Molecular Cloning of Human FKBP51 and Comparisons of Immunophilin Interactions with Hsp90 and Progesterone Receptor

Abstract

A cDNA for human FKBP51 has been cloned and sequenced, and protein products have been expressed in both in vitro and bacterial systems. The deduced amino acid sequence for human FKBP51 is 90% identical to sequences of recently described murine proteins and is 55% identical to the sequence of human FKBP52. Human FKBP51 mRNA is expressed in a wide range of tissues, and the protein has peptidylprolyl isomerase activity that is inhibited by FK506 but not cyclosporine. FKBP51 is the same as a previously described progesterone receptor-associated immunophilin that, similar to FKBP52 and cyclophilin 40, is an Hsp90-binding protein and appears in functionally mature steroid receptor complexes along with Hsp90 and p23. Each of the three receptor-associated immunophilins displays interactions with progesterone receptor that are more dynamic than Hsp90-receptor interactions. Whereas FKBP52 and FKBP51 compete about equally well for binding to Hsp90 in a purified system, FKBP51 accumulates preferentially in progesterone receptor complexes assembled in a cell-free system. This observation provides a precedent for differential interactions between Hsp90-associated immunophilins and target proteins such as steroid receptors.

Failure of hormone therapy in prostate cancer involves systematic restoration of androgen responsive genes and activation of rapamycin sensitive signaling

“…In a few cases, expression levels in the recurrent tumors exceeded those observed in the primary tumors. For example, the FKBP5 gene, which encodes for a steroid receptor interacting immunophilin (Nair et al, 1997), was one of the most strongly repressed (ratio 50.2) genes during therapy (Figures 2c and 3c). In contrast, FKBP5 expression in the recurrent tumors was twofold higher than in the primary tumors (Figures 2c and 3c), as also suggested by another study (Amler et al, 2000).…”

The human FK506-binding proteins: characterization of human FKBP19

“…The nuclear FKBPs (FKBP25 and FKBP135; (Jin et al, 1992, Ishikawa et al, 1998 contain N-terminal domains of unknown function, and one or more nuclear localisation sequences. The TPR-domain FKBPs contain two or three FKBP domains and tetratricopeptide repeats (TPRs) within the C-terminal FKBP domain (FKBP36, FKBP37, FKBP38, FKBP51 and FKBP52; (Meng et al, 1998, Kuzhandaivelu et al, 1996, Lam et al, 1995, Nair et al, 1997, Peattie et al, 1992.…”

Progesterone Receptor Deficient in Chromatin Binding Has an Altered Cellular State

“…Association of PR and FKBP51 was then examined. FKBP51 has been shown previously to be the preferred immunophilin in mature PR complexes (25,31). We immunoprecipitated PR from the various extracts and examined association of FKBP51 by immunoblotting as shown in Fig.…”

“…Second, is the composition of the complexes different between the two functionally distinct forms of PR? In the unliganded state, the PR has been shown to associate with chaperone proteins in an ordered sequence ultimately resulting in a mature, hormonebinding competent complex containing hsp90, p23, and a large immunophilin, preferentially FKBP51 (25). To examine the chaperone composition of PR complexes and determine whether the sPR and the tPR are processed differently, a series of immunoprecipitation experiments were performed.…”