C5-convertase

C5 convertase is an enzyme belonging to a family of serine proteases that play key role in the innate immunity. It participates in the complement cascade ending with cell death.

There are four different C5 convertases able to specifically convert C5 glycoprotein (α-, β-chain) to C5a and C5b fragments. Two of them are physiological complement enzymes, associate to the cell-surface and mediate the classical pathway (C4b2a3b) or the alternative pathway (C3bBbC3b) of complement cascade. Two fluid phase C5 convertases have been described: the classical pathway enzyme, C4b2aoxy3b and the cobra venom factor-dependent C5 convertase, CVFBb.

Cell-bound C3 and C5 convertase differ in their C3b requirement. C3-convertase (C3bBb) need only one molecule of C3b to form, whereas two or more C3b are required for generation of C5 convertase (C3bBb). It means, when C3b is randomly distributed on the surface of a cell, only C3 convertase activity appears after addition of Factors B and D. However, when C3b is distributed in clusters, C3 and C5 convertase activity is generated upon addition of Factors B and D.

The classical pathway C5 convertase is composed of the larger fragments of complement proteins, C4b, C2a produced by cleavage mediated by C1 complex, and C3b produced by cleavage mediated by the classical pathway C3 convertase (C4bC2a). The formation of the alternative pathway C5 convertase (C3bBbC3b) starts by spontaneous cleavage of C3 protein exposing previously hidden thioester bond. In the presence of pathogen the fragment C3b binds to microbial cell-surface through the newly showed thioester bond. On the other hand, if the infection does not occur, C3b interacts with molecules of water, therefore the protein becomes inactive. However, when C3b undergoes its post-cleveage conformational change, a binding site for a plasma protein called Factor B is also exposed. Factor B then binds to C3b and is cleaved by a plasma serine protease Factor D. The C3bBb complex (= alternative pathway C3 convertase) remains attached to the cell-surface. This complex might interact with another C3b and thus form the alternative pathway C5 convertase.CVFBb is a noncovalent association product of CVF3 and the complement fragment Bb. The catalytic subunits of these multimolecular proteases are C2a and Bb. These subunits belong to atypical serine proteases. CVFBb does not require C3 for cleavage of C5, whereas C4b2aoxy need native C3 for cleavage of C5 protein. The modified C5 convertase, C4b2aoxy3b, contains C2a that is derived from C2 oxidized by iodine.

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