Type III intermediate filaments: molecular structure to understand muscular disease

Intermediate filaments (IFs) are core elements of metazoan cytoskeleton which assemble from two identical or homologous protein chains. As IFs play a key role in cell mechanics, their contribution to cell resilience and migration provides a link to cancer progression. Moreover, there is an increasing number of inherited IF mutations that cause currently incurable skin, muscular and neuronal diseases. Here we will focus on desmin mutations R350P and R406W linked to myofibrillar myopathies. The understanding of the 3D architecture of IFs is still elusive, which is aggravated by partial disorder. We hypothesize that achieving progress into IF structure requires a combined use of various pieces of evidence. First, we will rely on the detailed atomic structure of tetramer, the filament building block, which was made possible through X-ray crystallography. Second, we will perform cryoelectron microscopy on the ‘unit length’ filaments as well as on the filaments formed by mutated desmins in immortalized myoblasts. Third, chemical cross-linking coupled to mass spectrometry (MS) will be used to decipher the interactions between tetramers. Finally, integrative modelling should marry the atomic resolution data with the spatial constraints provided by other methods, yielding a trustworthy molecular model of cytoplasmic IFs. This should enable novel insights into the molecular mechanism of currently incurable desminopathies.