Cooperative DNA binding by the B-isoform of human progesterone receptor: thermodynamic analysis reveals strongly favorable and unfavorable contributions to assembly

Biochemistry
Aaron F HeneghanDavid L Bain

Abstract

Progesterone receptors (PR) play critical roles in eukaryotic gene regulation, yet the mechanisms by which they assemble at multisite promoters are poorly understood. Here we present a thermodynamic analysis of the interactions of the PR B-isoform (PR-B) with promoters containing either one or two progesterone response elements (PREs). Utilizing quantitative footprinting, we have resolved the microscopic energetics of PR-B binding, including cooperativity terms. The results of this analysis challenge a number of assumptions found in traditional models of receptor function. First, PR-B interactions at a single PRE can be equally well described by mechanisms invoking either the receptor monomer or the dimer as the active DNA binding species. If, as is commonly accepted, PR-B interacts with response elements only as a preformed dimer, then its intrinsic binding affinity is not the typically observed nanomolar but is rather picomolar. This high affinity binding is opposed, however, by a large energetic penalty. The penalty presumably pays for costly structural rearrangements of the receptor dimer and/or response element that are needed to form the protein-DNA complex. If PR-B assembles at a single response element via successive mo...Continue Reading

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Citations

Feb 13, 2009·The Journal of Biological Chemistry·Hany Abdel-HafizKathryn B Horwitz
Oct 22, 2008·Human Reproduction Update·B GellersenJ J Brosens
Dec 2, 2006·Annual Review of Physiology·David L BainMichael T Miura
Feb 6, 2007·Proceedings of the National Academy of Sciences of the United States of America·Keith D Connaghan-JonesDavid L Bain
Dec 7, 2011·Comparative Biochemistry and Physiology. Part B, Biochemistry & Molecular Biology·Grace JonesWen-Hui Wu
Jun 24, 2011·Biophysical Chemistry·Keith D ConnaghanDavid L Bain
Aug 2, 2011·Molecular and Cellular Endocrinology·Krista K HillDean P Edwards
Feb 15, 2012·Molecular and Cellular Endocrinology·Dawn R CochraneJennifer K Richer

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