Hsp70 cochaperones HspBP1 and BAG-1M differentially regulate steroid hormone receptor function.
Hsp70 binding protein 1 (HspBP1) and Bcl2-associated athanogene 1 (BAG-1), the functional orthologous nucleotide exchange factors of the heat shock protein 70 kilodalton (Hsc70/Hsp70) chaperones, catalyze the release of ADP from Hsp70 while inducing different conformational changes of the ATPase domain of Hsp70. An appropriate exchange rate of ADP/ATP is crucial for chaperone-dependent protein folding processes. Among Hsp70 client proteins are steroid receptors such as the glucocorticoid receptor (GR), the mineralocorticoid receptor (MR), and the androgen receptor (AR). BAG-1 diversely affects steroid receptor activity, while to date the influence of HspBP1 on steroid receptor function is mostly unknown. Here, we compared the influence of HspBP1 and BAG-1M on Hsp70-mediated steroid receptor folding complexes and steroid receptor activity. Coimmunoprecipitation studies indicated preferential binding of Hsp40 and the steroid receptors to BAG-1M as compared to HspBP1. Furthermore, Hsp70 binding to the ligand-binding domain of GR was reduced in the presence of HspBP1 but not in the presence of BAG-1M as shown by pull-down assays. Reporter gene experiments revealed an inhibitory effect on GR, MR, and AR at a wide range of HspBP1 protein levels and at hormone concentrations at or approaching saturation. BAG-1M exhibited a transition from stimulatory effects at low BAG-1M levels to inhibitory effects at higher BAG-1M levels. Overall, BAG-1M and HspBP1 had differential impacts on the dynamic composition of steroid receptor folding complexes and on receptor function with important implications for steroid receptor physiology.
Max Planck Institute of Psychiatry, Chaperone Research Group, Munich, Germany.
Regina T
RT
Knapp
McGill University, Department of Biochemistry, Groupe de Recherche Axé sur la Structure des Protéines, Montreal, Canada.
Michael J H
MJ
Wong
Max Planck Institute of Psychiatry, Chaperone Research Group, Munich, Germany.
Lorenz K
LK
Kollmannsberger
Max Planck Institute of Psychiatry, Chaperone Research Group, Munich, Germany.
Nils C
NC
Gassen
Max Planck Institute of Psychiatry, Chaperone Research Group, Munich, Germany.
Anja
A
Kretzschmar
Max Planck Institute of Psychiatry, Chaperone Research Group, Munich, Germany.
Jürgen
J
Zschocke
Max Planck Institute of Psychiatry, Chaperone Research Group, Munich, Germany.
Kathrin
K
Hafner
McGill University, Department of Biochemistry, Groupe de Recherche Axé sur la Structure des Protéines, Montreal, Canada.
Jason C
JC
Young
Max Planck Institute of Psychiatry, Chaperone Research Group, Munich, Germany.
Theo
T
Rein
D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000378:metabolism*; D057809:HEK293 Cells; D050956:HSP40 Heat-Shock Proteins / Q000378:metabolism; D018840:HSP70 Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D011987:Receptors, Steroid / Q000378:metabolism*; D014157:Transcription Factors / Q000378:metabolism*; D014158:Transcription, Genetic
D048868:Adaptor Proteins, Signal Transducing; C091732:BCL2-associated athanogene 1 protein; D004268:DNA-Binding Proteins; D050956:HSP40 Heat-Shock Proteins; D018840:HSP70 Heat-Shock Proteins; C116331:HSPBP1 protein, human; D011987:Receptors, Steroid; D014157:Transcription Factors