Understanding the first steps of the complement classical pathway: Structural studies on C1-antibody complexes

The complement system is a complex network of plasma and membrane-associated proteins, which can produce effective immune responses to infectious micro-organisms. Deficiencies of complement proteins cause diseases like systemic lupus erythematosus (SLE), rheumatoid arthritis and angioedema. Recently, C1q has been found to play an important role in synaptic pruning which is crucial for the brain functioning and related to central nervous system diseases like glaucoma or Alzheimer’s disease. Since complement system has such a broad range of functions, understanding the molecular details of complement activation is fundamental. Classical Pathway of Complement is initiated by a large macromolecular complex called C1 binding to antibody-antigen complexes on the surface. C1 is a 790-kDa complex, which consists of 6 recognition proteins C1q and a hetero-tetramer of serine proteases, C1r2C1s2. In this thesis, we addressed issues about assembly of C1 (i.e. C1r2s2 binding to C1q), auto-activation of C1r and C1 binding to antibodies. Using the latest advances in native mass spectrometry and cryo-electron microcopy, our data provide new insights into the assembly and activation of the C1 complex and structural details of C1 bound to activating antibodies.