Coupling of conformational transitions in the N-terminal domain of the 51-kDa FK506-binding protein (FKBP51) near its site of interaction with the steroid receptor proteins
Abstract
Interchanging Leu-119 for Pro-119 at the tip of the β4-β5 loop in the first FK506 binding domain (FK1) of the FKBP51 and FKBP52 proteins, respectively, has been reported to largely reverse the inhibitory (FKBP51) or stimulatory (FKBP52) effects of these co-chaperones on the transcriptional activity of glucocorticoid and androgen receptor-protein complexes. Previous NMR relaxation studies have identified exchange line broadening, indicative of submillisecond conformational motion, throughout the β4-β5 loop in the FK1 domain of FKBP51, which are suppressed by the FKBP52-like L119P substitution. This substitution also attenuates exchange line broadening in the underlying β2 and β3a strands that is centered near a bifurcated main chain hydrogen bond interaction between these two strands. The present study demonstrates that these exchange line broadening effects arise from two distinct coupled conformational transitions, and the transition within the β2 and β3a strands samples a transient conformation that resembles the crystal structures of the selectively inhibited FK1 domain of FKBP51 recently reported. Although the crystal structures for their series of inhibitors were interpreted as evidence for an induced fit mechanism of association, the presence of a similar conformation being significantly populated in the unliganded FKBP51 domain is more consistent with a conformational selection binding process.more »
- Authors:
-
- New York State Dept. of Health, Albany, NY (United States); Univ. at Albany, SUNY, Albany, NY (United States)
- New York State Dept. of Health, Albany, NY (United States)
- Brookhaven National Lab. (BNL), Upton, NY (United States)
- Publication Date:
- Research Org.:
- Brookhaven National Laboratory (BNL), Upton, NY (United States)
- Sponsoring Org.:
- USDOE Office of Science (SC), Basic Energy Sciences (BES)
- OSTI Identifier:
- 1341503
- Report Number(s):
- BNL-108430-2015-JA
Journal ID: ISSN 0021-9258; R&D Project: LS001
- Grant/Contract Number:
- SC00112704
- Resource Type:
- Journal Article: Accepted Manuscript
- Journal Name:
- Journal of Biological Chemistry
- Additional Journal Information:
- Journal Volume: 290; Journal Issue: 25; Journal ID: ISSN 0021-9258
- Publisher:
- American Society for Biochemistry and Molecular Biology
- Country of Publication:
- United States
- Language:
- English
- Subject:
- 36 MATERIALS SCIENCE; allosteric regulation; conformational change; nuclear magnetic resonance (NMR); prolyl isomerase; x-ray crystallography
Citation Formats
LeMaster, David M., Mustafi, Sourajit M., Brecher, Matthew, Zhang, Jing, Heroux, Annie, Li, Hongmin, and Hernandez, Griselda. Coupling of conformational transitions in the N-terminal domain of the 51-kDa FK506-binding protein (FKBP51) near its site of interaction with the steroid receptor proteins. United States: N. p., 2015.
Web. doi:10.1074/jbc.M115.650655.
LeMaster, David M., Mustafi, Sourajit M., Brecher, Matthew, Zhang, Jing, Heroux, Annie, Li, Hongmin, & Hernandez, Griselda. Coupling of conformational transitions in the N-terminal domain of the 51-kDa FK506-binding protein (FKBP51) near its site of interaction with the steroid receptor proteins. United States. https://doi.org/10.1074/jbc.M115.650655
LeMaster, David M., Mustafi, Sourajit M., Brecher, Matthew, Zhang, Jing, Heroux, Annie, Li, Hongmin, and Hernandez, Griselda. 2015.
"Coupling of conformational transitions in the N-terminal domain of the 51-kDa FK506-binding protein (FKBP51) near its site of interaction with the steroid receptor proteins". United States. https://doi.org/10.1074/jbc.M115.650655. https://www.osti.gov/servlets/purl/1341503.
@article{osti_1341503,
title = {Coupling of conformational transitions in the N-terminal domain of the 51-kDa FK506-binding protein (FKBP51) near its site of interaction with the steroid receptor proteins},
author = {LeMaster, David M. and Mustafi, Sourajit M. and Brecher, Matthew and Zhang, Jing and Heroux, Annie and Li, Hongmin and Hernandez, Griselda},
abstractNote = {Interchanging Leu-119 for Pro-119 at the tip of the β4-β5 loop in the first FK506 binding domain (FK1) of the FKBP51 and FKBP52 proteins, respectively, has been reported to largely reverse the inhibitory (FKBP51) or stimulatory (FKBP52) effects of these co-chaperones on the transcriptional activity of glucocorticoid and androgen receptor-protein complexes. Previous NMR relaxation studies have identified exchange line broadening, indicative of submillisecond conformational motion, throughout the β4-β5 loop in the FK1 domain of FKBP51, which are suppressed by the FKBP52-like L119P substitution. This substitution also attenuates exchange line broadening in the underlying β2 and β3a strands that is centered near a bifurcated main chain hydrogen bond interaction between these two strands. The present study demonstrates that these exchange line broadening effects arise from two distinct coupled conformational transitions, and the transition within the β2 and β3a strands samples a transient conformation that resembles the crystal structures of the selectively inhibited FK1 domain of FKBP51 recently reported. Although the crystal structures for their series of inhibitors were interpreted as evidence for an induced fit mechanism of association, the presence of a similar conformation being significantly populated in the unliganded FKBP51 domain is more consistent with a conformational selection binding process. As a result, the contrastingly reduced conformational plasticity of the corresponding FK1 domain of FKBP52 is consistent with the current model in which FKBP51 binds to both the apo- and hormone-bound forms of the steroid receptor to modulate its affinity for ligand, whereas FKBP52 binds selectively to the latter state.},
doi = {10.1074/jbc.M115.650655},
url = {https://www.osti.gov/biblio/1341503},
journal = {Journal of Biological Chemistry},
issn = {0021-9258},
number = 25,
volume = 290,
place = {United States},
year = {Thu May 07 00:00:00 EDT 2015},
month = {Thu May 07 00:00:00 EDT 2015}
}
Web of Science
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Works referencing / citing this record:
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