Functions of the Hsp90-Binding FKBP Immunophilins - The Networking of Chaperones by Co-chaperones - page 50

Xap2
Apart from the highly characterized steroid hormone receptor-associated FKBPs,
several other TPR-containing FKBPs are present in higher vertebrates. As men-
tioned in earlier sections of this chapter, Xap2 is a TPR-containing immunophilin
that is found almost extensively in AhR complexes. As the name implies, Xap2
also functionally interacts with the hepatitis B virus protein X (Kuzhandaivelu
et al. 1996 ). Recently, Xap2 was shown to exert an inhibitory effect on both GR
and ERα, but not ERʲ activity, and may inhibit AR and PR as well (Cai et al. 2011 ;
Laenger et al. 2009 ; Schulke et al. 2010 ). In addition, Xap2 is known to have
functional interactions with peroxisome proliferator activated receptor α (PPARα)
(Sumanasekera et al. 2003 ) and thyroid hormone receptor ʲ, however, these in-
teractions have not been extensively characterized. AhR is a ligand-dependent
transcription factor that mediates the physiological response to specific environ-
mental contaminants termed polycyclic aromatic hydrocarbons, the most notori-
ous of which is 2,3,7,8-tetrachlorodibenzo-p-dioxin. Similar to steroid receptors,
AhR requires assembly with Hsp90 and p23 to achieve a mature ligand-binding
conformation (reviewed in Petrulis and Perdew 2002 ), although the AhR ligand
binding domain is unrelated to steroid receptor ligand binding domains. AhR com-
plexes also contain an FKBP component, but in this case it is Xap2 rather FKBP52
or FKBP51.
As with FKBP51 and FKBP52, Xap2 has a C-terminal TPR domain that is
known to facilitate binding to the MEEVD motif on Hsp90 (Carver et al. 1998 )
(Fig. 2.1 ). In addition Xap2 contains one N-terminal FK domain that lacks drug
binding and also likely lacks PPIase activity. Although the FK domain is not re-
quired for Hsp90 binding, it is required for an interaction with the AhR-Hsp90
complex that functionally influences receptor activity (Carver et al. 1998 ; Kazlaus-
kas et al. 2002 ). In a cell-free assembly system that lacks Xap2, AhR is capable
of assembling with Hsp90 and binding ligand, and upon ligand binding AhR is
capable of binding AhR response elements on DNA (Meyer et al. 1998 ). Again,
similar to FKBP52 or FKBP51 in steroid receptor complexes, Xap2 is not required
for basal maturation of AhR activity, but in both yeast and mammalian systems,
Xap2 can modulate AhR-mediated reporter gene expression (Miller 2002 ; Ma and
Whitlock 1997 ; Meyer et al. 1998 ; Carver et al. 1998 ). By titrating the relative level
of Xap2 protein in cells, AhR activity can be enhanced or decreased. For example,
when Xap2 is expressed at a level 2- to 3-fold higher than normal, binding of p23
in the AhR-Hsp90 complex is reduced (Hollingshead et al. 2004 ). Displacement
of p23 by high levels of Xap2 would destabilize binding of Hsp90 to AhR and
reduce the proportion of AhR in functionally mature complexes. Conversely, there
is also evidence that at elevated Xap2 levels, AhR is protected from ubiquitination
and proteosomal degradation which would increase total AhR levels (Lees et al.
2003 ; LaPres et al. 2000 ; Meyer et al. 2000 ; Meyer and Perdew 1999 ; Kazlauskas
et al. 2000 ). Finally, several studies suggest that Xap2 facilitates nucleocytoplasmic
shuttling of AhR following ligand binding (Berg and Pongratz 2002 ; Petrulis et al.
2000 ; Kazlauskas et al. 2000 ; Kazlauskas et al. 2001 ; Petrulis et al. 2003 ).