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Analysis of the interaction between properdin and factor B, components of the alternative-pathway C3 convertase of complement.

ABSTRACT: The interactions between Factor B (B), its activation products Ba and Bb, properdin (P) and C3i or C3b, components that together form the alternative-pathway C3 convertase enzyme of human complement, have been analysed. Fluid-phase complexes of the purified components C3i, B and P were probed with the homobifunctional cross-linking reagent disuccinimidyl tartarate, and efficient cross-linking of B to P was observed. The 140 kDa B-P conjugate formed was cleaved by Factor D to yield a single product of 85 kDa. This is consistent with a Ba-P heterodimer, and suggests that the initial interaction of B and P includes an interaction of P with the Ba domain of intact B. (The Ba fragment is not retained in the active P-stabilized complex, C3bBbP). By contrast, no cross-linking of P to the Bb domain of B could be demonstrated. Binding studies on cellular intermediates also provided evidence for a site of interaction between B and P, with high concentrations of B inhibiting P binding to EAC3b (sheep erythrocytes coated with antibody and C3b). Neither isolated Ba nor Bb had any effect on the P-EAC3b interaction. High concentrations of B also accelerated the decay of the functional EAC3bBbP complex. These data indicate that the positive co-operativity of binding to C3i or to C3b between B and P is mediated, at least in part, through a direct interaction between B and P.

SUBMITTER: Farries TC

PROVIDER: S-EPMC1149358 | biostudies-other | 1988 Aug

REPOSITORIES: biostudies-other

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Project description:The complement network is increasingly recognized as an important triage system that is able to differentiate between healthy host cells, microbial intruders, cellular debris and immune complexes, and tailor its actions accordingly. At the center of this triage mechanism is the alternative pathway C3 convertase (C3bBb), a potent enzymatic protein complex capable of rapidly converting the inert yet abundant component C3 into powerful effector fragments (C3a and C3b), thereby amplifying the initial response on unprotected surfaces and inducing a variety of effector functions. A fascinating molecular mechanism of convertase assembly and intrinsic regulation, as well as the interplay with a panel of cell surface-bound and soluble inhibitors are essential for directing complement attack to intruders and protecting healthy host cells. While efficiently keeping immune surveillance and homeostasis on track, the reliance on an intricate cascade of interaction and conversion steps also renders the C3 convertase vulnerable to derail. On the one hand, tissue damage, accumulation of debris, or polymorphisms in complement genes may unfavorably shift the balance between activation and regulation, thereby contributing to a variety of clinical conditions. On the other hand, pathogens developed powerful evasion strategies to avoid complement attack by targeting the convertase. Finally, we increasingly challenge our bodies with foreign materials such as biomaterial implants or drug delivery vehicles that may induce adverse effects that are at least partially caused by complement activation and amplification via the alternative pathway. The involvement of the C3 convertase in a range of pathological conditions put this complex into the spotlight of complement-targeted drug discovery efforts. Fortunately, the physiological regulation and microbial evasion approaches provide a rich source of inspiration for the development of powerful treatment options. This review provides insight into the current knowledge about the molecular mechanisms that drive C3 convertase activity, reveals common and divergent strategies of convertase inhibition employed by host and pathogens, and how this inhibitory arsenal can be tapped for developing therapeutic options to treat complement-related diseases.

Dataset Information

Analysis of the interaction between properdin and factor B, components of the alternative-pathway C3 convertase of complement.

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