乳腺癌相关 BIG3-PHB2 相互作用的生物物理特性：BIG3 非保守环区对结构和相互作用的影响。

Biophysical characterization of the breast cancer-related BIG3-PHB2 interaction: Effect of non-conserved loop region of BIG3 on the structure and the interaction.

机构信息

Department of Chemistry & Biotechnology, School of Engineering, The University of Tokyo, 7-3-1, Hongo, Bunkyo-ku, Tokyo, 113-8656, Japan.

Department of Chemistry & Biotechnology, School of Engineering, The University of Tokyo, 7-3-1, Hongo, Bunkyo-ku, Tokyo, 113-8656, Japan; The Institute of Medical Science, The University of Tokyo, 4-6-1, Shirokanedai, Minato-ku, Tokyo, 108-8639, Japan.

出版信息

Biochem Biophys Res Commun. 2019 Oct 8;518(1):183-189. doi: 10.1016/j.bbrc.2019.08.028. Epub 2019 Aug 14.

DOI:10.1016/j.bbrc.2019.08.028

PMID:31421830

Abstract

Brefeldin A-inhibited guanine nucleotide-exchange protein 3 (BIG3) interacts with and inhibits the tumor suppressor function of prohibitin-2 (PHB2), and recent in vivo studies have demonstrated that the BIG3-PHB2 interaction is a promising target for breast cancer therapy. However, little biophysical characterization on BIG3 and its interaction with PHB2 has been reported. Here we compared the calculated 8-class secondary structure of the N-terminal domains of BIG family proteins and identified a loop region unique to BIG3. Our biophysical characterization demonstrated that this loop region significantly affects the colloidal and thermodynamic stability of BIG3 and the thermodynamic and kinetic profile of its interaction with PHB2. These results establish a model for the BIG3-PHB2 interaction and an entry for drug discovery for breast cancer.

摘要

布雷菲德菌素 A 抑制的鸟嘌呤核苷酸交换蛋白 3（BIG3）与抑瘤蛋白-2（PHB2）相互作用并抑制其抑瘤功能，最近的体内研究表明，BIG3-PHB2 相互作用是乳腺癌治疗的一个有前途的靶点。然而，关于 BIG3 及其与 PHB2 的相互作用的生物物理特性尚未有报道。在这里，我们比较了 BIG 家族蛋白的 N 端结构域的计算 8 类二级结构，并鉴定了 BIG3 特有的一个环区。我们的生物物理特性研究表明，这个环区显著影响 BIG3 的胶体和热力学稳定性，以及其与 PHB2 相互作用的热力学和动力学特性。这些结果建立了 BIG3-PHB2 相互作用的模型，并为乳腺癌的药物发现提供了切入点。