Nanoclusters of Lipid-anchored Proteins in Membranes: How and where they appear

描述(由申请人提供)：膜中脂质锚定蛋白质的纳米簇：它们是如何形成的以及它们在哪里形成？摘要最近的研究表明，脂质锚定的信号蛋白在质膜上动态地组织成纳米级的亚结构。由此产生的蛋白质-脂质纳米簇作为高保真信号传输的枢纽。然而，纳米团簇如何形成和分布在异质膜结构域中的分子基础仍然不确定。因此，目前尚不清楚同源蛋白的纳米簇，如信号开关H-ras和K-ras是如何分离到不同的脂类结构域的。我们假设这将通过基于脂质和基于蛋白质的分类机制的组合来实现。我们计划使用多尺度分子模拟和理论方法来验证这一假设，并辅之以合作实验。我们将使用H-和K-ras癌蛋白作为模型系统。RAS纳米团簇对于质膜信号调节的独特机制具有有趣的意义。因此，阐明驱动RAS纳米团簇时空组织的机制将有助于更好地理解细胞信号。此外，尽管这项建议的重点是RAS，但所开发的方法和原理将适用于任何脂化信号蛋白的研究。这项工作的更广泛影响包括对靶向RAS纳米结构域的潜在治疗策略的贡献，以及耦合蛋白质/脂类分类的生物物理学。 公共卫生相关性：RAS纳米簇对质膜信号调节的独特机制具有耐人寻味的影响，并可能代表防止RAS信号缺陷的新治疗靶点，RAS信号缺陷是许多癌症的常见原因。阐明驱动RAS纳米簇时空组织的机制将有助于更好地理解细胞信号转导，并有助于针对RAS纳米结构域的潜在治疗策略。

DESCRIPTION (provided by applicant): Nanoclusters of Lipid-anchored Proteins in Membranes: How and where do they form? Abstract Recent studies have shown that lipid-anchored signaling proteins dynamically organize into nanoscale substructures on the plasma membrane. The resulting protein-lipid nanoclusters serve as hubs for high-fidelity signal transmission. However, the molecular basis of how nanoclusters form and distribute in heterogeneous membrane domains remains undetermined. As a result, it is unclear how nanoclusters of homologous proteins, such as the signaling switches H-ras and K-ras, segregate to different lipid domains. We hypothesize that this would be achieved by a combination of lipid-based and protein-based sorting mechanisms. We plan to test this hypothesis using multi-scale molecular simulations and theoretical approaches complemented by collaborative experiments. We will use the H- and K-ras oncoproteins as model systems. Ras nanoclusters have intriguing implications for unique mechanisms of signal regulation at the plasma membrane. Elucidating the mechanisms that drive the spatiotemporal organization of Ras nanoclusters will therefore lead to a better understanding of cell signaling. In addition, whil this proposal is focused on Ras, the approach and principles that are developed will be applicable for the study of any lipidated signaling protein. The broader impacts of the work include contributions to potential therapeutic strategies for targeting Ras nanodomains and the biophysics of coupled protein/lipid sorting. PUBLIC HEALTH RELEVANCE: Ras nanoclusters have intriguing implications for unique mechanisms of signal regulation at the plasma membrane and may represent novel therapeutic targets to prevent defective Ras signaling, a common cause of many cancers. Elucidating the mechanisms that drive the spatiotemporal organization of Ras nanoclusters will lead to a better understanding of cell signaling and contribute to potential therapeutic strategies for targeting Ras nanodomains.