Mechanistic insights into actin force generation during vesicle formation from cryo-electron tomography

Serwas, Daniel; Akamatsu, Matthew; Moayed, Amir; Vegesna, Karthik; Vasan, Ritvik; Hill, Jennifer; Schöneberg, Johannes; Davies, Karen M.; Rangamani, Padmini; Drubin, David G.

doi:10.1016/j.devcel.2022.04.012

Cited by 33 publications

(23 citation statements)

References 71 publications

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“…Mammalian Notch ligands are ubiquitinated by the E3 ligase Mindbomb-1 (MIB-1) then bound by epsins, which facilitate clathrin-mediated endocytosis (CME) ( 49 ). During CME, epsins couple with polymerizing actin filaments ( 50 ) and physically link invaginating pits to cellular force-generating machinery ( 51-52 ). Although many of the factors required for epsin-dependent uptake are known ( 53 ), the pulling capacity that they confer to ligands during CME is unknown.…”

Section: Resultsmentioning

confidence: 99%

Tension-Tuned SynNotch Receptors for Synthetic Mechanotranduction and Intercellular Force Detection

Sloas

Ngo

2022

Preprint

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Cells can sense and interpret mechanical stimuli from their environment, but the ability to engineer customized mechanosensing capabilities has remained a synthetic biology challenge. Here, we introduce a set of synthetic Notch (SynNotch)-derived proteins that can be used to convert extracellular tensile forces into specifiable gene expression changes. By elevating the tension levels needed to induce SynNotch activation, in combination with structure-guided mutagenesis, we designed tunable mechanoreceptors with sensitivities in the physiologically relevant picoNewton (pN) range. Cells expressing these receptors could distinguish between varying levels of ligand-mediated tension and enact customizable transcriptional responses in turn. The utility of these tools was demonstrated by the design of a decision-making circuit, through which fibroblasts could be made to differentiate into myoblasts in response to mechanostimulation with tensile forces of distinct magnitudes. This work provides insight regarding how mechanically-induced structural alterations in proteins can be used to transduce physical forces into biochemical signals, and the system should facilitate further programming of force-related phenomena in biological systems.

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Section: Resultsmentioning

confidence: 99%

Tension-Tuned SynNotch Receptors for Synthetic Mechanotranduction and Intercellular Force Detection

Sloas

Ngo

2022

Preprint

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“…These examples serve to highlight the extensibility of the framework, which does not require the introduction of coordinates and advanced tensor calculus commonly needed to solve problems on arbitrary manifolds. The software implementation was designed to facilitate coordination between theoretical modeling and wet experiments; we hope to support the modeling of scenes with well-resolved protein-membrane interactions such as in the electron tomograms ( 143 ). We expect that as the advances in biophysical modeling and membrane ultrastructure imaging progresses, will emerge as a useful tool to test new hypotheses and understand cellular mechanobiology.…”

Section: Discussionmentioning

confidence: 99%

Mem3DG: Modeling membrane mechanochemical dynamics in 3D using discrete differential geometry

Zhu

Lee

Rangamani

2022

Biophysical Reports

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“…We also anticipate that the interactions between protein-mediated tubulation and force-mediated tubulation would be necessary to capture cellular processes where both membrane-bound proteins and actin-mediated forces are involved (62)(63)(64). Simulations using general coordinates reveal that the early modes of deformation are axisymmetric (65).…”

Section: Discussionmentioning

confidence: 99%

Formation of protein-mediated bilayer tubes is governed by a snapthrough transition

Mahapatra

Rangamani

2022

Preprint

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Plasma membrane tubes are ubiquitous in cellular membranes and in the membranes of intracellular organelles. They play crucial roles in trafficking, ion transport, and cellular motility. The formation of plasma membrane tubes can be due to localized forces acting on the membrane or by curvature-induced by membrane-bound proteins. Here, we present a mathematical framework to model cylindrical tubular protrusions formed by proteins that induce anisotropic spontaneous curvature. Our analysis revealed that the tube radius depends on an effective tension that includes contributions from the bare membrane tension and the protein-induced curvature. We also found that the length of the tube undergoes an abrupt transition from a short, dome-shaped membrane to a long cylinder and this transition is characteristic of a snapthrough instability. Finally, we show that the snapthrough instability depends on the different parameters including coat area, bending modulus, and extent of protein-induced curvature. Our findings have implications for tube formation due to BAR-domain proteins in processes such as endocytosis, t-tubule formation in myocytes, and cristae formation in mitochondria.1Significance StatementCylindrical tubes are ubiquitous on cellular membranes and many studies have focused on how forces can give rise to tubes. How do curvature-inducing proteins, in the absence of forces, form cylindrical tubes on lipid bilayers? The answer to this question relies on minimizing the bending energy of the membrane to accommodate two different principal curvatures such that a cylindrical shape is an energy minimizer. Here, we build on previous works to develop such a model and show that the formation of an elongated cylindrical tube is accompanied by a snapthrough transition in the bending energy. Furthermore, we identify how this transition depends on different membrane properties, providing a landscape for comparing with different experimental observations. These findings have implications for our understanding how tubes forms in different cellular processes including trafficking, mitochondrial inner membrane cristae formation, and T-tubule formation in myocytes.

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Mechanistic insights into actin force generation during vesicle formation from cryo-electron tomography

Cited by 33 publications

References 71 publications

Tension-Tuned SynNotch Receptors for Synthetic Mechanotranduction and Intercellular Force Detection

Tension-Tuned SynNotch Receptors for Synthetic Mechanotranduction and Intercellular Force Detection

Mem3DG: Modeling membrane mechanochemical dynamics in 3D using discrete differential geometry

Formation of protein-mediated bilayer tubes is governed by a snapthrough transition

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