FK506-binding by calcineurin or FRAP (Harding, Galat

FK506-binding proteins (FKBPs) are a largefamily of proteins that possess peptidyl prolyl cis/trans isomerase (PPIase) domains. The founding member of thisfamily is FKBP12, which is a 107-amino acid peptide, containing the minimalsequence for a PPIase. (Siekierka, Hung etal. 1989) In the early 1990s, the discovery ofFKBP12 as the primary binding partner of the immunosuppressive agents FK506 andrapamycin caused a wave of excitement within the scientific community andtriggered substantial interest in the endogenous function of this protein (Schreiber 1991). Other memberswere subsequently identified in yeast, plants and mammals, based on theirsequence similarity to FKBP12. The closest homologue of FKBP12 is FKBP12.

6,which displays 83% sequence identity to FKBP12 (Timerman, Jayaraman et al. 1994). FKBP12, also known as Fkbp1a, is a 12-kDacytosolic protein. Although first identified in immune cells, FKBP12 occursabundantly in all tissues, with particular high densities in the brain, andappears to have been diverse functions (Snyder, Lai etal. 1998). It is a member of the immunophilinprotein family that interacts with multiple intracellular protein complexessuch as two intracellular calcium release channels (the inositol1,4,5-triphosphate receptor and the ryanodine receptor), bone morphogenetic (BMP)/activin/transforminggrowth factor (TGF)? type-1 receptors (Serra and Moses 1996), voltage-gatedsodium channels, FK506 and rapamycin, and inhibits calcineurin and mammaliantarget of rapamycin (mTOR) activity.

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This enzyme mediates the immunosuppressiveactivities of the two macrolides, FK506 and rapamycin, by binding to themacrolides and then recruiting, and thereby inactivating, the serine/threoninephosphatase calcineurin and serine kinase FKBP12-rapamycin-associated protein (FRAP),respectively. This results in the blockage of the signalling pathways bycalcineurin or FRAP (Harding, Galat etal. 1989). Since FKBP12 is ubiquitous invirtually all mammalian cell types and is highly conserved from plants toanimals, its physiological role is likely to be of high importance.  Since the identificationof the original FKBP12, numerous other FKBPs (FK506-binding proteins) have beenidentified. The FKBPs are named for their affinity for FK506, a compound withimmunosuppressant properties originally isolated from Streptomyces tsukubaensis (Galat 2013). The variabilityin domain organisation of FKBPs suggests that FKBPs have evolved to fillchanging roles within evolving organisms. Analysis of protein complexes in Saccharomyces cerevisiae has suggestedthat FKBPs interact with distinct sets of proteins (Ho, Gruhler etal.

2002) and have seemingly discretefunctions.  FKBP12as an immunophilinFKBP12 was originallyidentified as the primary binding target of FK506 and rapamycin. Both drugsbind non-covalently to FKBP12 and inhibit its PPIase activity (Bierer, Mattila etal. 1990). The drugs’ binding with FKBP12allows the drugs to subsequently interact with the mechanistic targets of theiraction in immunosuppression.

The FK506-FKBP12 complex specifically interactswith calcineurin (CaN), a calcium-dependent serine-threonine phosphatase (Liu, Farmer etal. 1991), whereas the rapamycin-FKBP12complex targets mammalian target of rapamycin. In T lymphocytes, CaN isa key component in the T-cell receptor mediated signalling that is required foractivation. Activated CaN dephosphorylates nuclear factor of activated T cells(NFAT) in the cytoplasm, allowing it to translocate into the nucleus, where itcooperates with other nuclear transcription factors to initiate thetranscription programme for T cell activation.

The FK506-FKBP12 complex bindsto CaN and blocks the access of NFAT to its catalytic site, preventing NFATdephosphorylation and consequently, T cell activation (Fig. 2.1). (Jain, McCafffrey etal. 1993) The FKBP12- rapamycincomplex inhibits cytokine stimulated T lymphocyte proliferation.

Cytokines, suchas interleukin-2 (IL-2), produced by activated T cells, bind to the cellsurface receptors to activate the phosphatidylinositol-3-kinase (PI3K)/proteinkinase B (AKT) pathway and the downstream effector mTOR (Abraham and Wiederrecht 1996). Activated mTORphosphorylates ribosomal protein 6 kinase (S6K) and eukaryotic initiationfactor 4E binding protein 1 (4EBP1), two factors involved in translationinitiation, resulting in an increase in protein synthesis, which in turnpromotes cell growth and cell proliferation. The rapamycin-FKBP12 complexspecifically binds to mTOR and interferes with its kinase function, thusblocking cytokine-stimulated protein synthesis.


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