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Register a new userEnergetic constraints on filament mediated cell polarization
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Cell polarization underlies many cellular processes, such as differentiation, migration, and budding. Many living cells, such as budding yeast and fission yeast, use cytoskeletal structures to actively transport proteins to one location on the membrane and create a high density spot of membrane-bound proteins. Yet, the thermodynamic constraints on filament-based cell polarization remain unknown. We show by mathematical modeling that cell polarization requires detailed balance to be broken, and we quantify the free-energy cost of maintaining a polarized state of the cell. Our study reveals that detailed balance cannot only be broken via the active transport of proteins along filaments, but also via a chemical modification cycle, allowing detailed balance to be broken by the shuttling of proteins between the filament, membrane, and cytosol. Our model thus shows that cell polarization can be established via two distinct driving mechanisms, one based on active transport and one based on non-equilibrium binding. Furthermore, the model predicts that the driven binding process dissipates orders of magnitude less free-energy than the transport-based process to create the same membrane spot. Active transport along filaments may be sufficient to create a polarized distribution of membrane-bound proteins, but an additional chemical modification cycle of the proteins themselves is more efficient and less sensitive to the physical exclusion of proteins on the transporting filaments, providing insight in the design principles of the Pom1/Tea1/Tea4 system in fission yeast and the Cdc42 system in budding yeast.
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In eukaryotic cells, KDEL receptors (KDELRs) facilitate the retrieval of endoplasmic reticulum (ER) luminal proteins from the Golgi compartment back to the ER. Apart from the well-documented retention function, recent findings reveal that the cellular KDELRs have more complex roles, e.g. in cell signalling, protein secretion, cell adhesion and tumorigenesis. Furthermore, several studies suggest that a sub-population of KDELRs is located at the cell surface, where they could form and internalize KDELR/cargo clusters after K/HDEL-ligand binding. However, so far it has been unclear whether there are cell-type- or species-specific differences in KDELR clustering. By comparing ligand-induced KDELR clustering in different mouse and human cell lines via live cell imaging, we show that macrophage cell lines from both species do not develop any clusters. Using RT-qPCR experiments and numerical analysis, we address the role of KDELR expression as well as endocytosis and exocytosis rates on the receptor clustering at the plasma membrane and discuss how the efficiency of directed transport to preferred docking sites on the membrane influences the exponent of the power-law distribution of the cluster size.
In many intracellular processes, the length distribution of microtubules is controlled by depolymerizing motor proteins. Experiments have shown that, following non-specific binding to the surface of a microtubule, depolymerizers are transported to the microtubule tip(s) by diffusion or directed walk and, then, depolymerize the microtubule from the tip(s) after accumulating there. We develop a quantitative model to study the depolymerizing action of such a generic motor protein, and its possible effects on the length distribution of microtubules. We show that, when the motor protein concentration in solution exceeds a critical value, a steady state is reached where the length distribution is, in general, non-monotonic with a single peak. However, for highly processive motors and large motor densities, this distribution effectively becomes an exponential decay. Our findings suggest that such motor proteins may be selectively used by the cell to ensure precise control of MT lengths. The model is also used to analyze experimental observations of motor-induced depolymerization.
The mitotic spindle lies at the heart of the spatio-temporal control over cellular components during cell division. The spindle consists of microtubules, which are not only crosslinked by motor proteins but also by passive binding proteins. These passive crosslinkers stabilize the highly dynamic mitotic spindle by generating friction forces between sliding filaments. However, it remains unclear how the friction coefficient depends on the number of crosslinkers and the size of the overlap between the microtubules. Here, we use theory and computer simulations to study the friction between two filaments that are crosslinked by passive proteins, which can hop between neighboring binding sites while physically excluding each other. The simulations reveal that the movement of one microtubule relative to the other is limited by free-energy barrier crossings, causing rare and discrete jumps of the microtubule that span the distance between adjacent crosslinker binding sites. We derive an exact analytical expression for the free-energy landscape and identify the reaction coordinate that governs the relative movement, which allows us to determine the effective barrier height for the microtubule jumps. Both through simulations and reaction rate theory, we make the experimentally testable prediction that the friction between the microtubules increases superexponentially with the density of crosslinkers.
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