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

基本信息

批准号：
8535794
负责人：
Alemayehu A. Gorfe
金额：
$ 27.87万
依托单位：
UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON
依托单位国家：
美国
项目类别：
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/8535794
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

项目摘要

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.

描述（由申请人提供）：膜中脂质锚定蛋白的纳米簇：它们如何以及在何处形成？摘要最近的研究表明，脂质锚定信号蛋白在质膜上动态组织成纳米级亚结构。由此产生的蛋白质-脂质纳米团簇可作为高保真信号传输的枢纽。然而，纳米簇如何在异质膜域中形成和分布的分子基础仍未确定。因此，目前尚不清楚同源蛋白的纳米簇（例如信号开关 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协作实验来检验这一假设。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传导。此外，虽然该提案的重点是 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。这项工作更广泛的影响包括对针对 Ras 纳米结构域的潜在治疗策略和耦合蛋白质/脂质分选的生物物理学的贡献。