Regulation of the adaptive actin response by force-dependent bonds
通过力依赖性键调节适应性肌动蛋白反应
基本信息
- 批准号:10537442
- 负责人:
- 金额:$ 6.72万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2022
- 资助国家:美国
- 起止时间:2022-09-01 至 2024-08-31
- 项目状态:已结题
- 来源:
- 关键词:Actin-Binding ProteinActinsAffinityBindingBiological AssayBiophysicsC-terminalCell AdhesionCell membraneCellsClathrinCytoskeletonDissociationEncapsulatedEndocytosisEnvironmentEquilibriumExtracellular MatrixF-ActinGenerationsGenetic ScreeningHomologous GeneHumanHuntington Interacting Protein 1-RelatedIntuitionKineticsMammalian CellMeasurementMeasuresMechanicsMediatingMembraneMembrane ProteinsMicrofilamentsMinus End of the Actin FilamentMolecularMolecular GeneticsMotorMuscle ContractionMyosin ATPasePatternPhysiologicalPolymersProteinsReceptor SignalingRegulationReportingRoleStructureSurfaceSystemTalinTestingTissuesUrsidae FamilyVesicleWorkYeastsbasecell motilityin silicoinsightlaser tweezermechanical forcemechanical loadmutantoptical trapspolymerizationresponsesimulationtransmission process
项目摘要
Abstract
Force transmission through the actin cytoskeleton is fundamental to how cells sense the geometric and
mechanical constraints of their environments, move through tissues, remodel the extracellular matrix, and
regulate signaling receptors at the plasma membrane (PM) to determine cell fate. In systems such as the leading
edge of migrating cells or in clathrin-mediated endocytosis (CME), polymerizing actin pushes against a
membrane to generate protrusive force. The dynamics, structure, and force generation of actin are regulated by
mechanics and actin binding proteins (ABPs) that bundle, branch, break, soften, stiffen, polymerize, tether, or
move actin filaments. Aside from myosin motors, how mechanical force regulates the affinity of ABPs has seldom
been investigated. When ABPs are mechanically anchored in the cell, force at the ABP-actin interface regulates
the lifetime of the ABP-actin bond, which I refer to hereafter as the force-dependent actin dissociation rate
(FDADR). While intuition suggests the lifetimes of molecular bonds should shorten when the molecules are
pulled apart (a “slip bond”)1, a surprising majority of recently characterized ABPs involved in cell adhesion form
“catch bonds” with actin that increase in lifetime (sometimes >100-fold2) as force increases2–5. These bonds are
highly tuned to the direction of force applied relative to the actin filament polarity2,4,6 with the most extreme
reported example being the asymmetric catch bond formed by talin's ABS3 domain2. The functional impact of
the FDADR of these ABPs is not known. Due to actin's importance in generating and transmitting mechanical
force, equilibrium bulk measurements of ABP-actin interactions provide an incomplete picture of how ABPs
contribute to actin cytoskeleton structure, function, and regulation.
During CME the PM is bent to encapsulate membrane-bound cargoes. When PM tension is high, actin
polymerization force is required to bend the membrane and pull the nascent vesicle into the cell7. Actin at the
CME pit “adapts” to PM tension by localizing to the surface of the pit preferentially in conditions of elevated PM
tension (i.e., precisely only when it is required for CME completion)8. I will test the hypothesis that the THATCH
actin binding domains of CME adapter HIP1R forms an asymmetric catch bond like homolog talin ABS3. I will
discover mutants with altered binding in a yeast molecular-genetic screen and characterize their FDADR. I will
develop a stochastic simulation to uncover the role of the FDADR in actin network structure and function during
CME. I hypothesize that HIP1R's FDADR is tuned to selectively bind actin filaments that bear mechanical load,
thus supporting endocytosis over a range of membrane tensions amidst dense cortical filamentous actin. Mutant
HIP1R THATCH with altered FDADR will be expressed in mammalian cells, and their impact on CME and actin
organization will be determined and compared to simulations, thus relating FDADR to actin structure and
function.
摘要
项目成果
期刊论文数量(0)
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Leanna Marie Owen其他文献
Leanna Marie Owen的其他文献
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{{ truncateString('Leanna Marie Owen', 18)}}的其他基金
Regulation of the adaptive actin response by force-dependent bonds
通过力依赖性键调节适应性肌动蛋白反应
- 批准号:
10689699 - 财政年份:2022
- 资助金额:
$ 6.72万 - 项目类别:
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Priority Programmes
STRUCTURE/INTERACTIONS OF ACTINS AND ACTIN-BINDING PROTEIN
肌动蛋白和肌动蛋白结合蛋白的结构/相互作用
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- 资助金额:
$ 6.72万 - 项目类别:














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