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High Mobility Group B Proteins Facilitate Strong Estrogen Receptor Binding to Classical and Half-Site Estrogen Response Elements and Relax Binding Selectivity

Departments of Chemistry (D.D., W.M.S.) and Biological Sciences (D.D.), and the Center for Biomolecular Dynamics (D.D., W.M.S.), Bowling Green State University, Bowling Green, Ohio 43403; and Department of Chemistry (R.C.P.), Ohio Northern University, Ada, Ohio 45810

Address all correspondence and requests for reprints to: W. M. Scovell, Bowling Green State University, Overman Hall, Bowling Green, Ohio 43403. 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 ER 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 EMSAs, 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 with ER binding to consensus ERE in the absence of HMGB proteins. These findings reveal that although HMGB proteins enhance binding affinity, they also relax ER binding specificity. Deoxyribonuclease I footprinting demonstrates that ER binds very differently to consensus ERE and ERE consensus half-sites, whereas both deoxyribonuclease I and exonuclease 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.

NURSA Molecule Pages Link:

Nuclear Receptors:   ERα

Coregulators:   HMG-1  |  HMG-2

Ligands:   17β-Estradiol

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