Protein homeostasis is important to maintain cellular function over time. A defective quality control (QC) mechanism or an overload of misfolded proteins due to cellular stress may result in accumulation of toxic protein aggregates. Alternatively, proteins may not adopt a correct fold due to a genetic mutation or to posttranslational damage caused by environmental factors. Due to this incorrect folding, the protein may expose hydrophobic residues that facilitate protein oligomerization and aggregation. The cell has evolved strict QC mechanisms to cope with misfolded proteins. Molecular chaperones bind to hydrophobic patches thereby preventing aggregation. Others may try to refold the protein. If a correct fold is not obtained the protein is targeted for degradation by the ubiquitin-proteasome system or translocated to storage vesicles such as aggresomes.
We are developing chemoenzymatic methods to label biomolecules that are in close proximity of misfolded proteins. As such we can visualize the players that are involved in the quality control machinery under different stress conditions to get a hint on the different mechanisms the cell has to cope with misfolded proteins.
This project is funded in part by the Marie Curie Career Integration Grant