Mechanotransduction via LIM Domain Protein Mechanosensing
通过 LIM 结构域蛋白机械传感进行机械转导
基本信息
- 批准号:10735689
- 负责人:
- 金额:$ 30.68万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2023
- 资助国家:美国
- 起止时间:2023-09-01 至 2028-07-31
- 项目状态:未结题
- 来源:
- 关键词:AblationActinsAdhesionsAffectArchitectureBindingBinding ProteinsBinding SitesBiochemicalBreathingCancerousCellsCellular StructuresCellular biologyChimera organismCytoskeletonDataDevelopmentDiseaseEnvironmentExtracellular MatrixFamilyFamily memberFocal AdhesionsImpairmentIndividualIntegrinsKineticsKnowledgeLIM DomainLIM Domain ProteinLasersLocationMachine LearningMeasuresMechanicsMediatingMicrofilamentsMolecular ConformationMotorPTK2 genePhenylalaninePhosphorylationPhysiological ProcessesPhysiologyPlayPolymersProcessProteinsResearchRoleSignal PathwaySignal TransductionSignaling ProteinSiteSmooth Muscle MyocytesStressStress FibersStretchingStructureTalinTestingTissuesTractionVinculinWorkZYX geneadhesion receptorbiophysical techniquescell behaviorexperimental studyextracellularinsightmechanical forcemechanical signalmechanotransductionmigrationnew therapeutic targetnoveloptogeneticspaxillinpolymerizationpressureprotein purificationrecruitrepairedrespiratory smooth muscleresponsetransmission process
项目摘要
Project Summary
Mechanical interactions play a fundamental role in physiology, allowing cells to move, generate forces, and
assemble into multicellular structures. Key to these processes is the ability of cells to turn mechanical signals
into biochemical signals, an activity known as mechanotransduction. The search for mechanosensitive proteins
that could facilitate mechanotransduction has primarily focused on proteins that undergo conformational
changes in response to force or proteins that display changes in the bond kinetics under load. There exists
another class of proteins, however, that recognize structures under strain.
The canonical example of this class of proteins is the LIM domain protein zyxin, which recognizes strained
actin stress fibers and recruits actin polymerization factors to repair them. Recent work has highlighted that the
strain sensing mechanism of the LIM domains is not unique to zyxin and that numerous other members of the
family of LIM domain proteins display a similar ability. This suggests LIM domain proteins could act as
mechanotransducers, recognizing strain via their LIM domains and converting it to other biochemical signals
via interactions with the other domains in the protein. To explore this hypothesis further it is crucial that we
understand how LIM domains recognize strained actin filaments, and how those interactions propagate signals
downstream of the strain sites.
Here we propose to establish rigorous experimental strategies to decipher the mechanisms underlying LIM
domain protein mechanotransduction. We employ a combination of biophysical techniques including laser
ablations, optogenetics and cell stretching to quantitatively and repeatedly induce strain sites in the actin
cytoskeleton. In Aim 1 we will test alternative mechanisms of LIM domain strain sensing by comparing proteins
from the testin family of LIM domain proteins which require only a single LIM domain to recognize strain sites,
compared to the three tandem LIM domains that zyxin requires. In Aim 2 we will test whether in addition to
stretched actin filaments in stress fibers, LIM domain proteins can recognize other strained actin structures,
such as compressed stress fibers or actin meshworks. Finally, in Aim 3 we will investigate how binding of LIM
domain proteins to strain sites leads to a propagation of that mechanical signal to other parts of the stress fiber
and the extracellular matrix. Together these studies will greatly expand our knowledge of mechanotransduction
and provide insight into this fundamental signaling mechanism.
项目摘要
机械相互作用在生理学中起着重要作用,使细胞能够移动,产生力,
组装成多细胞结构。这些过程的关键是细胞转换机械信号的能力
转化为生化信号,这种活动被称为机械传导。机械敏感蛋白的研究
可以促进机械转导的研究主要集中在经历构象转换的蛋白质上,
响应于力的变化或在负载下显示键动力学变化的蛋白质。存在
然而,另一类蛋白质在压力下识别结构。
这类蛋白质的典型例子是LIM结构域蛋白质zyxin,其识别应变的
肌动蛋白应力纤维和招募肌动蛋白聚合因子来修复它们。最近的研究表明,
LIM结构域的应变传感机制不是zyxin所独有的,
LIM结构域蛋白家族显示出类似的能力。这表明LIM结构域蛋白可以作为
机械传感器,通过其LIM结构域识别菌株并将其转化为其他生化信号
通过与蛋白质中其他结构域的相互作用。为了进一步探讨这一假设,我们必须
了解LIM结构域如何识别张力肌动蛋白丝,以及这些相互作用如何传播信号
应变位点的下游。
在这里,我们建议建立严格的实验策略来破译LIM的机制
结构域蛋白机械转导。我们采用生物物理技术的组合,包括激光
消融、光遗传学和细胞拉伸,以定量和重复地诱导肌动蛋白中的应变位点,
细胞骨架在目标1中,我们将通过比较蛋白质来测试LIM结构域应变传感的替代机制。
来自仅需要单个LIM结构域来识别菌株位点的LIM结构域蛋白的testin家族,
与zyxin需要的三个串联LIM结构域相比。在目标2中,我们将测试除了
在应力纤维中拉伸的肌动蛋白丝,LIM结构域蛋白可以识别其他拉伸的肌动蛋白结构,
例如压缩应力纤维或肌动蛋白网。最后,在目标3中,我们将研究LIM如何结合
结构域蛋白到应变位点导致该机械信号传播到应力纤维的其它部分
和细胞外基质。这些研究将极大地扩展我们对机械传导的认识
并提供对这种基本信号机制的深入了解。
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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{{ truncateString('Patrick William Oakes', 18)}}的其他基金
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