Structural basis of proprotein convertase activation

For our body cells to function properly, hundreds of chemical reactions must take place in a coordinated manner. The control of these processes is extremely important, so that they are triggered at the right time and in the right place. To do this, cells use a universal repertoire of tools, the enzymes. These protein molecules drive chemical reactions, can be selectively turned on and off and are transported to specific locations within the cell. If enzymes are activated or deactivated at the wrong time or in the wrong place, it leads to malfunctions in the cell. Accumulation of faulty cells can cause diseases in an organism including cancer, autoimmune diseases, or dementia. Pathogens, such as RSV or influenza viruses, can specifically influence cellular metabolism to drive their own reproduction. The proprotein-convertases are a class of control enzymes that are specialized in activating other enzymes. Therefore, a malfunction of these molecular switches can have a particularly drastic effect on cell function. On the other hand, a targeted control of proprotein-convertases activity also facilitates new possibilities for treating many diseases. For the development of such therapeutics, a detailed understanding of the function of these enzymes is essential. Currently, it is not adequately known how proprotein-convertases themselves are activated. It is known that these enzymes respond to conditions at different locations within the cell and can therefore automatically become active. However, how this switching mechanism works at the molecular level is still largely unclear. In this research project, we aim to examine this process in detail using biochemical and structural biology methods. We are particularly interested in how the structure of the proprotein-convertases changes during activation. To understand what molecular processes are taking place, we want to use X-ray protein crystallography. By means of this biophysical method, protein molecules can be made visible to the human eye in the size range of one ten millionth of a millimeter. Through this study, we expect to gain a better understanding of disease-related processes in the cell on the one hand. On the other hand, we want to explore new ways to employ proprotein- convertases as targets for drug development.