PMID: 19574954

 

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Title : Insights into complement convertase formation based on the structure of the factor B-cobra venom factor complex

Abstract :

1. Immune protection by the complement system critically depends on assembly of C3 convertases on the surface of pathogens and altered host cells
2. These short-lived protease complexes are formed through pro-convertases, which for the alternative pathway consist of the complement component C3b and the pro-enzyme factor B (FB)
3. Here, we present the crystal structure at 2.2-A resolution, small-angle X-ray scattering and electron microscopy (EM) data of the pro-convertase formed by human FB and cobra venom factor ( CVF ), a potent homologue of C3b that generates more stable convertases
4. FB is loaded onto CVF through its pro-peptide Ba segment by specific contacts, which explain the specificity for the homologous C3b over the native C3 and inactive products i C3b and C3c
5. The protease segment Bb binds the carboxy terminus of CVF through the metal-ion dependent adhesion site of the Von Willebrand factor A-type domain
6. A possible dynamic equilibrium between a 'loading' and 'activation' state of the pro-convertase may explain the observed difference between the crystal structure of CVFB and the EM structure of C3bB
7. These insights into formation of convertases provide a basis for further development of complement therapeutics