Functions of the Hsp90-Binding FKBP Immunophilins - The Networking of Chaperones by Co-chaperones - page 36

Fig. 2.1 Domain organization of representative Hsp90-binding TPR-containing FKBPs from ver-
tebrate, insect, and plant sources were selected for comparison of domain organizations. The pro-
teins are human FKBP52 (acc. # NP_002005), human FKBP51 (acc. # Q13451), human FKBPL
(acc. # NP_071393.2), human Xap2 (acc. # O00170), human FKBP36 (acc. # NP_003593),
human FKBP38 (acc. # NP_036313.3), Drosophila melanogaster FKBP59 (acc. # AAF18387),
Arabadopsis thaliana FKBP42 (acc. # CAC00654), and Arabadopsis thaliana FKBP62 (acc. #
AAB82062). The percent amino acid identity of each compared to human FKBP52 was deter-
mined from ClustalW2 alignments (http://www.ebi.ac.uk/clustalw). Each protein shown has at
least one FKBP12-like domain (FK), which in some cases has peptidylprolyl isomerase activity
and is the binding site for the immunosuppressant drug FK506, and one tetratricopeptide repeat
domain (TPR), which is typically an Hsp90 binding site. The black box in the C-terminus of
AtFKBP42 is a transmembrane domain used for anchoring the protein to the plasma and vacuolar
membranes
receptor complex are p23, a co-chaperone that stabilizes Hsp90 binding to receptor,
and any one of several TPR co-chaperones, including the immunophilin/PPIases
FKBP52 (also termed p59, Hsp56, p50, HBI, FKBP59, and FKBP4), FKBP51 (also
termed p54, FKBP54, and FKBP5), and CyP40, or the protein phosphatase PP5.
As discussed below, receptor activity can vary depending on the particular TPR co-
chaperone in mature receptor heterocomplexes.
The domain organization for several TPR co-chaperones is compared in Fig. 2.1 .
These co-chaperones compete for a common binding site in the C-terminal region
of Hsp90 that includes the highly conserved -MEEVD sequence that terminates
Hsp90. Co-crystallographic structures have shown how an MEEVD pentapeptide
associates with the TPR binding pocket (Scheufler et al. 2000 ; Wu et al. 2004 ).
Although the TPR domains for each of these co-chaperones are structurally similar
and interact in a similar manner with Hsp90, the client protein bound by Hsp90 can
influence the rank order of co-chaperone recruitment to Hsp90-client complexes
(reviewed in Riggs et al. 2004 ). For instance, PP5 and FKBP51 are preferred com-
ponents in glucocorticoid receptor (GR) complexes, FKBP51 is preferred in pro-
gesterone receptor (PR) complexes, and CyP40 is relatively enhanced in estrogen
receptor (ER) complexes (Silverstein et al. 1997 ; Barent et al. 1998 ). On the other