Regulation and deregulation of the fluid-phase classical pathway C3 convertase.
Three mechanisms that regulate the formation and function of the fluid-phase classical pathway C3 convertase (C4b2a) have been elucidated: a) a temperature-mediated intrinsic decay of the enzyme; b) an extrinsic accelerated decay mediated by the effect of the serum protein C4b-binding protein (C4-bp); and c) the inactivation of C4b in the C4b-C4b-p complex by the proteolytic action of C3b/C4b inactivator (I), which cleaves the alpha 1-chain of C4b yielding C4d (alpha 2-chain), and C4c (alpha 3-, alpha 4-, beta-, gamma-chains). A fourth mechanism is described based on the observation that the IgG fraction of the serum of certain patients with glomerulonephritis contains a protein that prevents the intrinsic and C4-bp-mediated decay of surface-bound C4b2a. This protein prolongs the half-life of fluid-phase C4b2a from 10 min to more than 5 hr, increasing the utilization of C3. It also inhibits the decay mediated by C4-bp by preventing the dissociation of C2a from the C4b, 2a complex. In addition, I alone or in the presence of C4-bp fails to cleave the alpha 1-chain of C4b in the stabilized C4b, 2a complex. This protective property of the stabilizing factor (NFc) requires the presence of C2a because C4b was not protected unless it was bound to C2a. Therefore, NFc provides a mechanism by which the serum regulatory proteins are bypassed.
Gigli
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I
Sorvillo
J
J
Halbwachs-Mecarelli
L
L
D002352:Carrier Proteins / Q000494:pharmacology; D003166:Complement Activating Enzymes / Q000097:blood*; D003167:Complement Activation; D003178:Complement C3 Nephritic Factor / Q000494:pharmacology; D050577:Complement C3-C5 Convertases / Q000096:biosynthesis / Q000097:blood*; D003181:Complement C4 / Q000096:biosynthesis / Q000502:physiology; D015935:Complement C4b; D017244:Complement Factor I; D003171:Complement Pathway, Classical; D010450:Endopeptidases / Q000494:pharmacology; D006801:Humans; D006868:Hydrolysis; D066298:In Vitro Techniques; D016167:Integrin alphaXbeta2; D013997:Time Factors
D002352:Carrier Proteins; D003178:Complement C3 Nephritic Factor; D003181:Complement C4; D016167:Integrin alphaXbeta2; D015935:Complement C4b; D003166:Complement Activating Enzymes; D010450:Endopeptidases; D050577:Complement C3-C5 Convertases; D017244:Complement Factor I