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Quantitative strategies for the self-assembly of intermediate filaments

One of the characteristics of eukaryotic cells is the existence of the cytoskeleton – an intricate network of protein filaments that extends throughout the cytoplasm. It enables the cells to adopt a variety of shapes, interact mechanically with the environment, organize the many components in their interior, carry out coordinated and directed movements. It also provides the machinery for intracellular movements, e.g. transport of organelles in the cytoplasm and the segregation of chromosomes at mitosis. There are three kinds of protein filaments that form the cytoskeleton: actin filaments, intermediate filaments (IFs) and microtubules. Each kind has different mechanical properties and is assembled from an individual type of proteins. Actin filaments and microtubules are formed from globular proteins (actin and tubulin subunits, respectively), whereas fibrous proteins are the building blocks of intermediate filaments. Thousands of these basic elements assemble into a construction of girders and ropes that spreads throughout the cell.

One of the main functions of intermediate filaments is to provide cells with mechanical strength and they are especially prominent in the cytoplasm of cells that are exposed to such conditions. For example, IFs are abundantly present along nerve cells axons where they provide crucial internal reinforcement of these long cell extensions. They can also be observed in great number in muscle cells and epithelial cells. IFs are characterized by great tensile strength. By stretching and distributing the effect of locally applied forces, they protect cells and their membranes against breaking due to mechanical shear. Compared with microtubules and actin filaments, IFs are more stable, tough and durable, e.g. remain intact during exposure of cells to salt solutions and nonionic detergents, while the rest of the cytoskeleton is mostly destroyed.

Intermediate filaments can be grouped into four classes: (1) keratin filaments in epithelial cells; (2) vimentin filaments in connective-tissue cells, muscle cells and supporting cells of the nervous system; (3) neurofilaments in nerve cells; and (4) nuclear lamins, which strengthen the nuclear membrane of all eukaryotic cells.

In our research we concentrate on the process of in vitro self-assembly of intermediate filaments from tetrameric vimentin. We investigate different plausible strategies for filament elongation through mathematical modelling, model fitting, model validation and sensitivity analysis. In the assessment of the potential variants the focus is on properties such as scalability, robustness and ability to explain experimental data. This systematic approach enables the formulation of certain hypotheses about how the still little-known process of filament self-assembly is executed. Based on this hypotheses future biological experiments that would verify them are proposed. This project is an example of a hypothesis-driven research in the field of systems biology.