C3a (complement)

C3a is one of the proteins formed by the cleavage of complement component 3; the other is C3b. C3a is a 77 residue anaphylatoxin that binds to the C3a receptor (C3aR), a class A G protein-coupled receptor. It plays a large role in the immune response.

C3a molecules induce responses through the GPCR C3a receptor. Like other anaphylatoxins, C3a is regulated by cleavage of its carboxy-terminal arginine, which results in a molecule with lowered inflammatory function (C3a desarginine).

C3a is an effector of the complement system with a range of functions including T cell activation and survival, angiogenesis stimulation, chemotaxis, mast cell degranulation, and macrophage activation. It has been shown to have both proinflammatory and anti-inflammatory responses, its activity able to counteract the proinflammatory effects of C5a.

Structure

C3a

C3a is a strongly basic and highly cationic 77 residue protein with a molecular mass of approximately 10 kDa. Residues 17-66 are made up of three anti-parallel helices and three disulfide bonds, which confer stability to the protein. The N-terminus consists of a fourth flexible helical structure, while the C terminus is disordered. C3a has a regulatory process and a structure homologous to complement component C5a, with which it shares 36% of its sequence identity.

Receptor

C3a induces an immunological response through a 482 residue G-protein-coupled receptor called C3aR. The C3aR is similarly structurally homologous to C5aR, but contains an extracellular domain with more than 160 amino acids. Specific binding sites for interactions between C3a and C3aR are unknown, but it has been shown that sulfation of tyrosine 174, one of the amino acids in the extracellular domain, is required for C3a binding. It has also been demonstrated that the C3aR N terminus is not required for ligand binding.

Formation

C3a formation occurs through activation and cleavage of complement component 3 in a reaction catalyzed by C3-convertase. There are three pathways of activation, each of which leads to the formation of C3a and C3b, which is involved in antigen opsonization. Other than the alternative pathway, which is constantly active, C3a formation is triggered by pathogenic infection.

Classical pathway

The classical pathway of complement activation is initiated when the C1 complex, made up of C1r and C1s serine proteases, recognizes the Fc region of IgM or IgG antibodies bound to a pathogen. C1q mediates the classical pathway by activating the C1 complex, which cleaves C4 and C2 into smaller fragments (C4a, C4b, C2a, and C2b). C4a and C2b form C4bC2b, also known as C3 convertase.

Lectin pathway

The lectin pathway is activated when pattern-recognition receptors, like mannan-binding lectin or ficolins, recognize and bind to pathogen-associated molecular patterns on the antigen, including sugars. These bound receptors then complex with Mannose-Binding Lectin-Associated Serine Proteases (MASPs), which have proteolytic activity similar to the C1 complex. The MASPs cleave C4 and C2, resulting in C3 convertase formation.

Alternative pathway

The alternative pathway of complement activation is typically always active at low levels in blood plasma through a process called tick-over, in which C3 spontaneously hydrolyzes into its active form, C3(H₂O). This activation induces a conformational change in the thioester domain of C3(H₂O) that allows it to bind to a plasma protein called Factor B. This complex is then cleaved by Factor D, a serine protease, to form C3b(H₂O)Bb, or fluid-phase C3-convertase. This complex has the ability to catalyze the formation of C3a and C3b after it binds properdin, a globulin protein, and is stabilized.

Functions

Anaphylatoxins are small complement peptides that induce proinflammatory responses in tissues. C3a is primarily regarded for its role in the innate