Differential binding of prohibitin-2 to estrogen receptor α and to drug-resistant ERα mutants

Takeru Chigira; Satoru Nagatoishi; Kouhei Tsumoto

doi:10.1016/j.bbrc.2015.06.002

Differential binding of prohibitin-2 to estrogen receptor α and to drug-resistant ERα mutants

Biochem Biophys Res Commun. 2015 Aug 7;463(4):726-31. doi: 10.1016/j.bbrc.2015.06.002. Epub 2015 Jun 4.

Authors

Takeru Chigira¹, Satoru Nagatoishi², Kouhei Tsumoto³

Affiliations

¹ Department of Chemistry and Biotechnology, School of Engineering, University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo 108-8639, Japan. Electronic address: 8120661875@mail.ecc.u-tokyo.ac.jp.
² Department of Bioengineering, School of Engineering, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8654, Japan. Electronic address: nagatoishi@bioeng.t.u-tokyo.ac.jp.
³ Department of Chemistry and Biotechnology, School of Engineering, University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo 108-8639, Japan; Department of Bioengineering, School of Engineering, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8654, Japan. Electronic address: tsumoto@bioeng.t.u-tokyo.ac.jp.

PMID: 26049107
DOI: 10.1016/j.bbrc.2015.06.002

Abstract

Endocrine resistance is one of the most challenging problems in estrogen receptor alpha (ERα)-positive breast cancer. The transcriptional activity of ERα is controlled by several coregulators, including prohibitin-2 (PHB2). Because of its ability to repress the transcriptional activity of activated ERα, PHB2 is a promising antiproliferative agent. In this study, were analyzed the interaction of PHB2 with ERα and three mutants (Y537S, D538G, and E380Q) that are frequently associated with a lack of sensitivity to hormonal treatments, to help advance novel drug discovery. PHB2 bound to ERα wild-type (WT), Y537S, and D538G, but did not bind to E380Q. The binding thermodynamics of Y537S and D538G to PHB2 were favorably altered entropically compared with those of WT to PHB2. Our results show that PHB2 binds to the ligand binding domain of ERα with a conformational change in the helix 12 of ERα.

Keywords: Breast cancer; Estrogen receptor alpha; Isothermal titration calorimetry; Prohibitin-2; Protein–protein interaction; Thermodynamics.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Breast Neoplasms / drug therapy*
Calorimetry, Differential Scanning
Circular Dichroism
Drug Resistance, Neoplasm
Estrogen Receptor alpha / chemistry
Estrogen Receptor alpha / genetics
Estrogen Receptor alpha / metabolism*
Female
Humans
Mutation*
Prohibitins
Protein Binding
Protein Conformation
Recombinant Proteins / metabolism
Repressor Proteins / metabolism*
Thermodynamics

Substances

Estrogen Receptor alpha
PHB2 protein, human
Prohibitins
Recombinant Proteins
Repressor Proteins