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

膜中脂质锚定蛋白的纳米簇：它们出现的方式和位置

• 批准号: 8373703
• 负责人: Alemayehu A. Gorfe
• 金额: $ 28.88万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-01 至 2017-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8373703
• 关键词: Address; Behavior; Biological Models; Biophysics; Catalytic Domain; Cell Proliferation; Cell membrane; Cells; Cereals; Cholesterol; Collaborations; Colorado; Complement; Coupled; Data; Elasticity; Electrostatics; Event; Exhibits; GTP Binding; Goals; HRAS gene; Homologous Protein; In Vitro; Lateral; Lead; Length; Letters; Lipids; Malignant Neoplasms; Membrane; Modeling; Molecular; Nature; Oncogene Proteins; Phase; Property; Protein Isoforms; Proteins; Regulation; Resources; Role; Shapes; Signal Transduction; Signaling Protein; Site; Sorting - Cell Movement; Testing; Therapeutic; Time; Universities; Unsaturated Fats; Variant; Vesicle; Work; abstracting; base; cell growth; driving force; interest; membrane model; molecular dynamics; molecular scale; nano; nanoscale; new therapeutic target; particle; prevent; ras Proteins; research study; saturated fat; segregation; simulation; spatiotemporal; supercomputer; theories; transmission process

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.

描述（由申请人提供）：膜中脂质锚定蛋白的纳米簇：它们如何形成以及在何处形成？ 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-脂质纳米团簇充当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域的分子基础仍然没有确定。因此，目前还不清楚同源蛋白质的纳米簇，如信号开关H-ras和K-ras，如何分离到不同的脂质结构域。我们假设这将通过基于脂质和基于蛋白质的分选机制的组合来实现。我们计划使用多尺度分子模拟和理论方法并辅以合作实验来验证这一假设。我们将使用H-和K-ras癌蛋白作为模型系统。Ras纳米团簇对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纳米簇时空组织的机制将有助于更好地理解细胞信号传导。此外，虽然该建议的重点是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和偶联蛋白/脂质分选的生物物理学的贡献。 公共卫生相关性：Ras纳米团簇对质膜上信号调节的独特机制具有有趣的影响，并且可能代表新的治疗靶点，以防止有缺陷的Ras信号传导，这是许多癌症的常见原因。阐明驱动Ras纳米簇的时空组织的机制将导致更好地理解细胞信号传导，并有助于靶向Ras纳米结构域的潜在治疗策略。