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J. Biol. Chem., Vol. 278, Issue 7, 4926-4931, February 14, 2003

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Essential Role of the Unusual DNA-binding Motif of BAG-1 for Inhibition of the Glucocorticoid Receptor^*,

Ulrike Schmidt, Gabriela M. Wochnik, Marcus C. Rosenhagen, Jason C. Young^§, F. Ulrich Hartl^§, Florian Holsboer, and Theo Rein^¶

From the  Max Planck Institute of Psychiatry, Kraepelinstraße 10, D-80804 Munich and ^§ Max Planck Institute of Biochemistry, Am Klopferspitz 18a, D-82152 Martinsried, Germany

The co-chaperone BAG-1 is involved in the regulation of steroid hormone receptors, including the glucocorticoid receptor (GR). More recently, BAG-1 was found in the nucleus where it decreases GR transactivation. Moreover, nonspecific DNA binding of BAG-1 has been reported. We discovered that of the N-terminal part of BAG-1M, the first 8 amino acids are sufficient for DNA binding, containing a stretch of three lysines and a stretch of three arginines. Changing the spacing between these stretches had no effect on DNA binding. Surprisingly, this small, nonsequence-specific DNA binding domain was nonetheless necessary for the inhibitory function of BAG-1 for GR-dependent transcription, whereas the following serine- and threonine-rich E₂X₄ repeat domain was not. Mutational analysis of these two domains revealed that only mutants retaining DNA binding capability were able to down-regulate GR-mediated transactivation. Intriguingly, lack of DNA binding could not be functionally rescued by BAG-1M harboring a point mutation abolishing interaction with hsp70. Thus, DNA binding and hsp70 interaction are required in cis. We propose that the nonsequence-specific DNA-binding protein BAG-1 acts at specific chromosomal loci by interacting with other proteins.

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