.6 ms to 75 +/- 41 ms) [7].
  • RyR1 function is modulated by proteins that bind to its large cytoplasmic scaffold domain, including the FK506 binding protein (FKBP12) and PKA [8].
  • RyR1 in skeletal muscle from animals with heart failure (HF), a chronic hyperadrenergic state, were PKA hyperphosphorylated, depleted of FKBP12, and exhibited increased activity, suggesting that the channels are "leaky." RyR1 PKA hyperphosphorylation correlated with impaired SR Ca2+ release and early fatigue in HF skeletal muscle [8].

Biological context of Fkbp1a

  • Whether FK506 affords neuroprotection that preserves penile erection through FKBP 12 upregulation is unclear [1].
  • We show that PKA phosphorylation of RyR1 at Ser2843 activates the channel by releasing FKBP12 [8].
  • Yeast expressing fusion proteins of the hormone binding domain of the rat glucocorticoid receptor fused to the LexA DNA-binding domain and FKBP12 fused to a transcriptional activation domain activated reporter genes when plated on medium containing the dexamethasone-FK506 heterodimer [9].
  • The rapamycin-mediated dimerization of FRB and FKBP12 also was studied in living mice by locating, quantifying, and timing the hRLUC complementation-based bioluminescence imaging signal using a cooled charged coupled device camera [10].
  • The time course for accumulation of FKBP-12 in sciatic nerve segments following nerve crush indicates rapid axonal transport at a rate similar to GAP-43 [11].

Anatomical context of Fkbp1a


Associations of Fkbp1a with chemical compounds

  • Cyclophilin is a ubiquitously expressed cytosolic peptidyl-prolyl cis-trans isomerase that is inhibited by the immunosuppressive drug cyclosporin A [14].
  • These data support our previous hypothesis [Halestrap & Davidson (1990) Biochem. J. 268, 153-160] that pore opening involves an interaction between matrix PPIase and the adenine nucleotide translocase [15].
  • 3. Neither ivermectin nor midecamycin removed FKBP12 from RyRs [16].
  • The NMR structures of the complexes formed between FKBP12 and ascomcyin or C24-deoxyascomcyin were very similar, suggesting that hydrogen-bonding interactions with the C24 hydroxyl moiety are not important for complex formation [17].
  • Physical interactions between the RyR and calcineurin were found in the CSMF in the presence of added 100 microM Ca(2+); however, the interactions were interrupted in the presence of 20 mM EGTA, 1 microM rapamycin or 1 microM FK506, suggesting that the interaction is Ca(2+)-dependent, and is mediated by FKBP12 [18].

Other interactions of Fkbp1a

  • RAFT1: a mammalian protein that binds to FKBP12 in a rapamycin-dependent fashion and is homologous to yeast TORs [6].
  • The presence of PEBP and FKBP12 in conditioned medium was confirmed immunologically [19].
  • We now demonstrate an association of FKBP-12 with neuronal regeneration and GAP-43 disposition [11].
  • Therefore, in the present study we characterised FKBP12 in osteoblasts and investigated the role of FK506 in modulating osteoblast-specific transcription factors, core-binding factor alpha1 (Cbfa1) and osterix gene expression in ROS 17/2.8 cells [4].
  • JNJ460 potentiated transforming growth factor beta (TGF-beta)-induced transcriptional activation and SCIP induction in Schwann cells, by altering the interaction between FKBP12 and the TGF-beta type I receptor, TbetaR1 [20].

Analytical, diagnostic and therapeutic context of Fkbp1a

  • Our demonstration that FKBP 12 is localized to penile innervation in the rat and becomes upregulated following cavernous nerve crush injury, independent of FK506 treatment, suggests that this immunophilin mediates a neurotrophic mechanism [1].
  • PHAS-I was phosphorylated more slowly by mTOR obtained either by immunoprecipitation with other antibodies or by affinity purification using a rapamycin/FKBP12 resin [21].
  • METHODS: Reverse transcription-polymerase chain reaction (RT-PCR) and Western blot analysis were performed on rat retinal tissue, and the immunophilin FKBP12 was found to be present in retina [22].
  • 6. The non-immunosuppressive CsA analogue [MeAla6]cyclosporin was shown to have a similar Ki to CsA on purified mitochondrial peptidyl-prolyl cis-trans-isomerase and mitochondrial pore opening, and also to have a similar protective effect against reperfusion injury [23].
  • FKBP12 was purified from epididymal plasma by FK506 affinity chromatography [24].


  1. FK506 binding protein 12 is expressed in rat penile innervation and upregulated after cavernous nerve injury. Sezen, S.F., Blackshaw, S., Steiner, J.P., Burnett, A.L. Int. J. Impot. Res. (2002) [Pubmed]
  2. Changes in peptidyl-prolyl cis/trans isomerase activity and FK506 binding protein expression following neuroprotection by FK506 in the ischemic rat brain. Brecht, S., Schwarze, K., Waetzig, V., Christner, C., Heiland, S., Fischer, G., Sartor, K., Herdegen, T. Neuroscience (2003) [Pubmed]
  3. Protection against ischemic brain damage in rats by immunophilin ligand GPI-1046. Li, F., Omori, N., Hayashi, T., Jin, G., Sato, K., Nagano, I., Shoji, M., Abe, K. J. Neurosci. Res. (2004) [Pubmed]
  4. Characterisation of cytosolic FK506 binding protein 12 and its role in modulating expression of Cbfa1 and osterix in ROS 17/2.8 cells. Varanasi, S.S., Datta, H.K. Bone (2005) [Pubmed]
  5. A nonimmunosuppressant FKBP-12 ligand increases nerve regeneration. Gold, B.G., Zeleny-Pooley, M., Wang, M.S., Chaturvedi, P., Armistead, D.M. Exp. Neurol. (1997) [Pubmed]
  6. RAFT1: a mammalian protein that binds to FKBP12 in a rapamycin-dependent fashion and is homologous to yeast TORs. Sabatini, D.M., Erdjument-Bromage, H., Lui, M., Tempst, P., Snyder, S.H. Cell (1994) [Pubmed]
  7. Stabilization of calcium release channel (ryanodine receptor) function by FK506-binding protein. Brillantes, A.B., Ondrias, K., Scott, A., Kobrinsky, E., Ondriasová, E., Moschella, M.C., Jayaraman, T., Landers, M., Ehrlich, B.E., Marks, A.R. Cell (1994) [Pubmed]
  8. PKA phosphorylation activates the calcium release channel (ryanodine receptor) in skeletal muscle: defective regulation in heart failure. Reiken, S., Lacampagne, A., Zhou, H., Kherani, A., Lehnart, S.E., Ward, C., Huang, F., Gaburjakova, M., Gaburjakova, J., Rosemblit, N., Warren, M.S., He, K.L., Yi, G.H., Wang, J., Burkhoff, D., Vassort, G., Marks, A.R. J. Cell Biol. (2003) [Pubmed]
  9. A three-hybrid system for detecting small ligand-protein receptor interactions. Licitra, E.J., Liu, J.O. Proc. Natl. Acad. Sci. U.S.A. (1996) [Pubmed]
  10. Molecular imaging of drug-modulated protein-protein interactions in living subjects. Paulmurugan, R., Massoud, T.F., Huang, J., Gambhir, S.S. Cancer Res. (2004) [Pubmed]
  11. Neuronal regeneration enhances the expression of the immunophilin FKBP-12. Lyons, W.E., Steiner, J.P., Snyder, S.H., Dawson, T.M. J. Neurosci. (1995) [Pubmed]
  12. Matrin CYP, an SR-rich cyclophilin that associates with the nuclear matrix and splicing factors. Mortillaro, M.J., Berezney, R. J. Biol. Chem. (1998) [Pubmed]
  13. Depletion of the mature CD4+8- thymocyte subset by FK506 analogs correlates with their immunosuppressive and calcineurin inhibitory activities. Koprak, S., Sirotina, A., Ok, H., Dumont, F.J. Transplantation (1996) [Pubmed]
  14. An endoplasmic reticulum-specific cyclophilin. Hasel, K.W., Glass, J.R., Godbout, M., Sutcliffe, J.G. Mol. Cell. Biol. (1991) [Pubmed]
  15. Further evidence that cyclosporin A protects mitochondria from calcium overload by inhibiting a matrix peptidyl-prolyl cis-trans isomerase. Implications for the immunosuppressive and toxic effects of cyclosporin. Griffiths, E.J., Halestrap, A.P. Biochem. J. (1991) [Pubmed]
  16. Effects of ivermectin and midecamycin on ryanodine receptors and the Ca2+-ATPase in sarcoplasmic reticulum of rabbit and rat skeletal muscle. Ahern, G.P., Junankar, P.R., Pace, S.M., Curtis, S., Mould, J.A., Dulhunty, A.F. J. Physiol. (Lond.) (1999) [Pubmed]
  17. Retention of immunosuppressant activity in an ascomycin analogue lacking a hydrogen-bonding interaction with FKBP12. Wiedeman, P.E., Fesik, S.W., Petros, A.M., Nettesheim, D.G., Mollison, K.W., Lane, B.C., Or, Y.S., Luly, J.R. J. Med. Chem. (1999) [Pubmed]
  18. Calcineurin regulates ryanodine receptor/Ca(2+)-release channels in rat heart. Bandyopadhyay, A., Shin, D.W., Ahn, J.O., Kim, D.H. Biochem. J. (2000) [Pubmed]
  19. Proteome analysis of conditioned medium from cultured adult hippocampal progenitors. Dahl, A., Eriksson, P.S., Persson, A.I., Karlsson, G., Davidsson, P., Ekman, R., Westman-Brinkmalm, A. Rapid Commun. Mass Spectrom. (2003) [Pubmed]
  20. A role for schwann cells in the neuroregenerative effects of a non-immunosuppressive fk506 derivative, jnj460. Birge, R.B., Wadsworth, S., Akakura, R., Abeysinghe, H., Kanojia, R., MacIelag, M., Desbarats, J., Escalante, M., Singh, K., Sundarababu, S., Parris, K., Childs, G., August, A., Siekierka, J., Weinstein, D.E. Neuroscience (2004) [Pubmed]
  21. The mammalian target of rapamycin phosphorylates sites having a (Ser/Thr)-Pro motif and is activated by antibodies to a region near its COOH terminus. Brunn, G.J., Fadden, P., Haystead, T.A., Lawrence, J.C. J. Biol. Chem. (1997) [Pubmed]
  22. The effects of FK506 on retinal ganglion cells after optic nerve crush. Freeman, E.E., Grosskreutz, C.L. Invest. Ophthalmol. Vis. Sci. (2000) [Pubmed]
  23. Mitochondrial non-specific pores remain closed during cardiac ischaemia, but open upon reperfusion. Griffiths, E.J., Halestrap, A.P. Biochem. J. (1995) [Pubmed]
  24. The 12 kD FK 506 binding protein FKBP12 is released in the male reproductive tract and stimulates sperm motility. Walensky, L.D., Dawson, T.M., Steiner, J.P., Sabatini, D.M., Suarez, J.D., Klinefelter, G.R., Snyder, S.H. Mol. Med. (1998) [Pubmed]
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