化学介导的14-3-3蛋白翻译后修饰干预:分子胶设计及其在肿瘤治疗中的应用

Chemically mediated 14-3-3 protein post-translational modification interference:design of molecular glue and the application in cancer treatment

蛋白-蛋白相互作用(protein-protein interactions,PPIs)不仅是构建蛋白质复合体的关键途径,也是维护正常生物功能的基础。这些相互作用对于蛋白质结构及其生物学功能至关重要,并在细胞的信号传导、代谢途径和调控网络中扮演核心角色。14-3-3蛋白是一种在真核生物中广泛表达的高度保守的功能性蛋白,主要通过识别并结合其伴侣蛋白参与细胞周期控制、信号转导和能量代谢等关键生命过程。本文综述了14-3-3蛋白与其伴侣蛋白如雌激素受体α(estrogenreceptorα,ERα)、RAF原癌基因丝氨酸/苏氨酸蛋白激酶(RAFproto-oncogeneserine/threonine-protein kinase,C-RAF/RAF-1)和p53的PPIs失调在肿瘤的发生和发展中的角色,并集中讨论了14-3-3/ERα、14-3-3/C-RAF和14-3-3/p53分子胶的研究进展。这些分子胶通过模拟或增强伴侣蛋白的磷酸化丝氨酸位点,形成与14-3-3蛋白的共价键、盐桥和氢键,从而提高了PPIs的稳定性,并有效地干预了病理状态下的蛋白活性与信号传递。此外,本文还探讨了这种化学干预策略在临床上抑制肿瘤发展的潜力,为未来的研究方向提供了理论基础和实践指南。

Protein-protein interactions(PPIs)are not only crucial for the assembly of protein complexes but also fundamental for maintaining normal biological functions.These interactions are vital for protein structure and biological functionality and play a central role in cellular signaling,metabolic pathways,and regulatory networks.The 14-3-3 protein,highly conserved and widely expressed in eukaryotes,primarily recognizes and binds to its partner proteins to participate in essential life processes such as cell cycle control,signal transduction,and energy metabolism.This review discusses the role of dysregulated PPIs between 14-3-3 proteins and their partner proteins such as estrogen receptorα(estrogen receptorα,ERα),RAF proto-oncogene serine/threonine-protein kinase(C-RAF/RAF-1),and p53 in the onset and progression of tumors,focusing on the research progress of 14-3-3/ERα,14-3-3/C-RAF,and 14-3-3/p53 molecular glues.These molecular glues,by mimicking or enhancing the phosphorylation sites of serine on partner proteins,form covalent bonds,salt bridges,and hydrogen bonds with 14-3-3 proteins,thereby enhancing the stability of PPIs and effectively intervening in protein activity and signaling under pathological conditions.Additionally,this article explores the potential of this chemical intervention strategy in clinically suppressing tumor progression,providing a theoretical foundation and practical guidance for future research directions.