Complement C3a Anaphylatoxin

Complement C3a Anaphylatoxin Background

The complement system is a major arm of the innate immune system. One of the major biological consequences of complement activation is the generation of three small cationic peptides collectively referred to as complement anaphylatoxins. One of the complement anaphylatoxins, C3a, is a potent activator of mast cells, basophils, and eosinophils and causes smooth muscle contraction and increases vascular permeability.

Complement C3a Anaphylatoxin Structure

The human complement C3a, is comprised of 77 amino acid residues, is highly cationic, and contains six cysteine residues that form three intra-chain disulfide bonds. This latter feature has been thought to impart stability to the molecule.

For example, extremes of pH (1 to 13 ranges) and heat (56°C for 30 min) do not destroy C3a biological activity. Circular dichroism (CD) spectra indicated that 40 to 45 % of the molecule is of regular helical structure and that very little beta-structure is present. Confirmation of the high helical content was provided by crystallographic analysis, which indicated a 56 % alpha-helical content.

The crystal structure of C3a in combination with NMR studies have indicated that C3a assumes a "drumstick" or "dagger" shape that contains a rigid disulfide-linked core portion (residues 17-66) comprised of three anti-parallel helical structures (helix 2, residues 17-28; helix 3, residues 35-43, and helix 4, residues 47-66). The N-terminal end of complement anaphylatoxin C3a (residues 1-15), which also contains a helical segment (helix 1, residues 8-15), exhibits a high degree of flexibility with helix 1 folding back against the core portion of the molecule. The C-terminal or effector region of complement anaphylatoxin C3a (residues 69-77) assumes no regular conformation and may either remain flexible or fold back onto the helical portion in a pseudo-beta turn conformation.

Complement C3a Anaphylatoxin Regulation

C3a is known to promote strong chemotaxis (for eosinophils, and human mast cells), cytokine and chemokine production, leukotriene production by basophils, and platelet aggregation. Although a functional C3aR has recently been characterized on cultured human umbilical cord endothelial cells (HUVEC), little is known about the role of C3a or even C5a on endothelial cells.

The biological function of this complement C3a is regulated by carboxypeptidase B, a plasma protease that cleaves off the C-terminal arginine yielding C3a desArg, an inactive form. While functional assays demonstrate strikingly different physiological effects between C3a and C3a desArg, no structural information is available on the possible conformational differences between the two proteins.

Complement C3a Anaphylatoxin References

1. Bajic G, et al. (2013). Human C3a and C3a desArg anaphylatoxins have conserved structures, in contrast to C5a and C5a desArg. Protein Science, 22(2), 204-212.
2. MONSINJON T, et al. (2003). Regulation by complement C3a and C5a anaphylatoxins of cytokine production in human umbilical vein endothelial cells. The FASEB Journal, 17(9), 1003-1014.