Analysis of FKBP51/FKBP52 Chimeras and Mutants for Hsp90 Binding and Association with Progesterone Receptor Complexes
Open accessAbstract
FKBP51, FKBP52, and Cyp40 bind competitively to Hsp90 through their respective tetratricopeptide repeat (TPR) domains, and any one of the three immunophilins can be isolated in mature steroid receptor complexes. During cell-free assembly reactions, FKBP51 associates preferentially with progesterone and glucocorticoid receptors, but less preference is observed in FKBP51 association with estrogen receptor. A number of mutant FKBP forms were generated to map sequences responsible for FKBP51's preferred association with progesterone receptor. A double-point mutation in the peptidyl prolyl isomerase domain of FKBP51 that reduces enzymatic activity by greater than 90% had no observed effect on FKBP51 interactions with progesterone receptor or Hsp90. Coprecipitation of FKBP51 and FKBP52 truncation mutants with Hsp90 indicated that sequences both upstream and downstream of the TPR domain are necessary for Hsp90 binding. FKBP chimeric constructs were also generated and tested for Hsp90 binding and receptor association. The TPR domain of FKBP51 required appropriate downstream sequences for Hsp90 binding, but FKBP52's TPR domain did not. The C-terminal region of FKBP51 that functionally interacts with the TPR domain to permit Hsp90 binding also conferred preferential association with PR. In conclusion, despite the overall similarity of FKBP51 and FKBP52, these two immunophilins associate differentially with steroid receptors, and the difference relates to both the Hsp90-binding TPR domain and to poorly conserved C-terminal sequences.
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The M1 mutant form of FKBP51 has two amino acid changes in the FK1 domain that reduce prolyl isomerase activity.
“The M1 mutant form characterized by Smith and coworkers (2) has two amino acid changes in the FK1 domain that reduce prolyl isomerase activity.”
From FKBP51 Promotes Assembly of the Hsp90 Chaperone Complex and Regulates Androgen Receptor Signaling in Prostate Cancer Cells (2010) · cites this paper as [2]
In a reticulocyte lysate assembly system, PR complexes showed a preference for FKBP51, GR complexes preferred FKBP51 and PP5, and ER complexes preferred Cyp40.
“In a reticulocyte lysate assembly system, PR complexes showed a preference for FKBP51, GR complexes preferred FKBP51 and Protein Phosphatase 5 (PP5), and ER complexes preferred Cyclophilin 40 (Cyp40) [13].”
From FKBP51 and FKBP52 in signaling and disease (2011) · cites this paper as [13]
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“Hsp90 and p23, respectively, were previously described (32, 33).”
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Miyagawa, S., Matsumaru, D., Murashima, A., Omori, A., Satoh, Y., Haraguchi, R., Motoyama, J., Iguchi, T., Nakagata, N., Hui, C.-C., et al. (2011) · Endocrinology · doi:10.1210/en.2011-0263 · Cited by 78 · see citing works
Assembly and function of small RNA – Argonaute protein complexes
Dueck, A., & Meister, G. (2014) · Biological Chemistry · doi:10.1515/hsz-2014-0116 · Cited by 79 · see citing works
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“Both mutants have been previously reported to possess reduced catalytic activity toward artificial substrates (Barent et al., 1998; Tradler et al., 1997).”
Schmid, F. X. (2001) · Advances in protein chemistry · doi:10.1016/s0065-3233(01)59008-7 · Cited by 76 · see citing works
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“For example, FKBP5l is preferentially assembled with progesterone and glucocorticoid receptors in cell-free rabbit reticulocyte lysate [54].”
BackgroundKim, K.-Y., Choi, K.-C., Auersperg, N., & Leung, P. (2006) · Endocrine-Related Cancer · doi:10.1677/erc.1.01033 · Cited by 68 · see citing works
“Furthermore, pretreatment with GF109203X, which inhibits PKC by competing with ATP (Barent et al. 1998), abolished the activation of ERK1/2 induced by GnRH-I, II or TPA.”
BackgroundDenny, W. B., Prapapanich, V., Smith, D. F., & Scammell, J. (2005) · Endocrinology · doi:10.1210/en.2005-0027 · Cited by 68 · see citing works
“We tested the activities of chimeras of human and squirrel monkey FKBP51 in which most of the FK1 domain, [h26–133]smFKBP51, or the entire FK2 domain of squirrel monkey FKBP51, [h133–361]smFKBP51, was exchanged with the same region of human FKBP51 (see Fig.”
BackgroundInfluentialSelf-citationDeficiency of Immunophilin FKBP52 Promotes Endometriosis
Hirota, Y., Tranguch, S., Daikoku, T., Hasegawa, A., Osuga, Y., Taketani, Y., & Dey, S. K. (2008) · The American Journal of Pathology · doi:10.2353/ajpath.2008.080527 · Cited by 67 · see citing works
“Functionally mature steroid hormone receptors including that of PR consist of a receptor monomer, a 90-kDa heat shock protein (Hsp90) dimer, the cochaperone p23, and one of the four cochaperones containing a tetratricopeptide repeat that binds to Hsp90.”
BackgroundInfluentialMangé, A., Coyaud, É., Desmetz, C., Laurent, E., Béganton, B., Coopman, P., Raught, B., & Solassol, J. (2019) · Theranostics · doi:10.7150/thno.35561 · Cited by 66 · see citing works
“Mechanistically, many studies have reported that FKBP4 and FKBP5 exhibit an antagonistic role in the functions and activities of the steroid receptors GR, PR or mineralocorticoid receptors [52, 53, 54 ].”
BackgroundDenny, W. B., Valentine, D. L., Reynolds, P. D., Smith, D. F., & Scammell, J. G. (2000) · Endocrinology · doi:10.1210/en.141.11.4107 · Cited by 66 · see citing works
“It is unlikely to reside within the TPR domain, which is necessary for the interaction of FKBP51 with hsp90 (16, 45) but is virtually identical between human and squirrel monkey FKBP51.”
Self-citationKumar, P., Mark, P., Ward, B. K., Minchin, R., & Ratajczak, T. (2001) · Biochemical and Biophysical Research Communications - BBRC · doi:10.1006/bbrc.2001.4952 · Cited by 66 · see citing works
Interaction of the Hsp90 cochaperone cyclophilin 40 with Hsc70
Carrello, A., Allan, R. K., Morgan, S., Owen, B., Mok, D., Ward, B. K., Minchin, R., Toft, D., & Ratajczak, T. (2004) · Cell stress & chaperones (Print) · doi:10.1379/csc-26r.1 · Cited by 61 · see citing works
Cox, M. B., Riggs, D. L., Hessling, M., Schumacher, F., Buchner, J., & Smith, D. F. (2007) · Molecular Endocrinology · doi:10.1210/me.2006-0547 · Cited by 60 · see citing works
“The ability of the FKBP52 mutants to bind Hsp90 and to assemble in vitro with PR complexes were assessed by coimmunoprecipitation as described previously (30, 31).”
MethodSelf-citationMolecular mechanisms involved in progesterone receptor regulation of uterine function
Lee, K., Jeong, J., Tsai, M., Tsai, S. Y., Lydon, J. P., & DeMayo, F. J. (2006) · The Journal of Steroid Biochemistry and Molecular Biology · doi:10.1016/j.jsbmb.2006.09.006 · Cited by 61 · see citing works
“First, in vitro evidence demonstrates that Fkbp4 potentates Pgr transcriptional activity (Barent et al., 1998).”
BackgroundCisplatin Abrogates the Geldanamycin-induced Heat Shock Response
McCollum, A., Lukasiewicz, K. B., Teneyck, C., Lingle, W., Toft, D., & Erlichman, C. (2008) · Molecular Cancer Therapeutics · doi:10.1158/1535-7163.mct-08-0157 · Cited by 58
“H9010 mouse monoclonal antibody recognizing Hsp90 was previously described (32).”
BackgroundHaraguchi, H., Saito‐Fujita, T., Hirota, Y., Egashira, M., Matsumoto, L., Matsuo, M., Hiraoka, T., Koga, K., Yamauchi, N., Fukayama, M., et al. (2014) · Molecular Endocrinology · doi:10.1210/me.2014-1097 · Cited by 66 · see citing works
“FKBP52 is required for optimal PR activity, as evident from studies of Fkbp52 / mice in which PR activity is compromised with exacerbated estrogenic influence despite normal levels of PR and P4, resulting in implantation failure (19, 22).”
BackgroundXu, W.-P., Beebe, K., Chavez, J. D., Boysen, M., Lu, Y., Zuehlke, A., Keramisanou, D., Trepel, J., Prodromou, C., Mayer, M. P., et al. (2019) · Nature Communications · doi:10.1038/s41467-019-10463-y · Cited by 54 · see citing works
Macedo, J. A., Hesse, J., Turner, J. D., Meyer, J., Hellhammer, D. H., & Muller, C. P. (2008) · Psychoneuroendocrinology · doi:10.1016/j.psyneuen.2008.03.012 · Cited by 53 · see citing works
“nuclear distribution of steroid hormone receptors (Barent et al., 1998; Davies et al., 2002).”
Prapapanich, V., Chen, S.-Y., & Smith, D. F. (1998) · Molecular and Cellular Biology · doi:10.1128/mcb.18.2.944 · Cited by 54
Self-citationAlternative approaches to Hsp90 modulation for the treatment of cancer
Hall, J. A., Forsberg, L. K., & Blagg, B. (2014) · Future Medicinal Chemistry · doi:10.4155/fmc.14.89 · Cited by 50 · see citing works
“Other co-chaperones that exhibit client protein specificity are the peptidyl-prolyl isomerases (PPIases), and include FK506 binding protein (FKBP) 51, FKBP52, and cyclophylin (Cyp)40 [57,58].”
BackgroundAllan, A., Goggin, S. L., & Caldwell, K. K. (2014) · PLoS ONE · doi:10.1371/journal.pone.0096200 · Cited by 50 · see citing works
“Barent and colleagues [39] reported that, in the presence of FKBP51, FKBP52 and CYP40, GR-Hsp90 complexes bind preferentially to FKBP51.”
BackgroundThe Involvement of Mammalian and Plant FK506-Binding Proteins (FKBPs) in Development
Breiman, A., & Camus, I. (2002) · Transgenic research · doi:10.1023/a:1016331814412 · Cited by 50 · see citing works
“The unactivated steroid receptor heterocomplexes contain multidomain PPIases of the CyP and FKBP families that are composed of functional sequence motifs in addition to the catalytic core (Nair et al., 1997; Barent et al., 1998; Chen et al., 1998; Duina et al., 1998).”
HSP70 and HSP90 expression in leucocytes after exercise in moderately trained humans.
Shastry, S., Toft, D., & Joyner, M. (2002) · Acta Physiologica Scandinavica · doi:10.1046/j.1365-201x.2002.00979.x · Cited by 49 · see citing works
Chaperones in progesterone receptor complexes.
Smith, D. F. (2000) · Seminars in Cell and Developmental Biology · doi:10.1006/scdb.1999.0350 · Cited by 49 · see citing works
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Hsp90 co-chaperones, FKBP52 and Aha1, promote tau pathogenesis in aged wild-type mice
Criado‐Marrero, M., Gebru, N. T., Blazier, D. M., Gould, L. A., Baker, J. D., Beaulieu‐Abdelahad, D., & Blair, L. J. (2021) · Acta Neuropathologica Communications · doi:10.1186/s40478-021-01159-w · Cited by 51 · see citing works
“Dickey CA, Kamal A, Lundgren K, Klosak N, Bailey RM, Dunmore J, Ash P, Shoraka S, Zlatkovic J, Eckman CB et al (2007) The high‑affinity HSP90‑ CHIP complex recognizes and selectively degrades phosphorylated tau client proteins.”
BackgroundAn emerging role for comprehensive proteome analysis in human pregnancy research.
Shankar, R., Gude, N., Cullinane, F., Brennecke, S., Purcell, A., & Moses, E. (2005) · Reproduction · doi:10.1530/rep.1.00524 · Cited by 46 · see citing works
“FKBP52 (FK506 binding protein 4), an Hsp90 binding immunophilin and a co-chaperone of steroid hormone receptors (Barent et al. 1998), was observed to be downregulated in Hoxa102/2 mice and was selected for further investigation.”
Ruffaner‐Hanson, C. D., Noor, S., Sun, M. S., Solomon, E. R., Marquez, L. E., Rodriguez, D. E., Allan, A. M., Caldwell, K. K., Bakhireva, L. N., & Milligan, E. D. (2022) · Experimental Neurology · doi:10.1016/j.expneurol.2022.114121 · Cited by 52 · see citing works
“Additionally, in the presence of both FKBP52 and FKBP51, GRs preferentially associate with FKBP51 (Barent et al., 1998), further supporting the role of FKBP51 as a factor capable of mediating GR insensitivity.”
BackgroundLone, S. N. (2018) · Biological Chemistry · doi:10.1515/hsz-2017-0329 · Cited by 57 · see citing works
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Calcium‐ and FK506‐independent interaction between the immunophilin FKBP51 and calcineurin*
Li, T., Baksh, S., Cristillo, A. D., & Bierer, B. E. (2002) · Journal of Cellular Biochemistry · doi:10.1002/jcb.10026 · Cited by 40 · see citing works
“In a number of proteins, the TPR-containing sequences mediate binding to heat shock protein (HSP)90 [Barent et al., 1998; Young et al., 1998].”
BackgroundInfluentialPromotion of Myoblast Differentiation by Fkbp5 via Cdk4 Isomerization
Ruiz-Estevez, M., Staats, J., Paatela, E., Munson, D., Katoku-Kikyo, N., Yuan, C., Asakura, Y., Hostager, R., Kobayashi, H., Asakura, A., et al. (2018) · Cell Reports · doi:10.1016/j.celrep.2018.11.006 · Cited by 39 · see citing works
“Fkbp5FD67DV lacked PPIase activity due to the replacement of the two amino acids FD with DV at the mouth of the PPIase pocket, potentially causing a major conformational change of the PPIase domain (Barent et al., 1998; Riggs et al., 2007).”
Background
- Authors
- Barent, R. L., Nair, S. C., Carr, D. C., Ruan, Y., Rimerman, R. A., Fulton, J., Zhang, Y., & Smith, D. F.
- Affiliations
- University of Nebraska Medical Center (US)
- Corresponding author
- Smith, David F.
- Venue
- Molecular Endocrinology
- Publisher
- The Endocrine Society
- Published
- 1998-03
- Volume
- 12
- Issue
- 3
- Pages
- 342-354
- ISSN
- 0888-8809 (ISSN-L)
- 1944-9917
- OpenAlex
- W2094984646
- Cited by
- 190
- References
- 0
- Citations by year
- 2026: 1 · 2025: 2 · 2024: 3 · 2023: 5 · 2022: 6 · 2021: 5 · 2020: 4 · 2019: 8 · 2018: 4 · 2017: 3 · 2016: 2 · 2015: 8 · 2014: 11 · 2013: 10 · 2012: 6
- FWCI
- 3.73
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Molecular Endocrinology (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health
- U.S. Public Health Service (R01-48218)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Heat shock proteins research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Signaling Pathways in Disease
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Estrogen and related hormone effects
- Keywords
- FKBP51, FKBP52, immunophilins, HSP90, tetratricopeptide repeat domain, progesterone receptor, steroid-receptor complex, peptidyl-prolyl isomerase, glucocorticoid receptor, estrogen receptor, chimeric constructs, mutant analysis, C-terminal interaction, steroid receptor coactivators
- MeSH terms
- Amino Acid Sequence, Binding Sites, Carrier Proteins, DNA-Binding Proteins, Heat-Shock Proteins, Molecular Sequence Data, Mutation, Receptors, Progesterone, Recombinant Proteins, HSP90 Heat-Shock Proteins, Peptidylprolyl Isomerase, Tacrolimus Binding Proteins
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