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Results 1 - 7 of 7
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General Information
Commentary
Reference
metabolism
all pathways converge at the level of the C3 molecule, where downstream events can be amplified by a mechanism of positive feedback supported by complement convertases: the classical/lectin pathway C3 convertase (C4b2a) or the alternative pathway C3 convertase (C3bBb). These convertases further cleave C3 to C3b and C3a, of which C3b binds to nearby surfaces, providing a convertase assembly platform, or to pre-assembled C3 convertases, switching them to C5 convertases (C4b2aC3b or C3bBbC3b, respectively). The C5 convertase cleaves C5 molecules to C5a and C5b and the latter initiates formation of the membrane attack complex (MAC, C5b678polyC9) and its insertion into a target membrane. Enzyme regulation, overview
metabolism
complement activation results in the assembly of unstable protease complexes, denominated C3/C5 convertases, leading to inflammation and lysis. Regulatory proteins inactivate C3/C5 convertases on host surfaces to avoid collateral tissue damage. On pathogen surfaces, the glycoprotein properdin stabilizes C3/C5 convertases to efficiently fight infection. The N- and C-terminal ends of adjacent monomers in properdin oligomers conform a curly vertex that holds together the AP convertase, interacting with both the C345C and vWA domains of C3b and Bb, respectively. Properdin also promotes a large displacement of the TED (thioestercontaining domain) and CUB (complement protein subcomponents C1r/C1s, urchin embryonic growth factor and bone morphogenetic protein 1) domains of C3b, which likely impairs C3-convertase inactivation by regulatory proteins
metabolism
when factor B first associates with C3b, it bears two intact Arg234 salt bridges. The complex rapidly dissociates unless the Arg234-Glu446 salt bridge is released whereupon conformational changes occur that activate the metal ion-dependent adhesion site and partially stabilize the complex. The remaining salt bridge is then released, exposing the scissile bond and permitting factor D cleavage of proenzyme factor B
more
stabilization of the complement alternative pathway C3 convertase by properdin, structural basis, overview. Complex assembly between properdin and C3 convertase by incubation of C3b, Factor B, and Factor D in the presence of properdin. The Factor B-D279G mutant increases the stability of C3 convertase. Properdin cross-Links C3b and the Bb fragment, stabilizing the C3bBb convertase, structure overview
more
the classical C5 convertase requires factor D and factor B for activation and complex assembly
physiological function
Factor H-related protein 4 activates complement by serving as a platform for the assembly of alternative pathway C3 convertase via its interaction with C3b protein. Ability of CFHR4-bound C3b to bind factor B and properdin, leading to an active convertase that generates C3a and C3b from C3. The CFHR4-C3bBb convertase is less sensitive to the factor H-mediated decay compared with the C3bBb convertas. In contrast to the complement inhibitor factor H, CFHR4 acts as an enhancer of opsonization by promoting complement activation
physiological function
the alternative pathway is activated by zymosan in human serum after blocking the classical pathway activation with either a polyclonal antibody to C4d or with C1 inhibitor. Properdin (Factor P) binding to the erythrocyte membranes is necessary for C3b to attach and initiate alternative pathway activation, regulation, overview
Results 1 - 7 of 7