Molecular chaperones are the most important cellular defence against protein misfolding and aggregation, both potentially noxious off-pathways in protein biogenesis. Important human diseases, such as Alzheimer's, Creutzfeldt-Jacob's, polyglutamine expansion, cystic fibrosis and hypertrophic cardiomyopathy are associated with abnormal protein folding pathways, and direct links between molecular chaperones and several of these diseases have been demonstrated. Extensive knowledge of the mechanisms by which molecular chaperones counteract the tendency of non-native proteins to aggregate is thus a necessary step not only towards our eventual understanding of the molecular pathways involved in such protein misfolding diseases, but also towards their prevention and curing.
Bona fide molecular chaperones are known to act under both "normal" non-stressful growth conditions and following various cellular stresses. They participate in a plethora of cellular processes such as de novo protein folding, protein targeting to membranes, protein translocation and degradation, as well as the assembly or disassembly of protein complexes. These very diverse functions are generally performed through cycles of binding and release of short hydrophobic, extended polypeptide stretches that are usually buried in the native form of the protein.
Our main goal is to understand in detail the mechanism of function of these molecular machines. Using the bacterium Escherichia coli as a model organism, we attempt to isolate new molecular chaperones and to pinpoint functional interplays among the major chaperone networks and their eventual participation in quality control mechanisms. The key contribution of molecular chaperones in the partitioning of cytoplasmic, integral membrane, or exported proteins is also investigated. Finally, we engineer and use chaperone-deficient mutants as biotechnological tools for the isolation of new molecular chaperones from higher eukaryotes, which can improve the folding of recombinant proteins expressed in bacteria.