Proteolysis, complex formation and conformational changes drive the complement pathways

The complement system is an important part of the mammalian immune defense in blood and interstitial fluids. This set of ~30 plasma proteins and receptors enables the host to recognize and clear invading pathogens and altered host cells, while protecting healthy host cells and tissues. Over the last 7 years, we have resolved the structural details of the central components of this system, which is referred to as the Alternative Pathway of complement activation, and deduced the molecular mechanisms that underlie the amplification and regulation of this protein network. In short, we revealed that large domain-domain rearrangements of these multi-domain proteins, upon proteolysis and complex formation, determine the specificity that provides a local and brief burst to mark targets cells for immune clearance. Most recently, we and others have revealed structural details of the Terminal Pathway that leads to pore formation by Membrane-Attack-Complexes in cell membranes yielding lysis.