Properdin pathway

The classical pathway is activated primarily by the antibody antigen complexes. In 1913, Browning and Mackie showed that cobra venom could trigger serum-mediated lysis of erythrocytes in the absence of an antibody. Pillemer described properdin as a component of the antibody-independent complement pathway in 1954, and proposed the name properdin pathway. His work was not accepted until the 1960s, however, when the alternative pathway was... 

Properdin pathway) complex, C3 convertase (C3bBb) thioester with nucleophilic molecules on cell surfaces ... 

P (properdin) can also bind to the C3 convertase. Its role is to stabilize the complex and hence it is considered a cofactor-activator in the alternative pathway. These components plus additional C3b molecules form the C5 convertase, an enzyme complex that peoteolytically converts C5 to C5a and CSb. Properdin stabilizes C3b and Bb in the complex and protects these proteins from proteolytic inactivation by factor I. Factor H competes for Bb in the C5 convertases, the same as it does in the C3 convertase. The alternative pathway has also been called the properdin pathway because of properdin s participation in alternative pathway C3 and C5 convertases. C5b is a component in the terminal complex of the complement activation process, the MAC. The MAC is composed of a self-assembled, noncovalent complex of C5b, C6, C7, C8, and C9. Together these components produce a pore-like structure that makes the membrane of the cell to which it is attached permeable and causes cell death. Under the electron microscope the MAC appears like an impact crater similar to those observed on the surface of the moon. C5a is also an anaphylatoxin like C3a, but it is more potent. C5a is also a chemokine and attracts phagocytic cells to the site of complement activation. 

Properdin (from the Latin verb perdere—to destroy) was first recognized as a distinct serum protein related to complement by Pillemer and associates in the early 1950s (Pillemer et aL, 1954). It was shown to play an essential role in the then described properdin pathway, which was conceived as an alternative mechanism for the activation of the late-acting complement components not requiring antibody. Cl, C4, and C2. 

Morrison DC, Kline LF (1977) Activation of the classical and properdin pathways of complement by bacterial lipopolysaccharides (LPS). / Immunol 118 362-368... 

Because of the total obstruction in the activation of the classical complement pathway in their serum, C4 deficient guinea pig serum has played an important role in elucidating the function of the alternative or properdin pathway ". ... 

In the alternative pathway of activation a small amount of C3b is formed and becomes bound to the cell surface. This binds another proenzyme factor B,165 which is converted by protease factor D166 to active protease Bb. The latter in its complex with C3b is the enzyme that cleaves C3 in large amounts and permits a rapid formation of more Bb and also of the complex (C3b)2 Bb P, which attacks C5 (Fig. 31-8). These complexes are stabilized by the abundant serum protein properdin (P).167... 

C3b is a dangerous protein to have floating around, since it can activate the destructive end of the complement pathway. In order to minimize random damage, two proteins (factors I and H), search out, stick to, and destroy C3b in solution. But if C3b is on the surface of a cell, then another protein (properdin), binds to and protects C3b from degradation so that it can do its job. How does C3b target foreign cells in the absence of antibodies C3b is effective only if it sticks to the surface of a cell. The chemical reaction by which it does so goes faster in the presence of the molecules typically found on the surface of many bacteria and viruses. ... 

Figure 15.1 Complement activation pathways. The classical, lectin and alternative pathways converge into a final common pathway when C3 convertase (C3 con) cleaves C3 into C3a and C3b. Ab = antibody, Ag = antigen, Cl-INH = Cl inhibitor, MAC = membrane attack complex, MASP = MBL-associated serine protease, MBL = mannose-binding lectin, P = properdin. Overbar indicates activation.

Human alternate complement pathway components /31H, C3bINA, factor B, and activated properdin (P)... 

Figure 7-2 Control of the alternative complement pathway by activating surfaces. When complement component C3b binds to a surface, there exist two possible outcomes. Under normal conditions, when no activating surface is present (e g., if C3b has contacted normal tissue), sequential addition of blood cofactors H and I converts C3b into C3c, inactivating the complement protein. If an activating surface such as a microbe or damaged tissue is encountered, sequential addition of factors B and D drives the alternative pathway to the normal properdin (P) intermediate, and the complement cascade is triggered. The properdin-containing component (C3bBbP) feeds back to the beginning of the pathway, generating more C3.

The alternative pathway, which includes C3, factors B and D, and properdin... 

Also see color figure.) Initiation of actron by complement occurs via three pathways classical, alternative (properdin), and lectin pathways. 

Complement deficiencies are associated with several diseases. Alternative pathway deficiencies are rare, but when they exist more than one-half of factor D or properdin-deficient individuals suffer from Neisseria infections of which 75% are fatal. Individuals with deficiencies in the MAC components, e.g., C5, C6, Cl, and C8, are also susceptible to infection with Neisseria. Deficiencies in C1, C4, and C2 are associated with systemic lupus erythematosus and glomerulonephritis. Hereditary angioedema, a disease characterized by recurrent submucosal and subcutaneous edema, is caused by a deficiency in Cl inhibitor. Complexes and interactions similar to those of the complement system are also characteristic of the clotting system (Chapter 36). 

Hourcade DE. The role of properdin in the assembly of the alternative pathway C3 convertases of complement. J Biol Chem 2006 281 (4) 2128-2132. 

Alternative Pathway Proposed recognition component Enzymatically activates B Enzymatically cleaves C3 analogous to C2 Cofactor for B necessary for C3 cleavage by B Properdin stabilizes the alternative pathway convertase Common to Both Pathways... 

Figure 5.4 The Alternative Pathway of Complement Activation. C3 is spontaneously hydrolysed without cleavage of C3a, to become C3b (like). This has the ability to cleave factor B. Combination of C3b (like) with Bb forms a C3 convertase capable of cleaving further C3 into C3b and the anaphylotoxin C3a. Fluid phase C3b is unstable and rapidly inactivated by control proteins, but the availability of a suitable protective surface serves to bind and stabilise the C3b. Stabilisation results in activation of the alternative pathway and constitutes recognition of the protective surface as foreign. C3b can then cleave more factor B to form the true C3 convertase C3bBbP, itself stabilised by the enhancing control protein Properdin (P).

Figure 6.3 A scheme of the alternative pathway or properdin system.

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