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Submitted on March 24, 2004
Accepted on July 9, 2004
Departments of Chemistry and Biological Sciences, and the Center for Biomolecular Dynamics, Bowling Green State University, Bowling Green, Ohio 43403 and Department of Chemistry, Ohio Northern University, Ada, OH, 45810
* To whom correspondence should be addressed. E-mail: wscovel{at}bgnet.bgsu.edu.
The estrogen receptor 
(ER) is a ligand-dependent transcription factor that regulates the expression of estrogen-responsive genes. A key step in the activation process is the initial binding of the estrogen receptor dimer to the estrogen response element (ERE). We examined the effect of the coactivator proteins, HMGB1 and HMGB2, in enhancing ER binding affinity to single and tandem EREs. Using electrophoretic mobility shift assays, both HMGB proteins are shown to enhance ER binding and induce cooperative ER binding on tandem ERE elements. We demonstrate that HMGB proteins facilitate strong ER binding to ERE consensus half-sites, exhibiting binding affinities comparable to ER binding to consensus ERE in the absence of HMGB proteins. These findings reveal that while HMGB proteins enhance binding affinity, they also relax ER binding specificity. DNase I footprinting demonstrates that ER binds very differently to consensus ERE (cERE) and ERE consensus half-sites (cEREm), while both DNase I and Exo III digestions show that the presence of HMGB1/2 does not alter the DNA protection in ER/ERE complexes. Protease digestions of the complexes support this conclusion and show that a global conformation change occurs in ER when bound to the different ER binding sites. Models for these interactions are discussed, together with a "hit-and-run" mechanism that HMGB proteins may utilize to produce these effects.
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