Lipid regulation of cellular signaling and protein-protein interactions

赵元华，博士。 项目摘要/摘要 细胞信号和蛋白质相互作用的脂质调节 细胞蛋白质通过与其他蛋白质相互作用来完成其功能，形成复合体。 蛋白质-蛋白质相互作用网络。细胞蛋白质-蛋白质相互作用通常涉及小分子 模块化蛋白相互作用结构域，如Src-Homology 2和PSD95、Dlg1、ZO-1结构域。 蛋白质相互作用结构域介导的蛋白质-蛋白质相互作用网络的生理意义 已经得到了大量由人类编码的蛋白质相互作用结构域的良好支持 基因组和许多人类疾病，包括癌症，由功能失调的蛋白质相互作用引起 结构域介导的细胞过程。有趣的是，大多数蛋白质相互作用区域都有适度的 结合亲和力和相当程度的混杂。这可能是可逆性所必需的， 细胞信号通路的冗余，但提出了一个基本问题，即多高的保真度 细胞功能和调控可以通过结构域介导的蛋白质相互作用来实现 蛋白质-蛋白质相互作用。我们最近发现，膜脂，包括胆固醇和 肌醇磷脂通过直接和特异的方式协调和调节蛋白质间的相互作用 与蛋白质相互作用结构域相互作用。这一重要的新发现和我们创新的现场 定量脂质成像技术为我们提供了一个独特而无与伦比的机会 阐明脂类调节蛋白质-蛋白质时空特异性的机制 相互作用和细胞信号传递，并开发新的策略来调节这些过程。给定 蛋白质相互作用结构域介导的蛋白质相互作用和细胞信号转导的重要性 健康和疾病，我们提议的研究应该对生物学和 并为人类开拓创新的药物发现战略奠定了基础 疾病，最明显的是癌症。

WONHWA CHO, PH.D. PROJECT SUMMARY/ABSTRACT Lipid regulation of cellular signaling and protein-protein interactions Cellular proteins accomplish their functions through interactions with other proteins, forming complex protein-protein interaction networks. Cellular protein-protein interaction typically involves small modular protein interaction domains, such as Src-homology 2 and PSD95, Dlg1, ZO-1 domains. Physiological significance of protein interaction domain-mediated protein-protein interaction networks has been well supported by a large number of protein interaction domains encoded by human genome and many human diseases, including cancer, caused by dysfunctional protein interaction domain-mediated cellular processes. Interestingly, most protein interaction domains have moderate binding affinity and a significant degree of promiscuity. This may be necessary for reversibility and redundancy of cell signaling pathways but raises a fundamental question as to how high-fidelity cellular function and regulation can be achieved through the protein interaction domain-mediated protein-protein interaction. We have recently shown that membrane lipids, including cholesterol and phosphoinositides, coordinate and regulate protein-protein interaction by directly and specifically interacting with protein interaction domains. This important new discovery and our innovative in situ quantitative lipid imaging technology provide us with a unique and unparalleled opportunity to elucidate the mechanisms by which lipids orchestrate spatiotemporal specificity of protein-protein interaction and cell signaling and develop new strategies to modulate these processes. Given the importance of protein interaction domain-mediated protein-protein interaction and cell signaling in health and disease, our proposed research should have a major impact on broad areas of biology and medicine and lay the foundation for a pioneering and innovative drug discovery strategy for human diseases, most notably cancer.