Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai 980-8578, Japan.
Sci Rep. 2016 Sep 14;6:32999. doi: 10.1038/srep32999.
Ras protein is involved in a signal transduction cascade in cell growth, and cluster formation of H-Ras and human galectin-1 (Gal-1) complex is considered to be crucial to achieve its physiological roles. It is considered that the complex is formed through interactions between Gal-1 and the farnesyl group (farnesyl-dependent model), post-translationally modified to the C-terminal Cys, of H-Ras. We investigated the role of farnesyl-bound Gal-1 in the cluster formation by analyzing the structure and properties of Gal-1 bound to farnesyl thiosalicylic acid (FTS), a competitive inhibitor of the binding of H-Ras to Gal-1. Gal-1 exhibited self-cluster formation upon interaction with FTS, and small- and large-size clusters were formed depending on FTS concentration. The galactoside-binding pocket of Gal-1 in the FTS-bound form was found to play an important role in small-size cluster formation. Large-size clusters were likely formed by the interaction among the hydrophobic sites of Gal-1 in the FTS-bound form. The present results indicate that Gal-1 in the FTS-bound form has the ability to form self-clusters as well as intrinsic lectin activity. Relevance of the self-clustering of FTS-bound Gal-1 to the cluster formation of the H-Ras-Gal-1complex was discussed by taking account of the farnesyl-dependent model and another (Raf-dependent) model.
Ras 蛋白参与细胞生长中的信号转导级联反应，H-Ras 和人半乳糖凝集素-1（Gal-1）复合物的聚集被认为是实现其生理功能的关键。该复合物被认为是通过 Gal-1 与 H-Ras 的 C 末端半胱氨酸的法呢基基团（法呢基依赖性模型）之间的相互作用形成的，该半胱氨酸经过翻译后修饰。我们通过分析与法尼基硫代水杨酸（FTS）结合的 Gal-1 的结构和性质来研究结合法尼基的 Gal-1 在聚集形成中的作用，FTS 是 H-Ras 与 Gal-1 结合的竞争性抑制剂。Gal-1 在与 FTS 相互作用时表现出自聚集形成，并且根据 FTS 浓度形成小尺寸和大尺寸的聚集体。发现 FTS 结合形式的 Gal-1 的半乳糖结合口袋在小尺寸聚集体形成中发挥重要作用。大尺寸聚集体可能是由 FTS 结合形式的 Gal-1 的疏水性位点之间的相互作用形成的。本研究结果表明，FTS 结合形式的 Gal-1 具有形成自聚集体的能力和内在凝集素活性。考虑到法尼基依赖性模型和另一种（Raf 依赖性）模型，讨论了 FTS 结合的 Gal-1 的自聚集与 H-Ras-Gal-1 复合物聚集形成的相关性。
