Fig. 1. Model of the
unactivated steroid receptor complex. Abbreviations: SR, steroid
receptor; S, steroid hormone; hsp90, 90-kDa heat shock protein;
hsp70, 70-kDa heat shock protein; p23, unique 23-kDa protein; FKBP52,
52-kDa FK506-binding immunophilin; CsA, cyclosporin A; Cyp40, 40-kDa
CsA-binding immunophilin; TAD, transcription activation domain; ID,
immune-reactive domain; BuGR, epitope for the BuGR anti-GR monoclonal
antibody; DBD, DNA-binding domain composed of two zinc (Z) finger
motifs; NLS, nuclear localization signal; and STD, signal
transduction domain. For all other aspects see text.
In
Fig. 1, a model of the macromolecular structure of untransformed
(unactivated) steroid receptor complexes is presented. This model is
based on the contributions of many laboratories. For detailed
information on the component nature of steroid receptors please see
the excellent reviews of Pratt and Toft (1), or Bohen and Yamamoto
(2). According to this model, the SR complex contains one molecule of
hormone-binding receptor (3), with the indicated functional domains
characteristic of steroid-induced transcription factors. In addition
to SR, the complex contains two molecules of hsp90 (3), and unknown
numbers of FKBP52 (hsp56) (4), cyclophilin-40 (Cyp40) (5) and p23
(6,7) molecules. The model also indicates the tentative presence of
hsp70. This heat shock protein has been found to co-purify with
progesterone receptors (8), but it does not co-purify with
glucocorticoid receptors (GR), except in CHO cells over-expressing
the mouse GR (9) and in insect cells containing the
baculovirus-expressed human GR (10). The binding of hsp90 to the SR
is indicated to occur in a region of the GR termed the Signal
Transduction Domain (11), but other regions of the much larger
hormone-binding domain have also been shown to contribute to hsp90
binding (12). The association of p23 with SRs has been shown to
require rapid and gentle purification procedures, and the binding of
p23 to the complex occurs through hsp90 (13). The FKBP52 immunophilin
(capable of binding the immunosuppressive drug FK506) has been shown
to associate with a variety of SRs (14-17), and this protein is also
referred to as FKBP59 (15), or as a heat shock
protein-binding immunophilin or HBI (16). In addition,
this protein has been shown to act as a heat shock protein in cell
subjected to stress and has thus been referred to as hsp56 (18). The
association of FKBP52 with the SR occurs through hsp90 (19). Cyp40 is
a recently discovered member of the immunophilin family, capable of
binding the immunosuppressive drug cyclosporin A (20), and its
association with steroid receptors also appears to occur via hsp90
(21,22). Most interestingly, recent evidence for distinct hsp90-Cyp40
and hsp90-FKBP52 complexes has been reported (21), suggesting that
hsp90 contains a single immunophilin binding site and that distinct
SR complexes may exist, each distinguishable by the presence of
FKBP52 or Cyp40 subunits. Indeed, a recent report has demonstrated
this to be the case for the mouse GR (5), although the relative
stoichiometry of FKBP52-containing versus Cyp40-containing GRs has
not been determined. This latest finding poses some interesting
questions. Are the two SR complexes functionally distinct? Is one the
precursor of the other?
References:
1. Pratt, W. B. and Toft, D. O. (1997) Endo. Rev. (in press)
2. Bohen, S. P. and Yamamoto, K. R. (1994) in The Biology of Heat Shock Proteins and Molecular Chaperones (Morimoto, R. I., Tissieres, A., and Georgopoulos, C., eds) pp. 313-334, Cold Spring Harbor Laboratory Press, Cold Spring Harbor
3. Denis, M., Wikstrom, A. C., and Gustafsson, J. -A. (1987) J. Biol. Chem. 262, 11803-11806
4. Tai, P. -K. K., Maeda, Y., Nakao, K., Wakim, N. G., Duhring, J. L., and Faber, L. E. (1986) Biochemistry 25, 5269-5275
5. Owens-Grillo, J. K., Hoffmann, K., Hutchison, K. A., Yem, A. W., Deibel, M. R.,Jr., Handschumacher, R. E., and Pratt, W. B. (1995) J. Biol. Chem. 270, 20479-20484
6. Smith, D. F., Faber, L. E., and Toft, D. O. (1990) J. Biol. Chem. 265, 3996-4003
7. Bresnick, E. H., Dalman, F. C., and Pratt, W. B. (1990) Biochemistry 29, 520-527
8. Estes, P. A., Suba, E. J., Lawler-Heavner, J., Elashry-Stowers, D., Wei, L. L., Toft, D. O., Sullivan, W. P., Horwitz, K. B., and Edwards, D. P. (1987) Biochemistry 26, 6250-6262
9. Sanchez, E. R., Hirst, M., Scherrer, L. C., Tang, H. -Y., Welsh, M. J., Harmon, J. M., Simons, S. S. Jr., Ringold, G. M., and Pratt, W. B. (1990) J. Biol. Chem. 265, 20123-20130
10. Srinivasan, G., Patel, N. T., and Thompson, E. B. (1994) Mol. Endocrinol. 8, 189-196
11. Housley, P. R., Sanchez, E. R., Danielsen, M., Ringold, G. M., and Pratt, W. B. (1990) J. Biol. Chem. 265, 12778-12781
12. Chambraud, B., Berry, M., Redeuilh, G., Chanbon, P., and Baulieu, E. E. (1990) J. Biol. Chem. 265, 20686-20691
13. Johnson, J. L. and Toft, D. O. (1995) Mol. Endocrinol. 9, 670-768
14. Yem, A. W., Tomasselli, A. G., Heinrikson, R. L., Zurcher-Neely, H., Ruff, V. A., Johnson, R. A., and Deibel, M. R. Jr. (1992) J. Biol. Chem. 267, 2868-2871
15. Tai, P. -K. K., Albers, M. W., Chang, H., Faber, L. E., and Schreiber, S. L. (1992) Science 256, 1315-1318
16. Callebaut, I., Renoir, J. -M., Lebeau, M. -C., Massol, N., Burny, A., Baulieu, E. -E., and Mornon, J. -P. (1992) Proc. Natl. Acad. Sci. USA 89, 6270-6274
17. Peattie, D. A., Harding, M. W., Fleming, M. A., Decenzo, M. T., Lippke, J. A., Livingston, D. J., and Benasutti, M (1992) Proc. Natl. Acad. Sci. USA 89, 10974-10978
18. Sanchez, E. R. (1990) J. Biol. Chem. 265, 22067-22070
19. Lebeau, M. C., Massol, N., Herrick, J., Faber, L. E., Renoir, J. M., Radanyi, C., and Baulieu, E. E. (1992) J. Biol. Chem. 267, 4281-4284
20. Kieffer, L. J., Seng, T. W., Li, W., Osterman, D. G., Handschumacher, R. E., and Bayney, R. M. (1993) J. Biol. Chem. 268, 12303-12310
21. Renoir, J. -M., Mercier-Bodard, C., Hoffmann, K., Bihan, S. L., Ning, Y. -M., Sanchez, E. R., Handschumacher, R. E., and Baulieu, E. -E. (1995) Proc. Natl. Acad. Sci. USA 92, 4977-4981
22. Ratajczak, T. and Carrello,
A. (1996) J. Biol. Chem. 271, 2961-2965
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