Protein Quality Control
Molecular mechanisms of housekeeping proteases and disaggregases
Proteins are relatively unstable molecules that can easily unfold in the cell. This misfolding is not always a spontaneous process, but is often induced by proteotoxic stress conditions such as heat or extreme pH conditions. In addition, metabolic challenges and/or specific mutations can affect the structural integrity leading to protein dysfunction and aggregation, as also seen in cancer. To prevent the accumulation of fragmented, misfolded and mislocalized proteins, cells developed a sophisticated quality-control system that permanently monitors the functional performance of all proteins. In this system, molecular chaperones, proteases and unfoldases channel aberrant proteins into refolding and degradation pathways, thereby reducing the amounts of misfolded and aggregated proteins. The first-aiders are most often chaperones of the AAA (ATPases Associated with a variety of cellular Activities) family, which utilize the energy from ATP hydrolysis to rescue non-native proteins. They can associate with cage-forming proteases, such as the 20S proteasome, yielding bipartite proteolytic complexes, or, alternatively, team up with partner chaperones to solubilize aggregated proteins and promote their refolding. In addition, several proteases and chaperones operate in an ATP-independent manner and have thus the ability to function as safeguards in extracytosolic compartments devoid of nucleotides.
Although it has been shown that damaged proteins can undergo dangerous interactions with other molecules and compose toxic protein aggregates, the molecular mechanisms underlying most "protein folding diseases" are still unclear. To address this point and to identify possible strategies against such diseases, we are studying the construction and working mode of prokaryotic and eukaryotic factors critical for an efficient protein quality control.
In this project, we are interested in
- the specific targeting of severely damaged proteins for degradation.
- the molecular mechanism of how proteases and chaperones deal with protein aggregates.
- the engine construction of complex proteolytic machines.