PhD defence: Molecular principles of enhanced complement activation by properdin

The complement system is a part of the innate immune system and consists out of a cascade of proteins. Complement is important for the defense against invasive microorganisms and for the clearance of foreign objects and altered host cells. Complement can be activated upon the recognition of danger patterns. In addition, there is continues low level complement activation which can lead to rapid activation upon invasion of a microorganism. It is essential that complement activation is regulated to protect healthy host cells and to enhance activation on targeted surfaces.

We investigated the protein properdin, which is important for increasing complement activation on surfaces. Properdin increases activation by stabilizing the C3 convertase C3bBb, which is a pivotal enzyme complex in the complement system. By using X-ray crystallography, we solved the 3D structures of properdin and properdin in complex with a piece of C3bBb. These structures provided new insights into the molecular mechanism behind stabilization of C3bBb by properdin. Furthermore, we used the structures to design a novel properdin inhibitor which, after further optimization, may be used to treat diseases related to overactivation of the complement system.

We also assessed the relationship between properdin and factor H, which is a protein that reduces complement activation by destabilizing C3bBb. Factor H and properdin have an opposing effect on the lifetime of the C3 convertase and we showed that they act independently.