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Register a new userComputation of a Theoretical Membrane Phase Diagram, and the Role of Phase in Lipid Raft-Mediated Protein Organization
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Lipid phase heterogeneity in the plasma membrane is thought to be crucial for many aspects of cell signaling, but the physical basis of participating membrane domains such as lipid rafts remains controversial. Here we consider a lattice model yielding a phase diagram that includes several states proposed to be relevant for the cell membrane, including microemulsion - which can be related to membrane curvature - and Ising critical behavior. Using a neural network-based machine learning approach, we compute the full phase diagram of this lattice model. We analyze selected regions of this phase diagram in the context of a signaling initiation event in mast cells: recruitment of the membrane-anchored tyrosine kinase Lyn to a cluster of transmembrane of IgE-Fc{epsilon}RI receptors. We find that model membrane systems in microemulsion and Ising critical states can mediate roughly equal levels of kinase recruitment (binding energy ~ -0.6 kBT), whereas a membrane near a tricritical point can mediate much stronger kinase recruitment (-1.7 kBT). By comparing several models for lipid heterogeneity within a single theoretical framework, this work points to testable differences between existing models. We also suggest the tricritical point as a new possibility for the basis of membrane domains that facilitate preferential partitioning of signaling components.
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Chromatin loop extrusion is a popular model for the formation of CTCF loops and topological domains. Recent HiC data have revealed a strong bias in favour of a particular arrangement of the CTCF binding motifs that stabilize loops, and extrusion is the only model to date which can explain this. However, the model requires a motor to generate the loops, and although cohesin is a strong candidate for the extruding factor, a suitable motor protein (or a motor activity in cohesin itself) has yet to be found. Here we explore a new hypothesis: that there is no motor, and thermal motion within the nucleus drives extrusion. Using theoretical modelling and computer simulations we ask whether such diffusive extrusion could feasibly generate loops. Our simulations uncover an interesting ratchet effect (where an osmotic pressure promotes loop growth), and suggest, by comparison to recent in vitro and in vivo measurements, that diffusive extrusion can in principle generate loops of the size observed in the data. Extra View on : C. A. Brackley, J. Johnson, D. Michieletto, A. N. Morozov, M. Nicodemi, P. R. Cook, and D. Marenduzzo Non-equilibrium chromosome looping via molecular slip-links, Physical Review Letters 119, 138101 (2017)
Dynamic patterning of specific proteins is essential for the spatiotemporal regulation of many important intracellular processes in procaryotes, eucaryotes, and multicellular organisms. The emergence of patterns generated by interactions of diffusing proteins is a paradigmatic example for self-organization. In this article we review quantitative models for intracellular Min protein patterns in E. coli, Cdc42 polarization in S. cerevisiae, and the bipolar PAR protein patterns found in C. elegans. By analyzing the molecular processes driving these systems we derive a theoretical perspective on general principles underlying self-organized pattern formation. We argue that intracellular pattern formation is not captured by concepts such as activators, inhibitors, or substrate-depletion. Instead, intracellular pattern formation is based on the redistribution of proteins by cytosolic diffusion, and the cycling of proteins between distinct conformational states. Therefore, mass-conserving reaction-diffusion equations provide the most appropriate framework to study intracellular pattern formation. We conclude that directed transport, e.g. cytosolic diffusion along an actively maintained cytosolic gradient, is the key process underlying pattern formation. Thus the basic principle of self-organization is the establishment and maintenance of directed transport by intracellular protein dynamics.
The bipolar organization of the microtubule-based mitotic spindle is essential for the faithful segregation of chromosomes in cell division. Despite our extensive knowledge of genes and proteins, the physical mechanism of how the ensemble of microtubules can assemble into a proper bipolar shape remains elusive. Here, we study the pathways of spindle self-organization using cell-free Xenopus egg extracts and computer-based automated shape analysis. Our microscopy assay allows us to simultaneously record the growth of hundreds of spindles in the bulk cytoplasm and systematically analyze the shape of each structure over the course of self-organization. We find that spindles that are maturing into a bipolar shape take a route that is distinct from those ending up with faulty structures, such as those of a tripolar shape. Moreover, matured structures are highly stable with little occasions of transformation between different shape phenotypes. Visualizing the movement of microtubules further reveals a fraction of microtubules that assemble between extra poles and push the poles apart, suggesting the presence of active extensile force that prevents pole coalescence. Together, we propose that a proper control over the magnitude and location of the extensile, pole-pushing force is crucial for establishing spindle bipolarity while preventing multipolarity.
Chaperone-assisted translocation through a nanopore embedded in membrane holds a prominent role in the transport of biopolymers. Inspired by classical Brownian ratchet, we develop a theoretical framework characterizing such translocation process through a master equation approach. In this framework, the polymer chain, provided with reversible binding of chaperones, undergoes forward/backward diffusion, which is rectified by chaperones. We drop the assumption of timescale separation and keep the length of a polymer chain finite, both of which happen to be the key points in most of the previous studies. Our framework makes it accessible to derive analytical expressions for mean translocation velocity and effective diffusion constant in stationary state, which is the basis of a comprehensive understanding towards the dynamics of such process. Generally, the translocation of polymer chain across membrane consists of three subprocesses: initiation, termination, and translocation of the main body part of a polymer chain, where the translocation of the main body part depends on the binding/unbinding kinetics of chaperones. That is the main concern of this study. Our results show that the increase of forward/backward diffusion rate of a polymer chain and the binding/unbinding ratio of chaperones both raise the mean translocation velocity of a polymer chain, and roughly speaking, the dependence of effective diffusion constant on these two factors achieves similar behavior.
Interactions mediated by the cell membrane between inclusions, such as membrane proteins or antimicrobial peptides, play important roles in their biological activity. They also constitute a fascinating challenge for physicists, since they test the boundaries of our understanding of self-assembled lipid membranes, which are remarkable examples of two-dimensional complex fluids. Inclusions can couple to various degrees of freedom of the membrane, resulting in different types of interactions. In this chapter, we review the membrane-mediated interactions that arise from direct constraints imposed by inclusions on the shape of the membrane. These effects are generic and do not depend on specific chemical interactions. Hence, they can be studied using coarse-grained soft matter descriptions. We deal with long-range membrane-mediated interactions due to the constraints imposed by inclusions on membrane curvature and on its fluctuations. We also discuss the shorter-range interactions that arise from the constraints on membrane thickness imposed by inclusions presenting a hydrophobic mismatch with the membrane.
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