Title :
structure of C3b in complex with
CRIg gives insights into regulation of complement activation
Abstract :
- The complement system is a key part of the innate immune system, and is required for clearance of pathogens from the bloodstream
- After exposure to pathogens, the third component of the complement system, C3, is cleaved to C3b which, after recruitment of factor B, initiates formation of the alternative pathway convertases
- CRIg , a complement receptor expressed on macrophages, binds to C3b and i C3b mediating phagocytosis of the particles, but it is unknown how CRIg selectively recognizes proteolytic C3-fragments and whether binding of CRIg to C3b inhibits convertase activation
- Here we present the crystal structure of C3b in complex with CRIg and, using CRIg mutants, provide evidence that CRIg acts as an inhibitor of the alternative pathway of complement
- The structure shows that activation of C3 induces major structural rearrangements, including a dramatic movement (>80 A) of the thioester-bond-containing domain through which C3b attaches to pathogen surfaces
- We show that CRIg is not only a phagocytic receptor , but also a potent inhibitor of the alternative pathway convertases
- The structure provides insights into the complex macromolecular structural rearrangements that occur during complement activation and inhibition
- Moreover, our structure-function studies relating the structural basis of complement activation and the means by which CRIg inhibits the convertases provide important clues to the development of therapeutics that target complement