Chemistry Reference
In-Depth Information
S100A proteins belong to the EF-hand type calcium (Ca
2+
) sensing protein fam-
ily that are linked to regulation of various intracellular processes and are often ex-
pressed in a cell- and tissue-specific fashion (Santamaria-Kisiel et al.
2006
; Wright
et al.
2009
). Based on biochemical evidence, it has been demonstrated that S100A1
and S100A6 interact with FKBP52 by competing with Hsp90 for the TPR domain
in a Ca
2+
-dependent manner (Shimamoto et al.
2010
). Cellular data has linked
S100A1s involvement in the neuronal cell dysfunction/death that occurs in AD by
reducing APP expression and stabilizing the intracellular Ca
2+
homeostasis (Zimmer
et al.
2005
). It seems that the function of FKBP52 can be regulated by Ca
2+
homeo-
stasis within the cell leading to effects on the phosphorylation of tau and pathol-
ogy in AD. Interestingly, a Drosophila orthologue of FKBP52 termed FKBP59 was
found to interact with the Ca
2+
channel protein TRPL in photoreceptor cells and to
influence Ca
2+
influx (Goel et al.
2001
). Subsequent studies revealed that FKBP52
similarly interacts with a subset of rat transient receptor potential channel (TRPC)
proteins that form Ca
2+
channels in the mammalian brain (Sinkins et al.
2004
). The
C-terminus of FKBP52 contains a predicted calmodulin binding domain, which en-
ables the protein to bind to calmodulin-Sepharose in a Ca
2+
-dependent manner, the
biological function of which is still unknown (Silverstein et al.
1999
).
Apart from the well-established roles of FKBP52 in steroid hormone receptor
function, FKBP52, as with other Hsp90 co-chaperones, has been identified in a
variety of client-Hsp90 heterocomplexes such as those containing kinases, aryl
hydrocarbon receptor, and heat shock transcription factor; however, many of these
interactions might reflect passive, transient association of the protein with Hsp90
and have no functional impact on client activity. FKBP52 is also linked to various
Hsp90-independent interactions. Aside from the aforementioned Hsp90-indepen-
dent interactors, FKBP52 has been found to interact directly with the interferon
regulatory factor 4 (Mamane et al.
2000
), which regulates gene expression in B
and T lymphocytes, forms a complex with tyrosine kinase receptor RET51, which
is involved in the development and maintenance of the nervous system (Fusco
et al.
2010
) and FKBP associated protein 48 (Chambraud et al.
1996
), which in-
fluences proliferation of Jurkat T cells (Krummrei et al.
2003
). Each of these in-
teractions was found to be disrupted by FK506 and to target the FKBP52 PPIase
domain to specific proline sites in each partner protein. Phenotypes potentially
related to these interactions have not yet been assessed in 52KO mice. Not only
does FKBP52 interact with proteins, but also FKBP52 is capable of directly bind-
ing adeno-associated virus DNA and regulating replication of the viral genome
(Qing et al.
2001
; Zhong et al.
2004
). The relevant DNA binding site in FKBP52
has not been identified.
FKBP51
FKBP51/p54/FKBP54 was originally identified as a component of chicken PR
complexes (Smith et al.
1990
; Smith et al.
1993a
; Smith et al.
1993b
) and is now
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