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Event Title

Binding of FK506 to FKBP12, Formation

Key Event Overview

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AOPs Including This Key Event

AOP Name Event Type Essentiality
The Adverse Outcome Pathway on binding of FK506-binding protein 12 (FKBP12) by calcineurin inhibitors leading to immunosuppression MIE Strong

Chemical Initiators

The following are chemical initiators that operate directly through this Event:

Taxonomic Applicability

Name Scientific Name Evidence Links

Level of Biological Organization

Biological Organization

How this Key Event works

FKBP12 is a 12-kDa protein localized in cytoplasm and has been isolated from Jurkat T-cells as a receptor that binds with the calcineurin inhibitor FK506 (Bram et al. 1993). FKBP12 has an FK506-binding domain (FKBD) that comprises 108 amino acids, and it functions as an accessory molecule to classes of intracellular calcium channels, namely IP3 receptors and ryanodine receptors (RyRs) (Schreiber and Crabtree 1992, Cameron et al. 1997). In addition, FKBP12 binds to transforming growth factor-β receptor 1 (TGF-βR1) and acts as a natural ligand to TGF-β. While FKBP12, FKBP12.6, FKBP13, and FKBP52 are all part of the FK506-binding FKBP family, FKBP12 has a significant involvement in the mechanism of action for FK506-induced immunosuppression (Siekierka et al. 1989a, Kang et al. 2008). FKBP12 demonstrates peptidylprolyl cis-trans isomerase (PPIase) activity as well as the ability to inhibit calcineurin activity when forming a complex with FK506. FKBP12.6 shows similar actions,, however, its influences are weaker than those of FKBP12 and its involvement in immunosuppression is not yet clearly understood. In addition to T-cells, FKBP12 is also expressed in B-cells, Langerhans cells, and mast cells (Siekierka et al. 1990, Panhans-Gross et al. 2001, Hultsch et al. 1991).

How it is Measured or Detected

The binding of FK-506 with FKBP12 can simply be detected by ELISA or competitive ELISA. Siekierka et al. (1989a) conducted that purified FK-506 binding protein coated onto the surface of plate wells and the amount of 3H dihydro FK-506 were incubated. In the competitive ELISA, unlabeled FK506 was used as the competitor.

Evidence Supporting Taxonomic Applicability

FKBP is found in a wide variety of organisms, from prokaryotes to multicellular organisms (Siekierka et al. 1989a). Multiple subfamilies of FKBP have been reported, with at least eight types having been found in mammals. FKBP12 is reported to be expressed in B-cells, Langerhans cells and mast cells as well as T cells of mammalian species including humans and mice.


[1] Bram, R.J., Hung, D.T., Martin, P.K., Schreiber, S.L. and Crabtree, G.R. (1993). Identification of the immunophilins capable of mediating inhibition of signal transduction by cyclosporin A and FK506: roles of calcimeurin binding and cellular location. Molecular and cellular biology 13 (8): 4760-9.

[2] Cameron, A.M., Nucifora, F.C. Jr., Fung, E.T., Livingston, D.J., Aldape, R.A., Ross, C.A. and Snyder, S.H. (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 272 (44): 27582-8.

[3] Hultsch, T., Albers, M. W., Schreiber, S.L. and Hohman, R. J. (1991). Immunophilin ligands demonstrate common features of signal transduction leading to exocytosis or transcription. Proceedings of the national academic science of the United States of America. 14: 6229-6233.

[4] Kang, C. B., Hong, Y., Dhe-Paganon, S. and Yoon, H. S. (2008). FKBP family proteins: immunophilins with versatile biological function. Neurosignals. 16: 318-325.

[5] Panhans-Gross, A., Novak, N., Kraft, S., and Bieber, T. (2001). Human epidermal Langerhans’ cells are targets for the immunosuppressive macrolide tacrolimus (FK506). Journal of Allergy and Clinical Immunology 107(2): 345-52.

[6] Schreiber, SL., and Crabtree, GR. (1992). The mechanism of action of cyclosporin A and FK506. Immunology Today 13(4): 136-42.

[7] Siekierka, JJ., Hung, SH., Poe, M., Lin, CS., and Sigal, NH. (1989a). A cytosolic binding protein for the immunosuppressant FK506 has peptidyl-prolyl isomerase activity but is distinct from cyclophilin. Nature 341(6244): 755-57.

[8] Siekierka, JJ., Wiederrecht, G., Greulich, H., Boulton, D., Hung, SH., Cryan, J., Hodges, PJ., and Sigal, NH. (1990). The cytosolic-binding protein for the immunosuppressant FK-506 is both a ubiquitous an highly conserved peptidyl-prolyl cis-trans isomerase. Journal of Biological Chemistry 265(34): 21011-5.