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

MPG-Autoren
http://pubman.mpdl.mpg.de/cone/persons/resource/persons78913

Young,  J. C.
Hartl, Franz-Ulrich / Cellular Biochemistry, Max Planck Institute of Biochemistry, Max Planck Society;

http://pubman.mpdl.mpg.de/cone/persons/resource/persons78072

Hartl,  F. U.
Hartl, Franz-Ulrich / Cellular Biochemistry, Max Planck Institute of Biochemistry, Max Planck Society;

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Zitation

Schmidt, U., Wochnik, G. M., Rosenhagen, M. C., Young, J. C., Hartl, F. U., Holsboer, F., et al. (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.


Zitierlink: http://hdl.handle.net/11858/00-001M-0000-0010-6CA7-8
Zusammenfassung
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.