Positive and negative regulation of the cytokinesis contractility controller
胞质分裂收缩性控制器的正向和负向调节
基本信息
- 批准号:9610830
- 负责人:
- 金额:$ 4.45万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2018
- 资助国家:美国
- 起止时间:2018-07-02 至 2020-07-01
- 项目状态:已结题
- 来源:
- 关键词:ActinsAcuteAffectAffinityBehaviorBindingBiochemicalBiochemical PathwayBiological ProcessBiologyCardiac MyosinsCell ShapeCell divisionCell physiologyCellsChemicalsComplexContractile ProteinsCrosslinkerCytokinesisCytoskeletal ProteinsDataDevelopmentDevelopmental ProcessDictyosteliumDimerizationDiseaseDominant-Negative MutationEmbryonic DevelopmentEnvironmentEnzymesExcisionFeedbackFilamentFluorescenceGeneticGoalsHepatocyteHuman BiologyImageImmunoprecipitationIn VitroInterphaseLightLungMalignant neoplasm of pancreasMass Spectrum AnalysisMeasuresMechanicsMediatingMitotic spindleModelingMolecularMorphogenesisMyoblastsMyosin ATPaseMyosin Type IINeoplasm MetastasisOxidoreductasePost-Translational Protein ProcessingProcessProductionProteinsRegulationResolutionRoleScaffolding ProteinShapesSignal PathwaySignal TransductionSignaling ProteinSiteSpectrum AnalysisStressSystemTestingTissuesWorkbiophysical analysiscancer cellcell motilitycortexillin Icrosslinkdaughter cellgenetic regulatory proteingenetic selectionhuman diseasein vivoinsightloss of functionmechanical behaviormechanical forcemethylmalonatemutantnon-muscle myosinoverexpressionpropionyl-coenzyme Arecruitresponsescaffoldsensorsingle molecule
项目摘要
PROJECT SUMMARY
Every biological process, ranging from cell migration to embryogenesis and tissue morphogenesis, relies on a
cell’s ability to adapt to changing mechanical environments. While we understand many biochemical signaling
pathways involved, the mechanisms that are integrated to govern a cell’s response to mechanical forces
remain a mystery. Deciphering these interactions will shed light on the mechanical changes that drive both
normal and disease state processes. To reveal how the cell responds to various forces, the Robinson lab
studies Dictyostelium cytokinesis, a model shape change process by which one cell divides to form two
daughter cells. The lab has discovered that cytokinesis is driven by an integrated control system composed of
proteins that modulate their behavior in response to both mechanical and biochemical signals. Although we
know many of the players involved in the cytokinetic control system, their biochemical interactions that allow
force propagation through the cortical network are still unknown. My goal is to characterize the regulatory
mechanisms that characterize these interactions, which will be critical to elucidate the mechanisms of a cell’s
response to its mechanical environment. To identify the direct interactions that govern a cell’s mechanical
response, we performed immunoprecipitation followed by mass spectrometry on two key nodes of the
cytokinetic control system, the scaffolding protein IQGAP2 and the actin crosslinker cortexillin I. This approach
led to the discovery of potential binding partners of these nodes. Using a combination of Fluorescence Cross-
Correlation Spectroscopy (FCCS) and Single Molecule Pulldown (SiMPull), we have discovered a potential
mechanism of inhibition by a negative regulator of the system, IQGAP1. To further understand how IQGAP1
mediates inhibition, I will purify key cytoskeletal proteins and use quantitative biochemical approaches to
measure binding affinities and implement a chemically-inducible dimerization system to assess the inhibitory
activity of IQGAP1. In addition, I will use super-resolution imaging during both interphase and cytokinesis to
characterize alterations in complexes formed by these key cytoskeletal proteins that allow force transduction
through the network. Moreover, I will determine the cellular role of methylmalonate semialdehyde
dehydrogenase (mmsdh), which catalyzes the production of propionyl-coA. Mmsdh was identified as an
interactor of cortexillin I, but was also previously identified in a genetic selection in our lab. It is possible that
proteins may modified by propionylation, an underappreciated post-translational modification, which may
facilitate positive regulation of the cytokinetic control system. Through a combination of genetics, mass
spectrometry, and biophysical analyses, I will elucidate the cellular function of mmsdh. The work proposed
here will decipher the molecular mechanisms of positive and negative regulation of the contractile network.
This information will be critical for understanding the cell’s ability to sense and respond to mechanical forces,
yielding insight into both normal developmental processes, as well as disease state progression.
项目摘要
每个生物过程,从细胞迁移到胚胎发生和组织形态发生,都依赖于
细胞适应不断变化的机械环境的能力。 虽然我们了解许多生化信号
所涉及的途径,整合来控制细胞对机械力的反应的机制
仍然是一个谜。 破译这些相互作用将揭示驱动两者的机械变化
正常和疾病状态过程。 为了揭示细胞如何对各种力做出反应,罗宾逊实验室
研究盘基网柄菌胞质分裂,这是一种模型形状变化过程,通过该过程一个细胞分裂形成两个细胞
子细胞。 实验室发现细胞分裂是由一个集成控制系统驱动的,该系统由以下部分组成:
响应机械和生化信号来调节其行为的蛋白质。 虽然我们
了解参与细胞因子控制系统的许多参与者,他们的生化相互作用使得
通过皮质网络的力传播仍然未知。 我的目标是描述监管的特征
表征这些相互作用的机制,这对于阐明细胞的机制至关重要
对其机械环境的响应。 识别控制细胞机械的直接相互作用
响应,我们对两个关键节点进行了免疫沉淀,然后进行了质谱分析
细胞因子控制系统、支架蛋白 IQGAP2 和肌动蛋白交联剂皮质西林 I。这种方法
导致这些节点的潜在结合伙伴的发现。 使用荧光交叉的组合
相关光谱 (FCCS) 和单分子下拉 (SiMPull),我们发现了一种潜在的
系统负调节因子 IQGAP1 的抑制机制。 进一步了解 IQGAP1 如何
介导抑制,我将纯化关键的细胞骨架蛋白并使用定量生化方法
测量结合亲和力并实施化学诱导二聚化系统来评估抑制
IQGAP1 的活性。 此外,我将在间期和胞质分裂期间使用超分辨率成像来
表征这些关键细胞骨架蛋白形成的复合物的变化,这些蛋白允许力转导
通过网络。 此外,我将确定丙二酸甲酯半醛的细胞作用
脱氢酶 (mmsdh),催化丙酰辅酶 A 的产生。 Mmsdh 被确定为
皮质西林 I 的相互作用者,但之前也在我们实验室的遗传选择中被鉴定出来。 有可能
蛋白质可以通过丙酰化进行修饰,丙酰化是一种未被充分重视的翻译后修饰,这可能
促进细胞因子控制系统的正向调节。 通过遗传学、质量的结合
通过光谱测定和生物物理分析,我将阐明 mmsdh 的细胞功能。 提议的工作
这里将破译收缩网络正向和负向调节的分子机制。
这些信息对于理解细胞感知和响应机械力的能力至关重要,
深入了解正常发育过程以及疾病状态进展。
项目成果
期刊论文数量(0)
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Priyanka Kothari其他文献
Priyanka Kothari的其他文献
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{{ truncateString('Priyanka Kothari', 18)}}的其他基金
Positive and negative regulation of the cytokinesis contractility controller
胞质分裂收缩性控制器的正向和负向调节
- 批准号:
9769504 - 财政年份:2018
- 资助金额:
$ 4.45万 - 项目类别:
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