Functions of the Hsp90-Binding FKBP Immunophilins - The Networking of Chaperones by Co-chaperones - page 37

hand, another TPR-containing FKBP, the hepatitis B virus protein X associated
protein 2 (Xap2; also termed AIP, ARA9, and FKBP37) shows little interaction
with steroid receptors but is strongly associated with the aryl hydrocarbon receptor-
Hsp90 complex (Ma and Whitlock 1997 ; Meyer et al. 1998 ). The distinctive pat-
terns of preference for co-chaperone association in client complexes is one line of
evidence that the co-chaperones bound to Hsp90 can also interact with the Hsp90-
bound client.
In addition to FKBP52, FKBP51, and XAP2, several other FKBP family mem-
bers contain TPR domains that are known or likely to bind Hsp90. FKBP36 is
structurally similar to XAP2 but is required for male fertility and homologous
chromosome pairing in meiosis (Crackower et al. 2003 ). FKBP38 is a unique fam-
ily member that is anchored to the mitochondrial and endoplasmic reticulum mem-
branes, and is involved in a variety of processes including protein folding and
trafficking, apoptosis, neural tube formation, cystic fibrosis transmembrane con-
ductance regulator (CFTR) trafficking, and viral replication (reviewed in Edlich
and Lucke 2011 ). FK506-binding protein like (FKBPL) protein is a divergent
member of the FKBP family that can associate and functionally regulate steroid
hormone receptors, has antiangiogenic properties, has a role in the DNA dam-
age response, and controls tumor growth (reviewed in Robson and James 2012 ).
Drosophila melanogaster express a TPR-containing immunophilin (DmFKBP59)
that has high similarity to FKBP52/51 in vertebrates (Goel et al. 2001 ; Zaffran
2000 ). Plants have several FKBP genes that encode TPR domains; for example, in
Arabidopsis thaliana there are 4 such genes: AtFKBP42, AtFKBP62, AtFKBP65
and AtFKBP72 (Romano et al. 2005; He et al. 2004 ). Although prokaryotic and
Archaeal genomes also contain FKBP family members (Maruyama et al. 2004 ),
none of these genes encode a TPR domain.
Structure/Function Relationships of Steroid
Receptor-Associated FKBPs
X-ray crystallographic structures have been resolved for full-length FKBP51 and
for overlapping fragments of FKBP52 (Fig. 2.2 ). FKBP51 and FKBP52 share
greater than 60 % amino acid sequence similarity, and individual domains do not
differ markedly between FKBP51 and FKBP52. Both share a similar TPR domain
composed of three tandem repeats of the degenerate 34-amino acid motif, which is a
typical characteristic of TPR proteins (Blatch and Lassle 1999 ). Each repeat adopts
a helix-turn-helix conformation and adjacent units stack in parallel to form a saddle-
shaped domain with a concave binding pocket for Hsp90. In addition to the TPR
domain, both FKBP51 and FKBP52 have two N-terminal domains, each of which
is structurally similar to FKBP12. FK506-binding and PPIase activities reside in the
most N-terminal domain (FK1), which has a pocket and active site residues similar
to FKBP12. Due to several amino acid differences, the second domain (FK2) lacks
drug binding and PPIase activity (Sinars et al. 2003 ).