PMID: 21217642

 

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Title : Substrate recognition by complement convertases revealed in the C5-cobra venom factor complex

Abstract :

1. Complement acts as a danger-sensing system in the innate immune system, and its activation initiates a strong inflammatory response and cleavage of the proteins C3 and C5 by proteolytic enzymes , the convertases
2. These contain a non-catalytic substrate contacting subunit ( C3b or C4b ) in complex with a protease subunit (Bb or C2a)
3. We determined the crystal structures of the C3b homologue cobra venom factor ( CVF ) in complex with C5, and in complex with C5 and the inhibitor SSL7 at 4.3 Å resolution
4. The structures reveal a parallel two-point attachment between C5 and CVF , where the presence of SSL7 only slightly affects the C5- CVF interface, explaining the IgA dependence for SSL7-mediated inhibition of C5 cleavage
5. CVF functions as a relatively rigid binding scaffold inducing a conformational change in C5, which positions its cleavage site in proximity to the serine protease Bb
6. A general model for substrate recognition by the convertases is presented based on the C5- CVF and C3b-Bb- SCIN structures
7. Prior knowledge concerning interactions between the endogenous convertases and their substrates is rationalized by this model