Protein Networks as Synergistic Drivers of Membrane Remodeling

蛋白质网络作为膜重塑的协同驱动因素

• 批准号: 10555287
• 负责人: Jeanne Casstevens Stachowiak
• 金额: $ 64.32万
• 依托单位: UNIVERSITY OF TEXAS AT AUSTIN
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-02-01 至 2026-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10555287
• 关键词: Area; Behavior; Biological Process; Biology; Cell physiology; Cells; Clathrin; Coupled; Defect; Diabetes Mellitus; Disease; Endocytosis; Event; Filopodia; Human; In Vitro; Individual; Integral Membrane Protein; Knowledge; Liquid substance; Malignant Neoplasms; Mediating; Membrane; Membrane Protein Traffic; Mission; Modeling; Molecular; Needles; Pathway interactions; Pharmaceutical Preparations; Proteins; Public Health; Research; Role; Shapes; Structure; Structure-Activity Relationship; Surface; Tertiary Protein Structure; Therapeutic; United States National Institutes of Health; Vesicle; Virus Replication; Work; disability; driving force; flexibility; human disease; insight; nervous system disorder; novel; pathogen; pressure; receptor recycling; scaffold; trafficking

Summary Abstract: Protein Networks as Synergistic Drivers of Membrane Remodeling Membrane curvature is required for many cellular processes, from assembly of highly curved trafficking vesicles to extension of needle-like filopodia. Consequently, defects in membrane curvature play a role in most human diseases, including altered recycling of receptors in cancer and diabetes, targeting of filopodia by pathogens, and hijacking of vesicle traffic during virus replication. Therefore, understanding the basic molecular mechanisms that drive membrane remodeling is essential to our knowledge of cellular physiology and human disease. Research on membrane curvature has primarily focused on individual protein domains with specialized structures, such as crescent-shaped scaffolds and wedge-like amphipathic insertions. While this work has provided invaluable insights, this “structure-centric” perspective ignores two essential facts. First, most membrane remodeling proteins contain large intrinsically disordered domains in addition to structured domains. And second these disordered domains drive assembly of large, multi-valent protein networks. During the past 5 years, our group has made pioneering discoveries in support of the hypothesis that disordered protein networks are essential drivers of membrane remodeling in the cell. Specifically, using clathrin-mediated endocytosis as a model pathway, we showed that intrinsically disordered domains generate steric pressure at membrane surfaces. This pressure provides a surprisingly potent driving force for membrane bending, especially when coupled synergistically to the contributions of structured domains. This work was the first to reveal the membrane remodeling abilities of disordered proteins, examples of which have since been discovered in diverse areas of biology. Additionally, we have recently found that disordered domains within endocytic proteins drive assembly of liquid-like protein networks which efficiently initiate endocytosis. Importantly, this liquid-like behavior has the potential to resolve a long-standing paradox by explaining how curved membrane structures can be simultaneously highly interconnected, yet dynamic and flexible. These findings suggest urgent questions about the role of disordered protein networks in the key steps of membrane remodeling: (i) initiation, (ii) curvature induction, and (iii) cargo selection. First, how do protein networks initiate remodeling events, controlling their spatial and temporal dynamics? Second, once an event is initiated, how do protein networks bend membranes, stabilizing either a convex or a concave shape? Third, as the membrane bends, how does the protein network select cargo, such as transmembrane proteins, which are essential to the structure’s biological function? Building on our recent discoveries, this work will shift the paradigm for understanding membrane curvature beyond its present focus on in vitro structure-function relationships toward an understanding of disordered protein networks. By demonstrating novel synergistic mechanisms, this research will provide a blueprint for the study of protein networks at membrane surfaces throughout the cell.

摘要摘要：蛋白质网络作为膜重塑的协同驱动因素 膜曲率是许多细胞过程所必需的，来自高度弯曲的运输囊泡的组装 到针状丝状伪足的延伸。因此，膜曲率的缺陷在大多数人中起作用。 疾病，包括癌症和糖尿病中受体的再循环改变，病原体对丝状伪足的靶向， 以及在病毒复制期间劫持囊泡交通。因此，了解基本的分子机制 驱动细胞膜重塑的基因对我们了解细胞生理学和人类疾病至关重要。 对膜曲率的研究主要集中在具有专门功能的单个蛋白质结构域上。 结构，如新月形支架和楔形两亲插入物。虽然这项工作 这种“以结构为中心”的观点提供了宝贵的见解，但却忽略了两个基本事实。一是多数 膜重塑蛋白除了结构化结构域之外还含有大的内在无序结构域。 第二，这些无序的结构域驱动大型多价蛋白质网络的组装。 在过去的5年里，我们的团队已经取得了支持这一假设的开创性发现。 无序的蛋白质网络是细胞膜重塑的重要驱动力。具体地说， 使用网格蛋白介导的内吞作用作为模型途径，我们表明， 在膜表面产生空间压力。这种压力提供了一个令人惊讶的强大驱动力， 膜弯曲，特别是当耦合协同结构域的贡献。这 这项工作首次揭示了无序蛋白质的膜重塑能力，其中的例子有 已经在生物学的各个领域被发现。此外，我们最近发现，无序畴 在胞吞蛋白质内驱动有效启动胞吞作用的液体样蛋白质网络的组装。 重要的是，这种类似液体的行为有可能通过解释如何解决一个长期存在的悖论， 弯曲的膜结构可以同时高度互连，但仍然是动态的和柔性的。 这些发现提出了关于无序蛋白质网络在关键步骤中的作用的紧迫问题 膜重塑的步骤：（i）起始，（ii）曲率诱导，和（iii）货物选择。一、蛋白质如何 网络启动重塑事件，控制它们的空间和时间动态？第二，一旦一个事件 首先，蛋白质网络是如何使膜弯曲，从而稳定凸形或凹形的？三是随着 膜弯曲，蛋白质网络如何选择货物，如跨膜蛋白，这是 对结构的生物功能至关重要吗基于我们最近的发现，这项工作将改变 了解膜曲率超越其目前的重点在体外结构-功能关系 对无序蛋白质网络的理解。通过展示新的协同机制， 这项研究将为研究整个细胞膜表面的蛋白质网络提供蓝图。