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Structural and thermodynamic consequences of the replacement of zinc with environmental metals on estrogen receptor α–DNA interactions
Author(s) -
Deegan Brian J.,
Bona Anna M.,
Bhat Vikas,
Mikles David C.,
McDonald Caleb B.,
Seldeen Kenneth L.,
Farooq Amjad
Publication year - 2011
Publication title -
journal of molecular recognition
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.401
H-Index - 79
eISSN - 1099-1352
pISSN - 0952-3499
DOI - 10.1002/jmr.1148
Subject(s) - zinc finger , chemistry , zinc , cadmium , dna , estrogen receptor , divalent , dna binding domain , transcription factor , biophysics , metalloprotein , binding site , hormone response element , cysteine , biochemistry , biology , gene , genetics , enzyme , organic chemistry , cancer , breast cancer
Estrogen receptor α (ERα) acts as a transcription factor by virtue of the ability of its DNA‐binding (DB) domain, comprised of a tandem pair of zinc fingers, to recognize the estrogen response element within the promoters of target genes. Herein, using an array of biophysical methods, we probe the structural consequences of the replacement of zinc within the DB domain of ERα with various environmental metals and their effects on the thermodynamics of binding to DNA. Our data reveal that whereas the DB domain reconstituted with divalent ions of zinc, cadmium, mercury, and cobalt binds to DNA with affinities in the nanomolar range, divalent ions of barium, copper, iron, lead, manganese, nickel, and tin are unable to regenerate DB domain with DNA‐binding potential, although they can compete with zinc for coordinating the cysteine ligands within the zinc fingers. We also show that the metal‐free DB domain is a homodimer in solution and that the binding of various metals only results in subtle secondary and tertiary structural changes, implying that metal coordination may only be essential for binding to DNA. Collectively, our findings provide mechanistic insights into how environmental metals may modulate the physiological function of a key nuclear receptor involved in mediating a plethora of cellular functions central to human health and disease. Copyright © 2011 John Wiley & Sons, Ltd.