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:8291012
- 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):离子在细胞膜上精心编排的移动对几乎每一个生物过程都是至关重要的。因此,离子通道通过允许相关离子通过其水孔调节流动而发挥中心作用。在过去的几十年里,分子生物学和基因组学的进展揭示了在我们的细胞膜上表达的各种意想不到的离子通道。作为生物传感器和信号集成器的Trp通道家族在人类中有超过240个成员,就是这一发展的很好例证。它包括唯一已知的离子孔融合到酶区域的例子,即所谓的“Chanzymes”。TRPM7和它的近亲TRPM6都在其C末端含有一个能够使丝氨酸/苏氨酸残基上的蛋白底物磷酸化的激动区。TRPM7分布广泛,已被证明是几种遗传模型中必不可少且不可替代的分子,包括名为DT40的B淋巴细胞系。在这种情况下,TRPM7缺乏会导致细胞生长停滞和死亡,除非细胞外培养液中补充了镁离子,这表明TRPM7在镁离子稳态调节中发挥了作用。尽管对TRPM7的S的生理功能有了这些深入的了解,但其激酶区域的意义仍不清楚。了解这个独特的结构域的作用,有望为细胞适应不断变化的离子环境的新机制提供一些线索。这项建议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,以便进行详细的功能-结构关系研究。我们计划确定通过孔突变改变TRPM7通道的离子选择性如何影响其激酶活性。此外,将通过研究被解放的结构域和通过引入连接物结构来评估激酶和通道之间的共价连接的功能重要性。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。
与公共卫生相关:离子通道在生物膜上形成高度复杂的小孔,允许离子在与生物相关的隔室之间受控移动。大多数位于细胞表面,因此很容易进行药物干预;许多是有效的分子靶点。因此,了解离子通道的功能多样性是为我们提供干扰与人类健康相关的生物过程的新的潜在策略的关键。TRPM7蛋白作为离子通道/激酶融合蛋白的结构独特性似乎反映了它参与调节细胞功能以响应营养可获得性的复杂参与。因此,了解激酶和离子通道功能相互作用的分子决定因素将为我们提供新的机会来影响细胞增殖或免疫功能等过程。
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)
数据更新时间:{{ journalArticles.updateTime }}
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
数据更新时间:{{ journalArticles.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ monograph.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ sciAawards.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ conferencePapers.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ patent.updateTime }}
CARSTEN SCHMITZ其他文献
CARSTEN SCHMITZ的其他文献
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
{{ 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:
8075499 - 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: