Developing next-generation nanodiscs for the study and modulation of membrane proteins

开发下一代纳米圆盘用于膜蛋白的研究和调节

• 批准号: 10002560
• 负责人: Huan Bao
• 金额: $ 95.94万
• 依托单位: SCRIPPS FLORIDA
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-30 至 2022-04-01
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10002560
• 关键词: Address; Binding; Biochemistry; Complex; Detection; Detergents; Disease; Drug Targeting; Engineering; Environment; Exhibits; Homeostasis; Integral Membrane Protein; Label; Light; Lipid Bilayers; Lipids; Mediating; Membrane; Membrane Proteins; Peripheral; Pharmaceutical Preparations; Proteins; Reporter; Research; Signal Transduction; Specificity; Structure; Supporting Cell; System; Water; biophysical analysis; cell growth; chemical property; human disease; insight; macromolecule; nanodisk; next generation; therapeutic protein; tool; translational study

Abstract Membranes proteins are essential molecules to support cell growth, mediate signal transduction, and maintain homeostasis. They are either associated with, or embedded in the lipid bilayer, thus exhibit complex chemical properties and present formidable challenges for biophysical studies. Over the past few decades, enormous efforts have focused on providing mechanistic insights into these sophisticated macromolecules. However, the progress is hampered by the lack of robust tools to facilitate structural and functional studies for membrane proteins. Moreover, the water-insoluble lipid bilayer makes it notoriously difficult to modulate these proteins for therapeutic purposes. To address these problems, the proposed research aims to develop next-generation nanodiscs that enact simple and straightforward interrogation and modulation of membrane proteins. First, we will develop a detergent- free nanodisc system to ease the isolation of integral membrane proteins from their native lipid environment. Second, we will engineer nanodisc reporters to allow rapid and label-free detection of membrane binding and remodeling activities of peripheral membrane proteins. Finally, we will build fusogenic and switchable nanodiscs to drug membrane proteins with unprecedented specificity and efficacy. Together, these simple and versatile tools will significantly transform the field of membrane biochemistry and shed new light on membrane proteins that were previously thought to be unapproachable or undruggable.

摘要