Structure-function relationships of the chimeric TRPM7 channel-kinase
嵌合TRPM7通道激酶的结构-功能关系
基本信息
- 批准号:8075499
- 负责人:
- 金额:$ 27.26万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2010
- 资助国家:美国
- 起止时间:2010-06-01 至 2015-05-31
- 项目状态:已结题
- 来源:
- 关键词:14-3-3 ProteinsAdenosine Diphosphate RiboseAffectAntibodiesB-LymphocytesBiochemistryBiologicalBiological ProcessBiophysicsBiosensorC-terminalCell LineCell ProliferationCell modelCell physiologyCell surfaceCellsCellular MembraneCessation of lifeComplementComplexDevelopmentElongation FactorEnsureEnvironmentEventFamilyGeneticGenetic ModelsGenomicsGoalsHealthHomeostasisHomologous GeneHumanHydrolaseInterventionIon ChannelIonsLightLinkMediatingMembraneMetabolicModelingMoldsMolecularMolecular BiologyMolecular TargetMovementMutationN-terminalNutrientNutritionalPathway interactionsPatientsPermeabilityPhenotypePhosphorylationPhosphotransferasesPhysiologicalPlayPositioning AttributeProcessProteinsRegulationRelative (related person)RoleSerineSignal TransductionSpecificityStructureStructure-Activity RelationshipSubgroupSupplementationTRP channelThreonineTranslationsWorkaqueousbasecell assemblycell growthcyclic-nucleotide gated ion channelsdesignextracellularimmune functioninsightmembermonomermouse modelmutantnovelnovel strategiesphysical modelpublic health relevanceresearch studyresponsesulfated glycoprotein 2traffickingvoltage
项目摘要
DESCRIPTION (provided by applicant): The carefully orchestrated movement of ions across cellular membranes is crucial to virtually every biological process. Ion channels play thereby a central role by allowing the regulated flow of relevant ions through their aqueous pore. In the past few decades, progress made in Molecular Biology and Genomics has revealed the unsuspected variety of ion channels expressed in our membranes. The family of TRP channels with more than two dozens of members in humans that function as biosensors and signal integrators is a good illustration of this development. It includes the only known examples of ionic pores fused to enzymatic regions, so-called "chanzymes". TRPM7 and its close relative TRPM6 both harbor a kinase region at their C-terminus that is capable of phosphorylating protein substrates on Serine/Threonine residues. TRPM7 is widely distributed and has been shown to be an essential and irreplaceable molecule in several genetic models, including a B-lymphocyte cell line called DT40. TRPM7-deficiency in this context results in cell growth arrest and death, unless the extracellular media is supplemented with Mg2+, suggesting a role for TRPM7 in Mg2+- homeostasis regulation. Despite these insights into TRPM7's physiological function, the significance of its kinase region remains unclear. Understanding the role of this unique domain holds the promise to shed some light on novel mechanisms of cellular adjustments to a changing ionic environment. The main goal of this proposal is to investigate the relationship between the channel and kinase portions of TRPM7 by utilizing a combination of biochemistry, genetics and biophysics approaches, allowing for a detailed function-structure relationship study. We plan to determine how altering the ionic selectivity of TRPM7 channels through pore mutations might affect its kinase activity. Furthermore the functional importance of the covalent link between kinase and channel will be assessed by studying liberated domains and through the introduction of linker structures. Finally, we also designed experiments allowing us to define molecular determinants of channel assembly and trafficking to the cell surface.
PUBLIC HEALTH RELEVANCE: Ion channels form highly sophisticated pores in biological membranes allowing for the controlled movement of ions between biologically relevant compartments. Most are at the surface of the cell and therefore easily accessible for pharmacological intervention; many are validated molecular targets. Understanding the functional versatility of ion channels is therefore key to providing us with novel potential strategies of interfering with biological processes relevant to human health. The structural uniqueness of the TRPM7 protein as an ion channel/kinase fusion appears to be a reflection of its complex involvement in regulating cellular functions in response to nutrient availability. Understanding the molecular determinants of the interplay between kinase and ion channel function will therefore provide us with novel opportunities to influence processes such as cell proliferation or immune function.
描述(由申请人提供):离子穿过细胞膜的精心安排的运动对几乎每一个生物过程都是至关重要的。离子通道因此发挥中心作用,允许相关离子通过其水孔的调节流动。在过去的几十年里,分子生物学和基因组学的进步揭示了我们细胞膜中表达的各种离子通道。TRP通道家族在人类中有超过20个成员,其功能是生物传感器和信号整合器,这是这一发展的一个很好的例证。它包括唯一已知的离子孔融合到酶区域的例子,即所谓的“酶”。TRPM7及其近亲TRPM6在其c端都有一个激酶区域,能够磷酸化丝氨酸/苏氨酸残基上的蛋白质底物。TRPM7分布广泛,在包括b淋巴细胞系DT40在内的多种遗传模型中被证明是必不可少的不可替代的分子。在这种情况下,TRPM7缺乏会导致细胞生长停滞和死亡,除非细胞外培养基中补充了Mg2+,这表明TRPM7在Mg2+稳态调节中起作用。尽管对TRPM7的生理功能有了这些了解,但其激酶区域的意义仍不清楚。了解这一独特结构域的作用,有助于揭示细胞适应离子环境变化的新机制。本研究的主要目的是通过结合生物化学、遗传学和生物物理学的方法来研究TRPM7的通道和激酶部分之间的关系,从而进行详细的功能结构关系研究。我们计划确定通过孔隙突变改变TRPM7通道的离子选择性如何影响其激酶活性。此外,激酶和通道之间的共价连接的功能重要性将通过研究释放结构域和通过引入连接结构来评估。最后,我们还设计了实验,使我们能够定义通道组装和运输到细胞表面的分子决定因素。
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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CARSTEN SCHMITZ其他文献
CARSTEN SCHMITZ的其他文献
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{{ truncateString('CARSTEN SCHMITZ', 18)}}的其他基金
Modulation of PLCgamma2-Mediated Signaling Via its C2-Domain in B Lymphocytes
通过 B 淋巴细胞中的 C2 结构域调节 PLCgamma2 介导的信号传导
- 批准号:
8077419 - 财政年份:2010
- 资助金额:
$ 27.26万 - 项目类别:
Structure-function relationships of the chimeric TRPM7 channel-kinase
嵌合TRPM7通道激酶的结构-功能关系
- 批准号:
8477208 - 财政年份:2010
- 资助金额:
$ 27.26万 - 项目类别:
Structure-function relationships of the chimeric TRPM7 channel-kinase
嵌合TRPM7通道激酶的结构-功能关系
- 批准号:
8291012 - 财政年份:2010
- 资助金额:
$ 27.26万 - 项目类别:
Modulation of PLCgamma2-Mediated Signaling Via its C2-Domain in B Lymphocytes
通过 B 淋巴细胞中的 C2 结构域调节 PLCgamma2 介导的信号传导
- 批准号:
7875500 - 财政年份:2010
- 资助金额:
$ 27.26万 - 项目类别:
Structure-function relationships of the chimeric TRPM7 channel-kinase
嵌合TRPM7通道激酶的结构-功能关系
- 批准号:
7768667 - 财政年份:2010
- 资助金额:
$ 27.26万 - 项目类别: