Definition
C5a is the protein fragment released from the complement protein, C5. It is an anaphylotoxin and causes release of histamines from mast cells1.
Discovery
Complement system was first discovered in the 1880’s as a heat liable bactericidal activity component in fresh serum2. Later several components of the complement proteins were identified by protein purification techniques3. C5a was originally purified from rat or porcine plasma that was treated with dextran or cobra venom factor4.
Classification
C3a, C4a and C5a serum proteins of the complement system are all anaphylotoxins5.
Structural Characteristics
In humans, C5a contains 74 amino acids. The molecule is composed of four helices and loops connecting the helices. On the N terminus a short 1.5 turn helix is also present1. The longest helix -IV- develops three disulfide bonds with helix II and III. C5a is rapidly metabolised by a serum enzyme, carboxypeptidase B to a 73 amino acid form, C5a des-Arg1.
Mode of action
C5a binds to a receptor protein on the surface of target cells, C5aR or CD88, a member of the G-protein-coupled receptor superfamily of proteins, predicted to have seven transmembrane helical domains of largely hydrophobic amino acid residues6,7. C5a binding to the receptor is a two-stage process: an interaction between basic residues in the helical core of C5a and acidic residues in the extracellular N-terminal domain allows the C-terminus of C5a to bind to residues in the receptor transmembrane domains6,7. The latter interaction leads to receptor activation, and the transduction of the ligand binding signal across the cell plasma membrane to the cytoplasmic G protein Gi type GNAI26,7.
Functions
C5a is an anaphylatoxin, causing the release of histamine from mast cells; C5a des-Arg is a much less potent anaphylatoxin8. Both C5a and C5a des-Arg are effective leukocyte chemoattractants, causing the accumulation of white blood cells, especially neutrophil granulocytes, at sites of complement activation. It activates white blood cells by increasing avidity for white blood cell integrins and upregulating the Lipoxygenase pathway for arachidonic acid metabolism9. C5a is a powerful inflammatory mediator, and seems to be a key factor in the development of pathology of many inflammatory diseases such as sepsis, asthma and cystic fibrosis10. C5a modulates balance between activating versus inhibitory IgG Fc receptors on leukocytes thereby enhances autoimmune response11.
References
1. Monk PN, Scola AM, Madala P, Fairlie DP (2007). Function, structure and therapeutic potential of complement C5a receptors. Brit. J Pharma., 152, 429–48.
2. Buchner H (1889). Uber die bakterientodtende, Wirkunk des zellenfrien Blutserums. Zentralbl Bakteriol., 5, 1-11.
3. Muller-EHJ (1968). Chemistry and reaction mechanisms of complement. Adv Immunol., 8, 1-80.
4. Stegemann H, Vogt W, and Friedberg KD (1964). Hoppe-Seyler’s Z. Physiol. Chem., 337, 269-276.
5. Klos A, Tenner AJ, Johswich KO, Ager RR, Reis ES, Köhl J (2009). The role of the anaphylatoxins in health and disease. Mol. Immunol., [EPub ahead of print].
6. Gerard NP, Gerard C (1991). The chemotactic receptor for human C5a anaphylatoxin. Nature, 349, 614.
7. Gerard C, Gerard NP (1994). C5A anaphylatoxin and its seven transmembrane-segment receptor. Annu Rev Immunol., 12, 775.
8. Schulman ES, Post TJ, Henson PM and Giclas PC (1998). Differential effects of the complement peptides, C5a and C5a des Arg on human basophil and lung mast cell histamine release. J. Clin. Invest., 81(3), 918-923.
9. Mamoru K, Noriyuki S, Yukio T, Hiro-o K, Takeshi K, Tony E. H and Masayoshi A (2000). Intratracheal administration of anaphylatoxin C5a potentiates antigen-induced pulmonary reactions through the prolonged production of cysteinyl–leukotrienes. Immunopharmacology, 49 (3), 263-74.
10. Guo RF, Ward PA (2005). Role of C5a in inflammatory responses. Annu Rev Immunol., 23:821-52.
11. Schmidt RE, Gessner (2005). JEFc receptors and their interaction with complement in autoimmunity. Immunol Lett., 100(1), 56-67.