Projects of the Mogk lab
Novel bacterial disaggregases provide extreme heat resistance |
| AAA+ protein disaggregases rescue aggregated proteins and provide heat resistance to cells. While this activity is sufficient to ensure bacterial survival during physiological heat stress, it fails protecting cells against man-made, temperature-based sterilization protocols applied in food industry and clinics. The novel disaggregases ClpG and ClpL provide extreme heat resistance to bacteria including the major pathogens P. aeruginosa and L. monocytogenes. They differ from the canonical ClpB/Hsp70 disaggregation system by working autonomously and exhibiting increased thermal stability and disaggregation power. We are studying the regulatory modes of these AAA+ threading machines: how can protein aggregates trigger activation of the ClpG and ClpL disaggregases? |
 |
| sHsp sequestrases: mechanism and interplay with protein disaggregases |
| Small heat shock proteins (sHsps) form dynamic oligomeric assemblies that sequester misfolded proteins during stress conditions. This sequestration activity protects both, the substrate but also the PQC system from overload. sHsp-bound substrates are not spontaneously released but need to be displaced by protein disaggregases. We are studying the mechanism of sHsp sequestrase activity and the interplay with the diverse bacterial disaggregation systems. |
 |
| The central ClpC/ClpP protease as antibacterial drug target |
| General and regulatory proteolysis via the major ClpC/ClpP AAA+ protease is crucial for bacterial stress resistance and virulence. ClpC is forming an inactive resting state that is converted to a functional hexamer in presence of diverse adaptor (partner) proteins or substrates. We are studying how these signals are integrated to tightly control proteolytic activity of ClpC/ClpP. Deregulation of M. tuberculosis ClpC1/ClpP by natural peptides creates toxicity. We are exploring whether it is possible to also deregulate ClpC/ClpP of the major pathogen S. aureus by small molecules and are dissecting the molecular mechanism of drug-induced ClpC/ClpP deregulation. |
 |
| PQC and the heat shock response in yeast cells |
| Stress conditions that limit import of mitochondrial precursor proteins (mitoPREs) lead to their accumulation in the yeast cytosol and nucleus, where they are subjected to diverse PQC strategies. The nuclear J-domain protein Apj1 functions as Hsp70 co-chaperones and is involved in protein disaggregation, the regulation of the Hsf1-controlled heat shock response and the handling of mitoPREs. In a project together with Dr. Fabian den Brave (University of Bonn) we are studying how Apj1 chaperones mitoPREs, how it mechanistically works and how it might link mitoPRE accumulation to activation of the heat shock response |
 |