SNARE function and phosphoinositide induced conformational and oligomeric changes

SNARE 功能和磷酸肌醇诱导的构象和寡聚变化

• 批准号: 2216742
• 负责人: Rutilio Fratti
• 金额: $ 112.37万
• 依托单位: University of Illinois at Urbana-Champaign
• 依托单位国家: 美国
• 项目类别: Continuing Grant
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-07-15 至 2026-06-30
• 项目状态: 未结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=2216742&HistoricalAwards=false
• 关键词: SNARE; function; phosphoinositide; induced; conformational

Cellular communication is important for a multitude of physiological processes. Organelles are membrane bound structures within the cell that communicate through the transport and fusing of materials in vesicles. Many proteins control fusion, yet the role of the membrane itself remains unclear. Membranes contain specialized lipids, and it is known that altering these lipids will negatively impact vesicle fusion; however, the mechanism of this is unknown. The investigator will study how lipids affect protein function during fusion to paint a better picture of this process. The Broader Impact activities include training of scientists at all levels, including female and other underrepresented students. In addition, the investigator is also a member of the Boy Scouts of America and will serve as a merit badge counselor for Chemistry, Nuclear Science, and Public Health where he hopes to spark a life-long curiosity in science.Eukaryotes rely on membrane fusion to maintain cellular homeostasis, including processes such as exocytosis, endocytosis, and exosome release, making it imperative to understand the processes that make membrane fusion possible. SNARE proteins are critical in the membrane fusion process and in this project, the investigator seeks to understand how SNARE proteins drive membrane fusion. This project focuses on the SNARE protein Vam7, which is known to trigger vesicle fusion; however, Vam7’s regulation by the lipid environment is unclear. The investigator will use biochemical and biophysical approaches to understand how membrane lipids interact with Vam7 domains, elucidate how lipid binding induces Vam7 conformational changes and multimerization, and investigate how Vam7 lipid binding and multimerization can affect different stages of macroautophagy. The completion of this project will define the how Vam7 is regulated by the membrane to promote fusion. In parallel to the research aims, the investigator actively recruits women and underrepresented minorities as both graduate students and undergraduates.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.

细胞通信对于许多生理过程是重要的。细胞器是细胞内的膜结合结构，其通过囊泡中的物质的运输和融合进行通信。许多蛋白质控制融合，但膜本身的作用仍不清楚。膜含有专门的脂质，并且已知改变这些脂质会对囊泡融合产生负面影响;然而，其机制尚不清楚。研究人员将研究脂质如何影响融合过程中的蛋白质功能，以更好地描绘这一过程。“更广泛影响”活动包括培训各级科学家，包括女学生和其他代表性不足的学生。此外，研究人员也是美国童子军的成员，并将担任化学，核科学和公共卫生的功勋徽章顾问，他希望在那里激发对科学的终身好奇心。真核生物依靠膜融合来维持细胞内稳态，包括胞吐，内吞和外泌体释放等过程，这使得我们必须了解使膜融合成为可能的过程。SNARE蛋白在膜融合过程中至关重要，在这个项目中，研究人员试图了解SNARE蛋白如何驱动膜融合。该项目的重点是SNARE蛋白Vam 7，这是已知的触发囊泡融合;然而，Vam 7的调节脂质环境是不清楚的。研究人员将使用生物化学和生物物理方法来了解膜脂质如何与Vam 7结构域相互作用，阐明脂质结合如何诱导Vam 7构象变化和多聚化，并研究Vam 7脂质结合和多聚化如何影响不同阶段的macroautophagy。该项目的完成将定义Vam 7如何被膜调节以促进融合。在研究目标的同时，研究人员积极招募妇女和代表性不足的少数民族作为研究生和本科生。该奖项反映了NSF的法定使命，并被认为是值得通过使用基金会的智力价值和更广泛的影响审查标准进行评估的支持。