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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

Abstract

Interchanging Leu-119 for Pro-119 at the tip of the β45 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 β45 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 » 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.« less

Authors:
 [1];  [2];  [2];  [2];  [3];  [1];  [1]
  1. New York State Dept. of Health, Albany, NY (United States); Univ. at Albany, SUNY, Albany, NY (United States)
  2. New York State Dept. of Health, Albany, NY (United States)
  3. 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}
}

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Cited by: 11 works
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Works referenced in this record:

FKBP51 Reciprocally Regulates GRα and PPARγ Activation via the Akt-p38 Pathway
journal, August 2014


FKBP51 Controls Cellular Adipogenesis through p38 Kinase-Mediated Phosphorylation of GRα and PPARγ
journal, August 2014


Investigating Protein−Ligand Interactions with a Mutant FKBP Possessing a Designed Specificity Pocket
journal, March 2000


Statistical allosteric coupling to the active site indole ring flip equilibria in the FK506-binding domain
journal, August 2014


A 59-kilodalton protein associated with progestin, estrogen, androgen, and glucocorticoid receptors
journal, September 1986


Glucocorticoid Receptor Function Regulated by Coordinated Action of the Hsp90 and Hsp70 Chaperone Cycles
journal, June 2014


Selective inhibitors of the FK506-binding protein 51 by induced fit
journal, December 2014


SHIFTX2: significantly improved protein chemical shift prediction
journal, March 2011


Multi-Timescale Dynamics Study of FKBP12 Along the Rapamycin–mTOR Binding Coordinate
journal, January 2011


The role of dynamic conformational ensembles in biomolecular recognition
journal, October 2009


FK506-binding Proteins 51 and 52 Differentially Regulate Dynein Interaction and Nuclear Translocation of the Glucocorticoid Receptor in Mammalian Cells
journal, December 2004


Crystal Structures of the Free and Ligand-Bound FK1–FK2 Domain Segment of FKBP52 Reveal a Flexible Inter-Domain Hinge
journal, November 2013


Ligand-switchable Substrates for a Ubiquitin-Proteasome System
journal, July 2011


Differential conformational dynamics in the closely homologous FK506-binding domains of FKBP51 and FKBP52
journal, June 2014


Measurement of 15N relaxation rates in perdeuterated proteins by TROSY-based methods
journal, June 2012


[16] SHELXL: High-resolution refinement
book, January 1997


The Hsp90-binding peptidylprolyl isomerase FKBP52 potentiates glucocorticoid signaling in vivo
journal, March 2003


Calibration of ring-current effects in proteins and nucleic acids
journal, December 1995


Crystal structure and conformational flexibility of the unligated FK506-binding protein FKBP12.6
journal, February 2014


UCSF Chimera?A visualization system for exploratory research and analysis
journal, January 2004


Structural characterization of the PPIase domain of FKBP51, a cochaperone of human Hsp90
journal, May 2011


Tissue Distribution and Abundance of Human FKBP51, an FK506-Binding Protein That Can Mediate Calcineurin Inhibition
journal, March 1997


A Rapid, Reversible, and Tunable Method to Regulate Protein Function in Living Cells Using Synthetic Small Molecules
journal, September 2006


Fast and Accurate Predictions of Protein NMR Chemical Shifts from Interatomic Distances
journal, October 2009


A New First Step in Activation of Steroid Receptors: HORMONE-INDUCED SWITCHING OF FKBP51 AND FKBP52 IMMUNOPHILINS
journal, December 2001


FKBP51 Affects Cancer Cell Response to Chemotherapy by Negatively Regulating Akt
journal, September 2009


The immunophilin FKBP52 inhibits the activity of the epithelial Ca 2+ channel TRPV5
journal, May 2006


InterAKTions with FKBPs - Mutational and Pharmacological Exploration
journal, February 2013


Model-free approach to the interpretation of nuclear magnetic resonance relaxation in macromolecules. 1. Theory and range of validity
journal, August 1982


Targeting FKBP isoforms with small-molecule ligands
journal, August 2011


Structural basis of conformational transitions in the active site and 80′s loop in the FK506-binding protein FKBP12
journal, February 2014


Features and development of Coot
journal, March 2010


Dynamics of Ribonuclease H:  Temperature Dependence of Motions on Multiple Time Scales
journal, January 1996


Polymorphisms in FKBP5 are associated with increased recurrence of depressive episodes and rapid response to antidepressant treatment
journal, November 2004


PHENIX: a comprehensive Python-based system for macromolecular structure solution
journal, January 2010


NMR paves the way for atomic level descriptions of sparsely populated, transiently formed biomolecular conformers
journal, July 2013


Structure of the N-terminal domain of human FKBP52
journal, December 2002


Hormone Binding and Co-regulator Binding to the Glucocorticoid Receptor are Allosterically Coupled
journal, March 2010


Analysing the visible conformational substates of the FK506-binding protein FKBP12
journal, July 2013


The Static Magnetic Field Dependence of Chemical Exchange Linebroadening Defines the NMR Chemical Shift Time Scale
journal, March 2000


NMRPipe: A multidimensional spectral processing system based on UNIX pipes
journal, November 1995


Different Regions of the Immunophilin FKBP52 Determine Its Association with the Glucocorticoid Receptor, hsp90, and Cytoplasmic Dynein
journal, December 1999


Functional Dynamics of Human FKBP12 Revealed by Methyl 13 C Rotating Frame Relaxation Dispersion NMR Spectroscopy
journal, May 2006


Redesigning an FKBP-ligand interface to generate chemical dimerizers with novel specificity
journal, September 1998


Chemical exchange in biomacromolecules: Past, present, and future
journal, April 2014


Noncatalytic Role of the FKBP52 Peptidyl-Prolyl Isomerase Domain in the Regulation of Steroid Hormone Signaling
journal, October 2007


A ligand-specific kinetic switch regulates glucocorticoid receptor trafficking and function
journal, May 2013


Functional Drift of Sequence Attributes in the FK506-Binding Proteins (FKBPs)
journal, April 2008


Ring current theories in nuclear magnetic resonance
journal, January 1979


Calculation of chemical shift anisotropy in proteins
journal, August 2011


A new model for chemical shifts of amide hydrogens in proteins
journal, April 2007


Hsp56: a novel heat shock protein associated with untransformed steroid receptor complexes.
journal, December 1990


Purification of unactivated progesterone receptor and identification of novel receptor-associated proteins.
journal, March 1990


Squirrel Monkey Immunophilin FKBP51 Is a Potent Inhibitor of Glucocorticoid Receptor Binding 1
journal, November 2000


[20] Processing of X-ray diffraction data collected in oscillation mode
book, January 1997


Analysis of FKBP51/FKBP52 Chimeras and Mutants for Hsp90 Binding and Association with Progesterone Receptor Complexes
journal, March 1998


Works referencing / citing this record:

The Many Faces of FKBP51
journal, January 2019