The hsp70 cochaperones BAG-1M and HspBP1 as possible cause for glucocorticoid resistance

Proteins can exert their function only in their correct three-dimensional conformation. It is estimated that 15% of all proteins need assistance by so-called „chaperone“ proteins to attain their correct folding, including steroid receptors such as the glucocorticoid receptor (GR). Incorrect folding of GR entails severe malfunctioning. The heat shock protein 70 (hsp70) is one of the essential players in protein folding. Assisted folding is an energy-dependent process, enabled by the ATPase domain of hsp70, which involves nucleotide exchange factors (NEFs). Two structurally distinct proteins acting as NEF for hsp70 are known: bcl-2 associated athanogene 1 (BAG-1) and hsp70 binding protein 1 (HspBP1). There are at least four human isoforms of BAG-1 (L, M, S and p29) which derive from the same mRNA by alternative translation initiation. In comparison to BAG-1M, which has been shown to bind GR and to inhibit its transcriptional activity, the effect of HspBP1 on GR is not known. Based on the functional homology of BAG-1M and HspBP1 with respect to hsp70, we wished to compare the effects of the two proteins on GR activity, and elucidate the underlying mechanisms. Our preliminary results show that HspBP1 has the potential to inhibit GR, similarly to BAG1M. However, we provide evidence that HspBP1 operates by a different mechanism, because in contrast to BAG-1M, HspBP1 is not able to bind GR under the same experimental conditions.