The co-chaperone BAG-1 as a candidate for causing cortisteroid receptor resistance: A detailed mutational analysis

Corticosteroid receptor function is frequently impaired in patients with major depression. Since molecular chaperones and co-chaperones are essential for these receptors to become competent of binding to hormone, a defective chaperone cascade could give rise to receptor-resistance in depressive patients.

To analyze the domain structure of the co-chaperone BAG-1 we created several deletion and point mutants of human BAG-1 and studied their influence on GR-mediated transactivation. We demonstrate here that the first 10 N-terminal amino acids of human BAG-1M are essential for its inhibitory effects on GR-mediated transcription. Further, we demonstrated that these 10 amino-acids constitute a DNA-binding domain and that DNA-binding of BAG-1 is essential for its inhibitory effect on GR.

By identifying distinct regions of BAG-1 that are indispensable for its inhibitory effects on GR-mediated transcription, this work elucidates the functional structure of BAG-1 and may lead to further enlightenment of the mechanisms regulating GR.