Physicochemical foundations of lipid phosphomonoester group mediated cell signaling events

脂质磷酸单酯基团介导的细胞信号传导事件的理化基础

• 批准号: 1058719
• 负责人: Arne Gericke
• 金额: $ 44.25万
• 依托单位: Kent State University
• 依托单位国家: 美国
• 项目类别: Continuing Grant
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-01-15 至 2012-01-31
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=1058719&HistoricalAwards=false
• 关键词: Physicochemical; foundations; lipid; phosphomonoester; group

The extraordinary chemical diversity of lipids provides the foundation for the many roles they fulfill in cellular systems, which ranges from controlling the structural and morpho¬logical properties of cell membranes to mediating crucial cell signaling events. Lipids with phosphate groups are ideally suited to affect protein functions and they have been shown to control an ever-increasing array of cell signaling events. The selective binding of proteins to lipid molecules with phosphate groups like phosphoinositides, ceramide-1-phosphate, sphingosine-1-phosphate or phosphatidic acid provides the specificity of the signaling event. Kinases and phosphatases, which upon activation alter the number of phosphate groups attached to the lipid headgroup, provide the temporal control, while the spatial control is rooted in the rich chemical functionality of the respective headgroup that gives rise to local enrichment through interactions with other membrane resident molecules. Despite the importance for lipid signaling, lipids with phosphate groups in their headgroup have not been identified as a unit with a common theme and their properties have not been investigated in a comparative manner. The experiments outlined by the PIs are designed to identify the physico¬chemical commonalities these lipid signaling molecules exhibit, while at the same time they are designed to highlight the disparities among these lipids that give rise to their selective protein binding, differences in lateral distribution and their varying subcellular localization. The PIs will investigate the extent and consequences of hydrogen bond formation between like and unlike lipid species with phosphate groups, the effect of cholesterol on the lateral distribution of these lipids species, the interaction of these lipids with arginine, lysine and histidine amino acid residues and the impact of lipid morphology on the activity of lipid modifying enzymes. The PIs will continue their partnership with the Max Planck Institute (MPI) for Colloids and Interfaces (Germany). One undergraduate student each summer will visit the MPI for a 10 week inter¬national research experience that exposes the student to a different cultural environ¬ment and at the same time allows the student to work at a premier research institution. During the academic year undergraduate students will work in the PIs research labs, which will prepare them for their summer research experience. As in the past, the PIs will strive to identify students from groups underrepresented in the sciences for these experiences.

脂质的非凡化学多样性为其在细胞系统中发挥的许多作用提供了基础，这些作用的范围从控制细胞膜的结构和形态学特性到介导关键的细胞信号传导事件。具有磷酸基团的脂质非常适合影响蛋白质功能，并且它们已被证明可以控制不断增加的细胞信号传导事件。蛋白质与具有磷酸基团的脂质分子如磷酸肌醇、神经酰胺-1-磷酸、鞘氨醇-1-磷酸或磷脂酸的选择性结合提供了信号传导事件的特异性。激酶和磷酸酶在激活时改变连接到脂质头基的磷酸基团的数量，提供时间控制，而空间控制植根于各自头基的丰富化学功能性，其通过与其他膜驻留分子的相互作用引起局部富集。尽管对脂质信号传导的重要性，但在其头基中具有磷酸基团的脂质尚未被确定为具有共同主题的单元，并且尚未以比较的方式研究其性质。PI概述的实验旨在鉴定这些脂质信号传导分子表现出的物理化学共性，同时它们旨在突出这些脂质之间的差异，这些差异导致其选择性蛋白质结合、横向分布差异及其不同的亚细胞定位。PI将研究具有磷酸基团的相似和不同脂质物质之间氢键形成的程度和后果，胆固醇对这些脂质物质横向分布的影响，这些脂质与精氨酸，赖氨酸和组氨酸氨基酸残基的相互作用，以及脂质形态对脂质修饰酶活性的影响。 PI将继续与Max Planck胶体和界面研究所（MPI）（德国）合作。每年夏天，一名本科生将访问MPI进行为期10周的国际研究体验，使学生接触不同的文化环境，同时允许学生在一流的研究机构工作。在学年期间，本科生将在PI研究实验室工作，这将为他们的夏季研究经验做好准备。与过去一样，PI将努力从科学领域代表性不足的群体中识别学生，以获得这些经验。