title: Differential binding of prohibitin-2 to estrogen receptor α and to drug-resistant ERα mutants.
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.
authors.affiliation: 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.
authors.forename: Takeru
authors.initials: T
authors.lastname: Chigira
authors.affiliation: 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.
authors.forename: Satoru
authors.initials: S
authors.lastname: Nagatoishi
authors.affiliation: 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.
authors.forename: Kouhei
authors.initials: K
authors.lastname: Tsumoto
mesh_terms: D001943:Breast Neoplasms / Q000188:drug therapy*; D002152:Calorimetry, Differential Scanning; D002942:Circular Dichroism; D019008:Drug Resistance, Neoplasm; D047628:Estrogen Receptor alpha / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D005260:Female; D006801:Humans; D009154:Mutation; D000091402:Prohibitins; D011485:Protein Binding; D011487:Protein Conformation; D011994:Recombinant Proteins / Q000378:metabolism; D012097:Repressor Proteins / Q000378:metabolism*; D013816:Thermodynamics
chemical_list: D047628:Estrogen Receptor alpha; C000717331:PHB2 protein, human; D000091402:Prohibitins; D011994:Recombinant Proteins; D012097:Repressor Proteins
keywords: Breast cancer; Estrogen receptor alpha; Isothermal titration calorimetry; Prohibitin-2; Protein–protein interaction; Thermodynamics