FK506-binding the brain, and appears to have been

FK506-binding proteins (FKBPs) are a large
family of proteins that possess peptidyl prolyl cis/trans isomerase (PPIase) domains. The founding member of this
family is FKBP12, which is a 107-amino acid peptide, containing the minimal
sequence for a PPIase. (Siekierka, Hung et
al. 1989) In the early 1990s, the discovery of
FKBP12 as the primary binding partner of the immunosuppressive agents FK506 and
rapamycin caused a wave of excitement within the scientific community and
triggered substantial interest in the endogenous function of this protein (Schreiber 1991). Other members
were subsequently identified in yeast, plants and mammals, based on their
sequence 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-kDa
cytosolic protein. Although first identified in immune cells, FKBP12 occurs
abundantly in all tissues, with particular high densities in the brain, and
appears to have been diverse functions (Snyder, Lai et
al. 1998). It is a member of the immunophilin
protein family that interacts with multiple intracellular protein complexes
such as two intracellular calcium release channels (the inositol
1,4,5-triphosphate receptor and the ryanodine receptor), bone morphogenetic (BMP)/activin/transforming
growth factor (TGF)? type-1 receptors (Serra and Moses 1996), voltage-gated
sodium channels, FK506 and rapamycin, and inhibits calcineurin and mammalian
target of rapamycin (mTOR) activity. This enzyme mediates the immunosuppressive
activities of the two macrolides, FK506 and rapamycin, by binding to the
macrolides and then recruiting, and thereby inactivating, the serine/threonine
phosphatase calcineurin and serine kinase FKBP12-rapamycin-associated protein (FRAP),
respectively. This results in the blockage of the signalling pathways by
calcineurin or FRAP (Harding, Galat et
al. 1989). Since FKBP12 is ubiquitous in
virtually all mammalian cell types and is highly conserved from plants to
animals, its physiological role is likely to be of high importance.  Since the identification
of the original FKBP12, numerous other FKBPs (FK506-binding proteins) have been
identified. The FKBPs are named for their affinity for FK506, a compound with
immunosuppressant properties originally isolated from Streptomyces tsukubaensis (Galat 2013). The variability
in domain organisation of FKBPs suggests that FKBPs have evolved to fill
changing roles within evolving organisms. Analysis of protein complexes in Saccharomyces cerevisiae has suggested
that FKBPs interact with distinct sets of proteins (Ho, Gruhler et
al. 2002) and have seemingly discrete
functions.  FKBP12
as an immunophilinFKBP12 was originally
identified as the primary binding target of FK506 and rapamycin. Both drugs
bind non-covalently to FKBP12 and inhibit its PPIase activity (Bierer, Mattila et
al. 1990). The drugs’ binding with FKBP12
allows the drugs to subsequently interact with the mechanistic targets of their
action in immunosuppression. The FK506-FKBP12 complex specifically interacts
with calcineurin (CaN), a calcium-dependent serine-threonine phosphatase (Liu, Farmer et
al. 1991), whereas the rapamycin-FKBP12
complex targets mammalian target of rapamycin. In T lymphocytes, CaN is
a key component in the T-cell receptor mediated signalling that is required for
activation. Activated CaN dephosphorylates nuclear factor of activated T cells
(NFAT) in the cytoplasm, allowing it to translocate into the nucleus, where it
cooperates with other nuclear transcription factors to initiate the
transcription programme for T cell activation. The FK506-FKBP12 complex binds
to CaN and blocks the access of NFAT to its catalytic site, preventing NFAT
dephosphorylation and consequently, T cell activation (Fig. 2.1). (Jain, McCafffrey et
al. 1993) 

The FKBP12- rapamycin
complex inhibits cytokine stimulated T lymphocyte proliferation. Cytokines, such
as interleukin-2 (IL-2), produced by activated T cells, bind to the cell
surface receptors to activate the phosphatidylinositol-3-kinase (PI3K)/protein
kinase B (AKT) pathway and the downstream effector mTOR (Abraham and Wiederrecht 1996). Activated mTOR
phosphorylates ribosomal protein 6 kinase (S6K) and eukaryotic initiation
factor 4E binding protein 1 (4EBP1), two factors involved in translation
initiation, resulting in an increase in protein synthesis, which in turn
promotes cell growth and cell proliferation. The rapamycin-FKBP12 complex
specifically binds to mTOR and interferes with its kinase function, thus
blocking cytokine-stimulated protein synthesis.

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