Structural basis for proteolytic cleavage of complement C4, C3 and C5

Orateur : Gregers R. ANDERSEN (Aarhus University, Denmark, Department of Molecular Biology and Genetics)

An essential aspect of complement is recognition of molecular patterns on the surface of pathogens or altered self through the lectin and classical pathways. This causes activation of the MASP-2 or the C1s serine proteases followed by cleavage of C4. We have determined the crystal structure of the substrate C4 and to provide a model of the enzyme-substrate the structure of the complex between C4 and a fragment of MASP-2 was determined. These structures will be described and a working model for the MBL:MASP-2:C4 complex will be presented and its properties discussed. Further downstream complement C3 and C5 are cleaved by the convertases. As these are unstable, we have determined the structure of cobra venom factor in complex with C5 to gain structural insight into substrate recognition by the convertases. By combining the C5:CVF structure with that of the C3b:Bb complex, a working model for convertase-substrate and convertase-product complexes can be proposed. I will present these and compare the structural models for C4, C3 and C5 cleavage.

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