Complement Component C5

Complement Component C5 Background

Complement component C5 is the initiator of the effector terminal phase of the complement system and shares the molecular structure consisting of two chains-α and β, linked by disulfide bonds, with C3 and C4, with the only difference being that complement component C5 does not contain an internal thio-ester bond. The terminal phase is similar for the classical, lectin, and alternative pathways. The incorporation of C3b in the C3 convertases results in the formation of the C5 convertases: C3bBbC3b for the alternative pathway/AP and C4bC2aC3b for the classical pathway/CP and lectin pathway/LP. These C5 convertases cleave C5 into C5a and C5b, ultimately resulting in the formation of the multimeric MAC (C5b-9). Other factors of the coagulation and fibrinolytic pathway including thrombin; human factors XIa, Xa, and IXa; and plasmin can cleave complement component C5, independent of other complement factors, in the so-called extrinsic complement pathway.

C5a, and the other anaphylatoxin C3a that generates from C3 cleavage, are potent bioactive molecules that can act on a wide variety of cell types expressing their high-affinity binding transmembrane receptors C5aR and C5L2 for C5a and C3aR for C3a. C5aR are canonical G-protein-coupled signaling receptors; however, in contrast, C5L2 is unable to couple to G proteins. All these receptors are expressed on immune as well as nonimmune cells; however, C5L2 is expressed at much lower levels compared with C5aR.

C5a and C3a are potent inflammatory mediators targeting a broad spectrum of immune and nonimmune cells. By interacting with their G-protein-coupled receptors C5aR and C3aR, C5a and C3a regulate vasodilatation, increase the permeability of small blood vessels, and induce contraction of smooth muscles. In macrophages, neutrophils and eosinophils C5a and C3a can trigger an oxidative burst and in basophils can stimulate the release of histamine. In eosinophils, C5a and C3a regulate the production of eosinophil cationic protein, their adhesion to endothelial cells, and their migration. C5a is a powerful chemoattractant for macrophages, neutrophils, activated B and T cells, basophils, and mast cells, the latter of which also migrate toward a C3a gradient.

On the other hand, the other C5a receptor, C5L2, may function as a decoy receptor regulating the extracellular bioavailability of C5a, and so limiting the proinflammatory response to C5a. It also may act as a negative modulator of C5aR-mediated signal transduction through the β-arrestin pathway. However, recent studies have suggested that C5L2 has a proinflammatory role in experimental sepsis,allergic asthma, and also may control the development of T-helper 17 cells that are essential in asthma as well as autoimmune arthritis.

Once plasma C5a and C3a are released, plasma carboxypeptidases rapidly metabolize them, by cleaving the C-terminal arginine to less-potent forms: C5adesArg and C3adesArg. C5adesArg still retains signaling activity at C5aR; however, it has 10-fold to 100-fold reduced affinity for C5aR than intact C5a. Thus, this metabolism of C5a by plasma carboxypeptidases effectively limits the activity of C5a, without eliminating all of its functions. Interestingly, C5adesArg still retains high affinity for C5L2, which may enhance the proposed scavenger/decoy receptor activity of C5L2. In contrast, C3aR does not recognize the desarginate form (C3adesArg) of C3a.

Complement Component C5 Reference

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