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Essential role of the unusual DNA-binding motif of BAG-1 for inhibition of the glucocorticoid receptor

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Holsboer,  F
Max Planck Institute of Psychiatry, Max Planck Society;

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引用

Schmidt, U., Wochnik, G., Rosenhagen, M., Young, J., Hartl, F., Holsboer, F., & Rein, T. (2003). Essential role of the unusual DNA-binding motif of BAG-1 for inhibition of the glucocorticoid receptor. Journal of Biological Chemistry, 278(7), 4926-4931.


引用: https://hdl.handle.net/11858/00-001M-0000-000E-9F37-4
要旨
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 protein