The interactions of small heat shock proteins with intermediate filaments.

Abstract

The interaction of small heat shock proteins (sHsps) and intermediate filaments (IFs) is essential to the cell. Mutations both in sHsps and IFs cause disease in humans, characterised by aggregates containing both sHsps and IFs, demonstrating the importance of this interaction. However, the molecular details of this interaction and the mechanisms which lead to disease are unknown. Investigations into the sHsp-IF interaction may allow future development of new therapeutic approaches to maintain the sHsp-IF interaction and therefore inhibit the formation of the pathological aggregates which cause disease. This thesis analyses the sHsp-IF interaction in vitro using the sHsp ‘aB crystallin’ and the IF ‘desmin’. I investigate the domains in both aB crystallin and desmin which are important for their interaction. I also analyse the effect of IF assembly conditions on filament properties and interaction with aB crystallin. In addition, I investigate the ‘beaded filament’ to gain insight into the factors affecting filament assembly, filament properties and filament interactions with aB crystallin. Furthermore, I investigate the effects of a disease causing aB crystallin mutation on activity in vitro. I also attempt to model the potential structural changes in aB crystallin resulting from mutation, using the sHsp, Hsp16.5. These studies provide important insight into the interaction between sHsps and IFs.