A biophysical perspective of the regulatory mechanisms of ezrin/radixin/moesin proteins

Senju, Yosuke; Tsai, Feng-Ching

doi:10.1007/s12551-021-00928-0

Cited by 17 publications

(18 citation statements)

References 109 publications

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“…An active form of ezrin capable of binding F-actin, i.e., the ezrin T567D mutant, was used. This mutant is known to form an open conformation that binds PtdIns[4,5]P 2 via its FERM domain and which is capable of binding F-actin via its C-terminal domain. , To ensure full protein coverage of the PtdIns[4,5]P 2 binding sites, an ezrin T567D concentration of 0.8 μM was chosen being in the saturation regime of the protein adsorption isotherm . The RIfS results clearly show that the protein binds with high specificity to PtdIns[4,5]P 2 .…”

Section: Resultsmentioning

confidence: 99%

“…In these epithelial cells, ezrin is the main player linking, with its N-terminal FERM domain (N-ERMAD) bound to phosphatidylinositol-4,5-bisphosphate (PtdIns[4,5]P 2 ) in the plasma membrane, the F-actin network via its C-terminal domain (C-ERMAD). , The recruitment of ezrin from the cytosol (inactive state) to the plasma membrane (active state) is a reversible and fine-tuned process . Activation of the inactive dormant state, in which a head-to-tail intra- (monomer) or intermolecular (dimer) interaction between the FERM domain and the C-ERMAD masks the actin-binding site, requires binding of the FERM domain to PtdIns[4,5]P 2 , and phosphorylation of threonine-567. , Once recruited to specific plasma membrane sites, activated ezrin serves as the linker between F-actin and the plasma membrane, whereas the myosin II motors actively reorganize the network being pivotal for cell polarity, morphogenesis, and the generation and modulation of membrane tension. , These processes depend on the local F-actin organization as well as the membrane–cortex linkage …”

Section: Introductionmentioning

confidence: 99%

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Bioinspired Membrane Interfaces: Controlling Actomyosin Architecture and Contractility

Liebe

Mey

Vuong

et al. 2023

ACS Appl. Mater. Interfaces

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The creation of biologically inspired artificial lipid bilayers on planar supports provides a unique platform to study membrane-confined processes in a well-controlled setting. At the plasma membrane of mammalian cells, the linkage of the filamentous (F)-actin network is of pivotal importance leading to cell-specific and dynamic F-actin architectures, which are essential for the cell's shape, mechanical resilience, and biological function. These networks are established through the coordinated action of diverse actin-binding proteins and the presence of the plasma membrane. Here, we established phosphatidylinositol-4,5-bisphosphate (PtdIns[4,5]P 2 )-doped supported planar lipid bilayers to which contractile actomyosin networks were bound via the membrane−actin linker ezrin. This membrane system, amenable to high-resolution fluorescence microscopy, enabled us to analyze the connectivity and contractility of the actomyosin network. We found that the network architecture and dynamics are not only a function of the PtdIns[4,5]P 2 concentration but also depend on the presence of negatively charged phosphatidylserine (PS). PS drives the attached network into a regime, where low but physiologically relevant connectivity to the membrane results in strong contractility of the actomyosin network, emphasizing the importance of the lipid composition of the membrane interface.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Bioinspired Membrane Interfaces: Controlling Actomyosin Architecture and Contractility

Liebe

Mey

Vuong

et al. 2023

ACS Appl. Mater. Interfaces

View full text Add to dashboard Cite

show abstract

“…[38] In contrast, the ERM proteins (Ezrin, Radaxin, Moesin) were shown to be PIP 2 specific. [39] These interactions of cofilin with the PIP lipids have been shown to occur by specific residues such as Asp and Lys but differences have been reported between the mutational studies. [16,20,35] Molecular dynamics simulations of cofilin in the presence of PIP 2 identified a large patch of surface-exposed charged residues, that further indicates that PIP 2 interactions may not be as highly specific as previously thought.…”

Section: Introductionmentioning

confidence: 99%

“…The interactions of PIP lipids appear to be dependent on the type of actin‐binding protein and some actin‐binding proteins such as twinfilin have been shown to bind both PIP 2 and PIP 3 through a multivalent electrostatic interaction [38] . In contrast, the ERM proteins (Ezrin, Radaxin, Moesin) were shown to be PIP 2 specific [39] . These interactions of cofilin with the PIP lipids have been shown to occur by specific residues such as Asp and Lys but differences have been reported between the mutational studies [16,20,35] .…”

Section: Introductionmentioning

confidence: 99%

Cofilin‐Membrane Interactions: Electrostatic Effects in Phosphoinositide Lipid Binding

2022

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The actin cytoskeleton interacts with the cell membrane primarily through the indirect interactions of actin-binding proteins such as cofilin-1. The molecular mechanisms underlying the specific interactions of cofilin-1 with membrane lipids are still unclear. Here, we performed coarse-grain molecular dynamics simulations of cofilin-1 with complex lipid bilayers to analyze the specificity of protein-lipid interactions. We observed the maximal interactions with phosphoinositide (PIP) lipids, especially PIP 2 and PIP 3 lipids. A good match was observed between the residues predicted to interact and previous experimental studies. The clustering of PIP lipids around the membrane bound protein leads to an overall lipid demixing and gives rise to persistent membrane curvature. Further, through a series of control simulations, we observe that both electrostatics and geometry are critical for specificity of lipid binding. Our current study is a step towards understanding the physico-chemical basis of cofilin-PIP lipid interactions.

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“…Among them, ezrin is found in epithelial cells (4), where it links the plasma membrane via PtdIns[4,5]P 2 to its N-terminal domain (N-ERMAD) (5) and F-actin to the C-terminal domain (CERMAD), respectively (4, 6). Ezrin activation from a cytosolic dormant conformation to an activated state occurs upon first binding to PtdIns[4,5]P 2 followed by phosphorylation of threonine-567 (7, 8). In the active conformation, it serves as a passive, reversible linker between F-actin and the plasma membrane, whereas myosin II motors actively reorganize the network and thereby generat tension in the cortex (9, 10).…”

mentioning

confidence: 99%

Impact of native-like lipid membranes on the architecture and contractility of actomyosin networks

Liebe

Mey

Vuong

et al. 2022

Preprint

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The connection between the actomyosin cortex and the plasma membrane of eukaryotic cells is investigated by creating a versatile, near-native model system that allows studying the architecture and contractility of the cortex as a function of lipid composition. We found that the concentration of phosphatidylserine, a characteristic lipid of the inner leaflet of mammalian plasma membranes, plays a pivotal role in the binding of the membrane-cytoskeleton linker protein ezrin and the resulting contractile behavior of an adjacent actin network. In addition to the specific receptor lipid for ezrin, i.e., PtdIns[4,5]P2 cross-linking the network to the inner leaflet, the presence of phosphatidylserine in the membrane is critical to enhancing the binding of ezrin to PtdIns[4,5]P2 and allows rapid local actin contraction at physiologically relevant concentrations in the regime of 1-3 mol% PtdIns[4,5]P2. In the presence of phosphatidylserine, the additional negative charges in the membrane may induce enhanced sliding of the filaments on the membrane surface due to repulsive interactions between F-actin and the bilayer readily leading to the emergence of contraction foci. Conversely, if phosphatidylserine is replaced by an increased PtdIns[4,5]P2 concentration of 5 or 8 mol%, a highly connected but non-contracting actin network is observed.

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A biophysical perspective of the regulatory mechanisms of ezrin/radixin/moesin proteins

Cited by 17 publications

References 109 publications

Bioinspired Membrane Interfaces: Controlling Actomyosin Architecture and Contractility

Bioinspired Membrane Interfaces: Controlling Actomyosin Architecture and Contractility

Cofilin‐Membrane Interactions: Electrostatic Effects in Phosphoinositide Lipid Binding

Impact of native-like lipid membranes on the architecture and contractility of actomyosin networks

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