Program
| MSA3a | |
|---|---|
| Harald Herrmann | |
| Functional Architecture of the Cell Lab, DKFZ, Heidelberg, Germany | |
| Title | Molecular mechanisms underlying intermediate filament organization: The impact of inherited human disease mutations |
| Abstract | Intermediate filaments constitute, in addition to microtubules and microfilaments, the third principal filament system of the cytoskeleton that determines the architecture of metazoan cells. They are fibrous, coiled-coil forming proteins, which in man are coded for by more than 70 genes. Through interaction with various junctional complexes they integrate cells with the extracellular matrix and neighboring cells, and hence are the main determinants of cellular plasticity. The investigation of the in vitro assembly mechanism of cytoplasmic intermediate filament proteins such as vimentin has revealed that filament formation is characterized by a very rapid lateral association of soluble tetrameric subunits into 60 nm long, full-width “unit-length” filaments (ULFs). We have demonstrated for this proto-type intermediate filament protein that filament elongation occurs by the longitudinal annealing of ULFs into short, regular filaments. These filaments further longitudinally anneal and thus constitute a progressively elongating population of filaments that overtime become several microns long. Previously, we have provided a mathematical model for the kinetics of the assembly process based on the average length distribution of filaments as determined by time-lapse electron and atomic force microscopy. Thereby, we were able to substantiate the concept that end-to-end-annealing of both ULFs and short filaments is obligatory for the formation of long intermediate filaments (R. Kirmse et al., 2007, J. Biol. Chem. 282, 18563-18572). In a next step of our investigations into intermediate filament function, we have characterized the impact of previously identified disease mutants of the muscle-specific protein desmin on its assembly properties. Thereby we have gained further deep insight into the mechanics of intermediate filament assembly and higher order network formation as well as into their role as central element of cellular mechanical stress buffering systems. (in collaboration with , Dorothee Möller1, Norbert Mücke1, Harald Bär1,2, Hugo A. Katus2, and Ueli Aebi3 (1) German Cancer Research Center (DKFZ), Heidelberg, Germany; (2) Internal Medicine III, University Clinics Heidelberg, Germany; (3) M. E. Müller Institute for Structural Biology, Biozentrum, University of Basel, Basel, Switzerland) |
| Location | Woodward 3 |