Maintaining the natural shape of proteins is essential for life. Failure to do so is origin of lethal, incurable diseases such as Cystic Fibrosis, Alzheimer, Parkinson, ALS, or cancer. Common to those diseases are fatal distortions in protein shape. Human life therefore depends on a defense system that maintains the shape of our proteins, the strongly regulated network of chaperones and folding enzymes. Why does this network fail in disease? Our work is dedicated to the origin of protein failure diseases and the regulation and mechanisms of our natural defense systems.
The focus of the group of prof. dr. Ineke Braakman is the endoplasmic reticulum (ER), the first compartment of the secretory pathway and the cradle of most proteins inside and outside the cell. N-terminal hydrophobic signal peptides destine these proteins to the ER, where they fold and oligomerize with assistance of molecular chaperones and folding enzymes in ER membrane, ER lumen, and in the cytosolic rim around the ER, the ‘continental waters’ of the ER. Quantity of chaperones as well as size and shape of the ER are highly dynamic and regulated by stress responses evoked by unfolded, folding, or misfolded proteins. The group studies regulation and mechanisms of ER function, protein folding, chaperone action, and related stress and immune signaling events, which are relevant for multiple diseases, for healthy ageing, and directly pertinent to cystic fibrosis, familial hypercholesterolemia, and viral infections.
The group of dr. Stefan Rüdiger aims to understand protein damage in the cell, and its consequence for the origin of fatal diseases. A key challenge in molecular medicine is to develop cures for diseases for which no cure exists – such as Alzheimer, Parkinson or ALS. These diseases have in common that the molecular cause is related to uncontrolled consequences of protein damage and aggregation. However, our body is not unprotected against protein damage. A powerful proteostasis network maintains protein fidelity in the cell. This defense system supresses the most folding related diseases for the best part of our life. Why does it suddenly fail when we get older? Why do some individuals get a protein-aggregation related disease and others do not? Can we boost the cellular defense system to prevent the origin of the disease, or at least prevent progress of the diseases for some cases?
The group of prof. dr. Assaf Friedler is interested in using peptides for the quantitative biophysical and structural analysis of protein-protein interactions (PPI) in health and disease. Based on this, we develop lead compounds that modulate PPI for therapeutic purposes. Peptides serve as major tools both for studying PPI and for modulating them (by inhibition or activation). His groups focusses on using peptides to modulate the oligomeric state of proteins, development of new synthetic methods for peptide modifications and studying intrinsically disordered proteins as drug targets.