The Interplay Between Membrane Structure and Protein Interactions

蛋白质-膜相互作用是免疫学和神经生物学等多种过程中的关键事件，因为它们是信息在细胞膜上流动的手段。因此，蛋白-膜相互作用是多细胞生物细胞间通讯的关键。虽然已经做了很多工作来确定膜结合蛋白的特征赋予其靶标特异性，但膜脂组成在这些高度精确的相互作用中的作用还不太清楚。在这个研究项目中，PI将开发一个全面的框架来了解膜的性质如何影响蛋白质-脂质识别事件。要研究的系统的复杂性需要一种真正的多学科方法。采用分子免疫学、神经生物学、膜物理化学和界面x射线散射等技术和思想，该项目将为下一代跨学科科学家提供独特的培训机会。研究机会将扩展到合格的高中生和本科生。跨学科科学的概念将通过外展活动“物理学大爆炸！”蛋白-膜相互作用的调节部分是由外周膜蛋白对特定脂质的特异性决定的。然而，似乎有不同的参数被编码到膜中，由细胞动态控制，提供了不同但相关的途径来影响蛋白质与膜的结合和随后的功能。这项工作将解决两个基本问题：(1)外周膜结合蛋白如何正确识别和区分嵌入在脂质膜组成和结构中的信息？(2)在决定传统上被认为是膜曲率感知的蛋白质的结合行为和后续功能时，膜曲率和膜张力之间的关系是什么？对于前一个目标，PI将主要关注识别外叶磷脂酰丝氨酸磷脂的蛋白质。对于后一个目标，将研究利用在α -突触核蛋白中发现的两亲α螺旋基序的蛋白质的相互作用。据推测，这两类蛋白质都利用对膜性质和几何形状差异的敏感性来调节它们的差异识别性质。因此，本研究的主要重点是建立它们对基本理化膜参数结合的敏感性。该奖项反映了美国国家科学基金会的法定使命，并通过使用基金会的知识价值和更广泛的影响审查标准进行评估，被认为值得支持。

Protein-membrane interactions are key events in processes as diverse as immunology and neurobiology, as they are the means by which information flows across the cell membrane. Thus protein-membrane interactions are the key to intercellular communication in multicellular organisms. While much work has been done to define what features of membrane -binding proteins confer specificity for their targets, the role of membrane lipid composition in these highly precise interactions is less well understood. In this research project, the PI will develop a comprehensive framework for understanding how the properties of the membrane impact protein-lipid recognition events. The complexity of the systems to be studied requires a truly multidisciplinary approach. With techniques and ideas adapted from molecular immunology, neurobiology, membrane physical chemistry, and interfacial X-ray scattering, this program will provide a unique training opportunity for the next generation of interdisciplinary scientists. Research opportunities will extend to qualified high school and undergraduate students. Concepts in interdisciplinary science will be brought to school children through the outreach activity “Physics with a Bang!” Regulation of protein-membrane interactions is governed in part by the specificity of peripheral membrane proteins for specific lipids. However, there appears to be a diverse landscape of parameters encoded into membranes that is dynamically controlled by the cell, offering distinct but correlated avenues to affect protein binding to membranes and subsequent functions. The work will address two fundamental questions: (1) How is information embedded in the composition and structure of lipid membranes properly recognized and distinguished by peripheral membrane-binding proteins? and (2) What is the relationship between membrane curvature and membrane tension in determining the binding behavior and subsequent function of proteins traditionally thought to be membrane curvature-sensing? For the former goal, the PI will largely focus on proteins that recognize phosphatidylserine phospholipids in the outer leaflet. For the latter goal, interactions with proteins that utilize amphipathic alpha helical motifs such as those found in alpha-synuclein will be studied. It is hypothesized that both classes of proteins employ sensitivity to differences in membrane properties and geometry to mediate their differential recognition properties. Thus, the primary focus of this research is to establish such sensitivities of their binding to fundamental physiochemical membrane parameters.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.