alpha-Helix-Peptides Comprising the Human Nuclear Receptor ERR gamma Competitively Provoke Inhibition of Functional Homomeric Dimerization

作者：Liu Xiaohui; Nishimura Hirokazu; Fujiyama Akina; Matsushima Ayami; Shimohigashi Miki; Shimohigashi Yasuyuki^*

来源：Biopolymers, 2016, 106(4): 547-554.

DOI：10.1002/bip.22795

• constitutive activity
• dimerization
• estrogen-related receptor gamma
• nuclear receptor

Estrogen-related receptor gamma (ERR gamma) is a constitutively active nuclear receptor functioning as a transcription factor. ERR gamma binds to a single half site designated as ERRE that has only a single DNA-binding motif. However, with regard to the subunit structure, it remains a matter of controversy whether ERR gamma binds as a monomer or dimer. Because the ligand-binding domain (LBD) of ERR gamma was in a homodimer form in its X-ray crystal structure, the peptide fragments present in the dimer interfaces would perturb or destabilize the dimer structure by inhibiting the mutual interaction among ERR gamma molecules. Thus, to demonstrate the essential homodimer structure of ERR gamma, we utilized the peptides corresponding to the alpha-helix peptides 7 (H7), H9, and H10/11 in order to test such inhibitor activity. These selections were done based on a structural analysis of the X-ray crystal structures of ERR gamma-LBD, which forms a head-to-head dimer structure. Peptides were evaluated by means of a luciferase reporter gene assay, in which ERR gamma exhibited a high constitutive activity with no ligand. When the peptide was expressed in the HeLa cells together with ERR gamma, these peptides clearly showed a concentration-dependent activity inhibition, indicating that ERRg is indeed homodimerized as required for DNA transcription activity. The present results strongly suggest that human nuclear receptor ERRg functions as a genuine homomeric dimer with symmetrical dimeric interface regions.

• 出版日期2016-7