SNARE function and phosphoinositide induced conformational and oligomeric changes

细胞通讯对许多生理过程都很重要。细胞器是细胞内的膜结合结构，通过囊泡内物质的运输和融合进行通信。许多蛋白质控制融合，但膜本身的作用尚不清楚。膜含有特殊的脂质，众所周知，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。研究者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。“更广泛的影响”活动包括培训各级科学家，包括女性和其他代表性不足的学生。此外，研究者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荣誉徽章顾问，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，因此了解膜融合的过程是必要的。SNARE蛋白在膜融合过程中至关重要，在这个项目中，研究者试图了解SNARE蛋白如何驱动膜融合。这个项目的重点是SNARE蛋白Vam7，已知它可以触发囊泡融合；然而，脂质环境对Vam7的调控尚不清楚。研究者将利用生物化学和生物物理方法来了解膜脂如何与Vam7结构域相互作用，阐明脂质结合如何诱导Vam7构象变化和多聚化，并研究Vam7脂质结合和多聚化如何影响巨噬的不同阶段。这个项目的完成将定义Vam7是如何被膜调节来促进融合的。在研究目标的同时，调查人员积极招募女性和少数族裔作为研究生和本科生。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。

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.