Characterization of the molecular interactions between intermediate filaments and small heat shock proteins

The cells we are made of contain a framework called the cytoskeleton that is important for defining their shape and architecture. Along with microtubules and actin filaments, intermediate filaments (IFs) are principal components of this network. IFs in particular have an essential role in providing mechanical support for the range of activities a cell can partake in. Not surprisingly a growing number of mutations in IF proteins has been associated with currently incurable human diseases such as myopathies, skin and neuronal diseases and premature ageing. To properly function IFs, and the two other cytoskeleton components, have to interact with a diverse array proteins. One such group shared among all three filament systems is called the small heat shock proteins (sHSPs). The sHSP family are chaperones typically associated with the prevention of protein aggregation. Congenital mutations in two human sHSPs lead to cataract, a build up of misfolded protein in the eye lens. Intriguingly these mutations, as well as others in different sHSPs, also show similar disease traits as those caused by mutations in IFs, suggesting an important association in maintaining IF integrity in the cell. The project aims at gaining insight into the interactions between IFs and sHSPs at the molecular level. We plan to establish a comprehensive picture of the role sHSPs have in filament assembly and identify the residues in each that are necessary for mediating their interaction.