One of the oldest defense mechanisms of our body is the complement system. Unlike white blood cells, which must learn to recognize pathogens, the complement system works from birth onwards. The system consists of proteins that initiate a chain reaction to kill bacteria and damaged cells. However the system is not perfect; it can run wild and attack our own healthy cells.
The chain reaction needs to be studied in detail in order to understand how it proceeds and how it can be stopped. Yet there is only one brief moment in the chain reaction during which the protein complex indicates whether cells are harmful. The complex then adjusts the surface of a pathogen so that the pathogen can be engulfed by white blood cells.
The researchers made smart use of the tricks that bacteria have developed over the years. They stopped the chain reaction using the protein SCIN (Staphylococcal complement inhibitor) from the pathogenic bacterium Staphylococcus aureus. The SCIN protein brings the chain reaction to a halt and consequently the message that a bacteria has entered does not reach the white blood cells.
By freezing the protein complex at this point in time, the researchers could study its structure. They could see how the central protein was activated to indicate the presence of harmful cells and how the protein complex initiated the chain reaction. Moreover, they could analyse how SCIN brought the chain reaction to a halt.
In a parallel study, a second team of researchers investigated how our own cells defend themselves against possible attacks from the complement system. Factor H (FH) is the most important inhibitor of attacks on healthy cells. The researchers analysed how FH worked at the moment it came into contact with the proteins from the complement system. They compared the structure of FH at this point in time with the structure of the protein complex if it comes into contact with SCIN. The research revealed that defence proteins on the cells ensure that the chain reaction is not activated and that the protein complex is broken down.
Jin Wu and Suzan Rooijakkers carried out most of the research. Suzan Rooijakkers received an NWO Veni grant in 2006. Both studies were supervised by Vici winner Piet Gros. Jos van Strijp received a TOP subsidy from the Netherlands Organisation for Health Research and Development (ZonMw).
‘Structural and functional implications of the alternative complement pathway C3 convertase stabilized by a staphylococcal inhibitor’, Suzan Rooijakkers, Jin Wu, Maartje Ruyken, Robert van Domselaar, Karel Planken, Apostolia Tzekou, Daniel Ricklin, John Lambris, Bert Janssen, Jos van Strijp and Piet Gros
‘Structure of complement component 3b-factor H and implications for host protection by complement regulators’, Jin Wu, You-Qiang Wu, Daniel Ricklin, Bert Janssen, John Lambris and Piet Gros,
Advance Online Publications on the website of Nature Immunology on 7 June.