Cells have developed a quality control system that ensures that the cellular proteome folds correctly, keeps its native conformation and that unproductive side reactions are prevented.. This is especially important under stress conditions such as high temperature when massive protein unfolding occurs or in the context of diseases when the cellular protein homeostasis is out of control.
The key elements of the cellular stress defense system are molecular chaperones. These cellular machines of protein folding share the remarkable ability of specifically recognizing non-native proteins and assisting their folding to the native state. There are several classes of molecular chaperones that evolved independently and are both structurally and mechanistically not related, such as the small heat shock proteins, Hsp70 and Hsp90. Progress in recent years based on a combination of different experimental approaches provided insight into the mechanistic principles of chaperones. With a view to define the key traits of different chaperone machines, we set out to reconstitute their mode of action using purified components. Our analysis reveals intriguing differences in the mode of action including sophisticated regulatory and control elements.

Approximately one third of all human proteins are produced in the endoplasmic reticulum (ER). These proteins co-translationally enter the ER and have to acquire their native structure, often including oligomerization, before traversing further along the secretory pathway. A dedicated quality control machinery exists within the ER that aids and controls protein folding. Failures in this process are associated with numerous human diseases, including the steadily increasing number of protein folding diseases.
In our work we use an interdisciplinary approach from biochemistry via structural biology to mammalian cell biology to dissect molecular mechanisms and the cellular machinery of protein folding in the ER. A particular focus of our work lies on understanding structural features within client proteins that are recognized by the ER quality control machinery to provide insights into how the cell distinguishes between mature and improperly folded proteins. Our model systems are proteins of the immune system, including antibodies, immune receptors and interleukins. As such, insights into the biogenesis of these proteins can have an immediate impact on designing better biopharmaceuticals as well as breaking ground for novel approaches in human immunotherapy. At the same time, our work aims at understanding common principles that underlie the quality control of the manifold clients that have to be produced in the ER.