Functions of the Hsp90-Binding FKBP Immunophilins - The Networking of Chaperones by Co-chaperones - page 44

known to assemble as an Hsp90 co-chaperone with all steroid receptors and other
Hsp90-client complexes. FKBP51 is functionally similar in some ways to FKBP52;
both have similar PPIase activity in the presence of model peptide substrates, both
hold misfolded proteins in a folding competent state, and they compete for binding
a common site on Hsp90 (Nair et al. 1997 ; Pirkl et al. 2001 ). As noted above, the
overall structural similarity of these FKBPs is consistent with these shared function-
al properties, yet their distinct effects on steroid receptor activity belie these simi-
larities. In addition to the aforementioned structural differences between FKBP51
and FKBP52, another distinction is that the FKBP51 gene is highly inducible by
glucocorticoids, androgens, and progesterone (Baughman et al. 1995 ; Kester et al.
1997 ; Zhu et al. 2001 ; Yoshida et al. 2002 ; Vermeer et al. 2003 ; Hubler et al. 2003 ;
Febbo et al. 2005 ).
FKBP51 acts as an inhibitor of GR, PR, and MR function excluding AR. The
first indication of its inhibitory role came from studies by Scammell and colleagues
of glucocorticoid resistance in New World primates (Reynolds et al. 1999 ; Denny
et al. 2000 ). In squirrel monkeys, GR has a relatively low affinity for hormone yet
the cloned monkey GR has an affinity similar to human GR in vitro . This observa-
tion led to a search for cellular factors in monkey cells that reduced GR binding
affinity. A key factor identified was FKBP51, which is constitutively overexpressed
in squirrel monkey cells as well as cells of other New World primates, all of which
display some degree of glucocorticoid resistance. Human FKBP51 was also found
to inhibit GR function but not to the degree of squirrel monkey FKBP51, which dif-
fers in amino acid sequence from its human counterpart at 15 of 457 amino acids.
These differences are scattered fair evenly along the sequence, and mapping stud-
ies have shown that amino acid changes in several domains contribute to the more
potent inhibitory actions of squirrel monkey FKBP51 (Denny et al. 2005 ). Crystal
structures for both human and squirrel monkey FKBP51 have been solved (Sinars
et al. 2003 ); although functionally relevant structural changes are not yet apparent,
comparison of these structures should ultimately help to understand why inhibitory
potencies differ. The function of FKBP51 is dichotomous with respect to regulation
of the steroid hormone receptors. In vitro experiments have shown that overex-
pression of human FKBP51 reduces glucocorticoid binding affinity and nuclear
translocation of GR which forms an ultra-short negative feedback loop for receptor
activity (Wochnik et al. 2005 ). This model is in agreement with the aforementioned
data from squirrel monkeys that have a general resistance to glucocorticoids even
though they express GR that has the full potential to bind cortisol with high affinity.
Another interesting possibility by which FKBP51 decreases overall GR signaling
is by promoting nuclear translocation of the transcriptionally inactive ʲ isoform of
GR (Zhang et al. 2008 ). Interestingly, FKBP51 has an opposing effect on AR; it
increases the receptor signaling in prostate cancer cells. Using both recombinant
protein- and cell-based assays, Ni et al . demonstrated that FKBP51 stimulates chap-
erone complex association with AR, which further enhances AR ligand binding and
androgen-dependent transcription and cell growth, resulting in an ultra-short posi-
tive feedback loop (Ni et al. 2010 ).