生物医学工程学杂志

生物医学工程学杂志

利用分子动力学模拟探究力学信号对 CD44/FERM 复合物结构的影响

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在肿瘤细胞的黏附、迁移和增殖中,分化抗原 44(CD44)与埃兹蛋白/根蛋白/膜突蛋白(ERM)的 FERM 结构域结合并招募脾酪氨酸激酶(Syk)至关重要。本文首先观察分析静态及平衡过程中 CD44/FERM 复合物的构象和接触面残基的相互作用,发现该复合物结构稳定,同时 ERM 蛋白上非传统的免疫受体酪氨酸活化基序(ITAM-like)以及磷酸化位点 Y191 和 Y205 都被包埋在了结构里面,不利于 ERM 蛋白的磷酸化以及对 Syk 的招募,影响后续的信号传导。接着采用拉伸分子动力学模拟的方法,模拟力学环境中 CD44/FERM 复合物的相互作用,比较分析复合物构象的变化以及溶剂可及表面积,发现力学信号可以调控 ITAM-like 序列以及磷酸化位点 Y205 的暴露。本研究首次在原子层面揭示力如何经由 CD44 胞内域调控下游信号的激活,为深入理解肿瘤细胞的黏附迁移路径和抗肿瘤药物的设计提供参考。

The intracellular domain of clusters of differentiation 44 (CD44) binding to the FERM (protein 4.1-ezrin-radixin-moesin) domain of ERM (ezrin/radixin/moesin) proteins and furthermore triggering the recruitment of spleen tyrosine kinase (Syk) are very important in the process of tumor cell adhesion, migration and proliferation. At first, it was found that CD44/FERM structure was stable by observing CD44/FERM complex conformation and analyzing the interaction of interface residues both in static crystal structure and in equilibrium process. Meanwhile, unconventional immunoreceptor tyrosine-based activation motif (ITAM-like), and phosphorylation sites Y191 and Y205 were buried in FERM domain, which would hinder the phosphorylation of ERM proteins, the recruitment of Syk and subsequent signal transduction. Then, steered molecular dynamics simulation was applied to simulate the interaction between CD44 and FERM domain in the mechanical environment. The results showed that mechanical signal could induce the exposure of the ITAM-like motif and phosphorylation site Y205 by tracking and analyzing CD44/FERM complex conformational changes and the solvent-accessible surface area. This study revealed how the force regulates the activation of downstream signal through CD44 intracellular domain for the first time, and would be useful for further understanding the adhesion and migration pathway of cancer cells and the design of antitumor drugs.

关键词: 分化抗原 44; FERM 结构域; 磷酸化; 分子动力学模拟;

Key words: clusters of differentiation 44; FERM domain; phosphorylation; molecular dynamic simulation; force

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