title: Na(+) and K(+) allosterically regulate cooperative DNA binding by the human progesterone receptor.
abstract: Cooperativity is a common mechanism used by transcription factors to generate highly responsive yet stable gene regulation. For the two isoforms of human progesterone receptor (PR-A and PR-B), differences in cooperative DNA binding energetics may account for their differing transcriptional activation properties. Here we report on the molecular origins responsible for cooperativity, finding that it can be activated or repressed with Na(+) and K(+), respectively. We demonstrate that PR self-association and DNA-dependent cooperativity are linked to a monovalent cation binding event and that this binding is coupled to modulation of receptor structure. K(+) and Na(+) are therefore allosteric effectors of PR function. Noting that the apparent binding affinities of Na(+) and K(+) are comparable to their intracellular concentrations and that PR isoforms directly regulate the genes of a number of ion pumps and channels, these results suggest that Na(+) and K(+) may additionally function as physiological regulators of PR action.
authors.affiliation: Department of Pharmaceutical Sciences, University of Colorado Denver, Aurora, Colorado 80045, USA.
authors.forename: Keith D
authors.initials: KD
authors.lastname: Connaghan
authors.forename: Aaron F
authors.initials: AF
authors.lastname: Heneghan
authors.forename: Michael T
authors.initials: MT
authors.lastname: Miura
authors.forename: David L
authors.initials: DL
authors.lastname: Bain
mesh_terms: D000494:Allosteric Regulation; D001665:Binding Sites; D004247:DNA / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D011188:Potassium / Q000378:metabolism*; D020033:Protein Isoforms / Q000737:chemistry / Q000378:metabolism; D011980:Receptors, Progesterone / Q000737:chemistry* / Q000378:metabolism; D012964:Sodium / Q000378:metabolism*; D013816:Thermodynamics
chemical_list: D020033:Protein Isoforms; D011980:Receptors, Progesterone; C101118:progesterone receptor A; C097314:progesterone receptor B; D004247:DNA; D012964:Sodium; D011188:Potassium