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: 10334421
• 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/10334421
• 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; Play; 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：蛋白质网络作为膜重塑的协同驱动因素 从高度弯曲的运输囊泡的组装开始，许多细胞过程都需要膜的曲率。 到针状丝状足的延伸。因此，膜弯曲缺陷在大多数人类中起作用。 疾病，包括癌症和糖尿病中受体循环的改变，病原体以丝状伪足为靶标， 以及在病毒复制期间劫持水泡流量。因此，理解基本的分子机制 驱动膜重塑对于我们对细胞生理学和人类疾病的了解是必不可少的。 膜曲率的研究主要集中在单个蛋白质结构域上，具有特殊的 结构，如新月形脚手架和楔形两亲性插入物。虽然这项工作已经 这种“以结构为中心”的观点提供了宝贵的见解，忽视了两个基本事实。第一，大多数 膜重塑蛋白除了含有结构域外，还含有较大的无序结构域。 其次，这些无序的结构域推动了大型多价蛋白质网络的组装。 在过去的5年里，我们团队取得了支持这一假说的开创性发现。 无序的蛋白质网络是细胞膜重塑的重要驱动因素。具体来说， 使用笼状蛋白介导的内吞作用作为模型途径，我们证明了本质上无序的结构域 在膜表面产生立体压力。这种压力提供了令人惊讶的强大推动力 膜弯曲，特别是当协同作用于结构域的作用时。这 这项工作首次揭示了无序蛋白质的膜重塑能力，例如 自那以后在生物学的各个领域都被发现了。此外，我们最近发现，无序的结构域 在内吞体内，蛋白质驱动液状蛋白质网络的组装，从而有效地启动内吞作用。 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 曲面膜结构可以同时高度相互连接，但又具有动态性和灵活性。 这些发现提出了关于无序的蛋白质网络在关键步骤中的作用的紧迫问题 膜重塑：(I)启动，(Ii)曲率诱导，(Iii)货物选择。首先，蛋白质是如何 网络启动重塑事件，控制其空间和时间动态？第二，一旦一个事件 蛋白质网络如何弯曲细胞膜，稳定凸形或凹形？第三，AS 膜弯曲，蛋白质网络如何选择货物，如跨膜蛋白，这些是 对这个结构的生物功能至关重要吗？在我们最新发现的基础上，这项工作将改变范式 为了了解膜的曲率，超越了目前对体外结构-功能关系的关注 有助于理解无序的蛋白质网络。通过展示新的协同机制，这 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。