Binding of the ERα nuclear receptor to DNA is coupled to proton uptake

Brian J. Deegan, Kenneth L. Seldeen, Caleb B. McDonald, Vikas Bhat, Amjad Farooq

Research output: Contribution to journalArticle

9 Citations (Scopus)

Abstract

Nuclear receptors act as ligand-modulated transcription factors and orchestrate a plethora of cellular functions central to health and disease. Although studied for more than half a century, many mysteries surrounding the mechanism of action of nuclear receptors remain unresolved. Herein, using isothermal titration calorimetry (ITC) in conjunction with macromolecular modeling (MM), we provide evidence that the binding of the ERα nuclear receptor to its DNA response element is coupled to proton uptake by two ionizable residues, H196 and E203, located at the protein-DNA interface. Alanine substitution of these ionizable residues decouples protonation and hampers the binding of ERα to DNA by nearly 1 order of magnitude. Remarkably, H196 and E203 are predominantly conserved across ∼50 members of the nuclear receptor family, implying that proton-coupled equilibrium may serve as a key regulatory switch for modulating protein-DNA interactions central to nuclear receptor function and regulation. Taken together, our findings unearth an unexpected but critical step in the molecular action of nuclear receptors and suggest that they may act as sensors of intracellular pH.

Original languageEnglish
Pages (from-to)5978-5988
Number of pages11
JournalBiochemistry
Volume49
Issue number29
DOIs
StatePublished - Jul 27 2010

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Cytoplasmic and Nuclear Receptors
Protons
DNA
Calorimetry
Protonation
Response Elements
Nuclear Family
Titration
Alanine
Proteins
Substitution reactions
Transcription Factors
Switches
Health
Ligands
Sensors

ASJC Scopus subject areas

  • Biochemistry

Cite this

Deegan, B. J., Seldeen, K. L., McDonald, C. B., Bhat, V., & Farooq, A. (2010). Binding of the ERα nuclear receptor to DNA is coupled to proton uptake. Biochemistry, 49(29), 5978-5988. https://doi.org/10.1021/bi1004359

Binding of the ERα nuclear receptor to DNA is coupled to proton uptake. / Deegan, Brian J.; Seldeen, Kenneth L.; McDonald, Caleb B.; Bhat, Vikas; Farooq, Amjad.

In: Biochemistry, Vol. 49, No. 29, 27.07.2010, p. 5978-5988.

Research output: Contribution to journalArticle

Deegan, BJ, Seldeen, KL, McDonald, CB, Bhat, V & Farooq, A 2010, 'Binding of the ERα nuclear receptor to DNA is coupled to proton uptake', Biochemistry, vol. 49, no. 29, pp. 5978-5988. https://doi.org/10.1021/bi1004359
Deegan, Brian J. ; Seldeen, Kenneth L. ; McDonald, Caleb B. ; Bhat, Vikas ; Farooq, Amjad. / Binding of the ERα nuclear receptor to DNA is coupled to proton uptake. In: Biochemistry. 2010 ; Vol. 49, No. 29. pp. 5978-5988.
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