Molecular Properties of Diacylglycerol Kinase Epsilon
二酰甘油激酶 Epsilon 的分子特性
基本信息
- 批准号:RGPIN-2018-05585
- 负责人:
- 金额:$ 3.06万
- 依托单位:
- 依托单位国家:加拿大
- 项目类别:Discovery Grants Program - Individual
- 财政年份:2019
- 资助国家:加拿大
- 起止时间:2019-01-01 至 2020-12-31
- 项目状态:已结题
- 来源:
- 关键词:
项目摘要
The proposal is focused on a unique member of the family of mammalian diacylglycerol kinases, i.e. DGK. DGK plays a key role in signal transduction and lipid synthesis. It is the only known member of this group that appears to have specificity for one particular species of substrate, i.e. 1-stearoyl-2-arachidonoyl glycerol. This is the same acyl chain composition as is found in lipid intermediates of the phosphatidylinositol (PI) cycle, the sole pathway for the synthesis of PI and its phosporylated products that play a major role in metabolic regulation and cancer. Interconversion of these phosphorylated forms of PI is highly dependent on the nature of the acyl chains. DGK contributes to the specific acyl chain composition of several lipids involved in cell signaling. The product of the reaction catalyzed by DGK, phosphatidic acid, is also an important signaling agent as well as being a precursor for several other lipids. We have successfully purified catalytically active DGK. This provides an opportunity to understand the molecular structure of this protein. It would be the first mammalian DGK isoform to have its structure determined and would provide a model for the analysis of other isoforms that have some homologous segments and for understanding the functioning of this important family of signaling proteins. We will also study how this protein interacts with membranes and with its substrate. It will be an important example of a peripheral membrane protein that interacts with lipid segments buried in the membrane. In cells DGK functions when bound to a bilayer membrane. Before our success in purifying this enzyme, all activity studies were done in assays using detergent micelles. However, we are now able to use the purified enzyme to assay the activity in liposomes made of bilayer membranes. We found a marked difference between the micellar-based and the liposome-based assays and a dependence of both the activity and specificity on the chemical and physical properties of the lipids used to make the liposomes. This will enable us to gain an understanding of how the functioning of DGK is dependent on the nature of the membrane to which it is bound. This research program will determine how peripheral membrane proteins can bind to membranes and recognize lipid substrates. The example of DGK is of particular importance because of its involvement in determining the acyl chain composition of PI. There is currently no structural information on this protein and no reported studies of its activity on liposomes. Our work will provide important novel structural and functional information. It will contribute to our general understanding of the mechanism of acyl chain recognition by interfacial enzymes and in particular as applied to DGK. This information will provide a more accurate description of an aspect of the regulation of biological systems that eventually will be used for their control.
该提议集中于哺乳动物二酰基甘油激酶家族的独特成员,即DGK。DGK在信号转导和脂质合成中起关键作用。它是该组中唯一已知的对一种特定底物(即1-硬脂酰-2-花生四烯酰甘油)具有特异性的成员。这与磷脂酰肌醇(PI)循环的脂质中间体中发现的酰基链组成相同,PI循环是合成PI及其磷酸化产物的唯一途径,其在代谢调节和癌症中起主要作用。PI的这些磷酸化形式的相互转化高度依赖于酰基链的性质。DGK有助于参与细胞信号传导的几种脂质的特定酰基链组成。由DGK催化的反应产物磷脂酸也是一种重要的信号传导剂,也是几种其他脂质的前体。我们成功地纯化了具有催化活性的DGK。这为了解这种蛋白质的分子结构提供了机会。这将是第一个哺乳动物DGK亚型有其结构确定,并将提供一个模型,分析其他亚型有一些同源片段,并了解这个重要的信号蛋白家族的功能。我们还将研究这种蛋白质如何与膜及其底物相互作用。这将是一个重要的例子,外周膜蛋白,与脂质段埋在膜。在细胞中,DGK在结合到双层膜时起作用。在我们成功纯化这种酶之前,所有的活性研究都是在使用洗涤剂胶束的测定中进行的。然而,我们现在能够使用纯化的酶来测定由双层膜制成的脂质体中的活性。我们发现基于胶束和基于脂质体的测定之间存在显著差异,并且活性和特异性均依赖于用于制备脂质体的脂质的化学和物理性质。这将使我们能够了解DGK的功能如何依赖于它所结合的膜的性质。这项研究计划将确定外周膜蛋白如何与膜结合并识别脂质底物。DGK的例子是特别重要的,因为它参与决定PI的酰基链组成。目前没有关于这种蛋白质的结构信息,也没有关于其对脂质体活性的研究报告。我们的工作将提供重要的新的结构和功能信息。这将有助于我们对界面酶的酰基链识别机制的一般理解,特别是适用于DGK。这一信息将提供一个更准确的描述的一个方面的调节生物系统,最终将用于其控制。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Epand, Richard其他文献
Epand, Richard的其他文献
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{{ truncateString('Epand, Richard', 18)}}的其他基金
Molecular Properties of Diacylglycerol Kinase Epsilon
二酰甘油激酶 Epsilon 的分子特性
- 批准号:
RGPIN-2018-05585 - 财政年份:2022
- 资助金额:
$ 3.06万 - 项目类别:
Discovery Grants Program - Individual
Molecular Properties of Diacylglycerol Kinase Epsilon
二酰甘油激酶 Epsilon 的分子特性
- 批准号:
RGPIN-2018-05585 - 财政年份:2021
- 资助金额:
$ 3.06万 - 项目类别:
Discovery Grants Program - Individual
Molecular Properties of Diacylglycerol Kinase Epsilon
二酰甘油激酶 Epsilon 的分子特性
- 批准号:
RGPIN-2018-05585 - 财政年份:2020
- 资助金额:
$ 3.06万 - 项目类别:
Discovery Grants Program - Individual
Molecular Properties of Diacylglycerol Kinase Epsilon
二酰甘油激酶 Epsilon 的分子特性
- 批准号:
RGPIN-2018-05585 - 财政年份:2018
- 资助金额:
$ 3.06万 - 项目类别:
Discovery Grants Program - Individual
Membrane Interactions and Diacylglycerol Kinases
膜相互作用和二酰甘油激酶
- 批准号:
9848-2013 - 财政年份:2017
- 资助金额:
$ 3.06万 - 项目类别:
Discovery Grants Program - Individual
Membrane Interactions and Diacylglycerol Kinases
膜相互作用和二酰甘油激酶
- 批准号:
9848-2013 - 财政年份:2016
- 资助金额:
$ 3.06万 - 项目类别:
Discovery Grants Program - Individual
Membrane Interactions and Diacylglycerol Kinases
膜相互作用和二酰甘油激酶
- 批准号:
9848-2013 - 财政年份:2015
- 资助金额:
$ 3.06万 - 项目类别:
Discovery Grants Program - Individual
Membrane Interactions and Diacylglycerol Kinases
膜相互作用和二酰甘油激酶
- 批准号:
9848-2013 - 财政年份:2014
- 资助金额:
$ 3.06万 - 项目类别:
Discovery Grants Program - Individual
Membrane Interactions and Diacylglycerol Kinases
膜相互作用和二酰甘油激酶
- 批准号:
9848-2013 - 财政年份:2013
- 资助金额:
$ 3.06万 - 项目类别:
Discovery Grants Program - Individual
Isothermal titration calorimeter
等温滴定量热仪
- 批准号:
439731-2013 - 财政年份:2012
- 资助金额:
$ 3.06万 - 项目类别:
Research Tools and Instruments - Category 1 (<$150,000)
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Molecular Properties of Diacylglycerol Kinase Epsilon
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