Complement C4a

Human C4a is a cationic polypeptide that can be directly isolated from fresh serum after the activation of the complement cascade. The C4a anaphylatoxin consists of 77 residues without histidine, tryptophan, and carbohydrate side chains, weighing 8,759 Da. C4a is homologous to C3a and C5a (two anaphylatoxins released by complement activation) in sequence and structure within or between species. During the activation of the complement classical pathway and the lectin pathway, the alpha-chain of the complement component 4 (C4) is respectively cleaved by activated C1s and MASP-2, releasing a small fragment C4a and a large fragment C4b. The C4b is involved in the next step of the complement pathways in the formation of convertases. C4a serves as an anaphylatoxin implicated in inflammatory reactions.

Although similar in structure to other anaphylatoxins, the functional properties of C4a are different from C3a and C5a. Firstly, C4a has no specific receptor and seems to function through the C3a receptor. Secondly, C4a is an anaphylatoxin local inflammation, induces smooth muscle contraction, increases vascular permeability, and causes the release of histamine by mast cells and basophilic leukocytes, but these induced bio-functions are much weaker compared to C3a and C5a. Besides, C4a, as well as C3a, exhibit antibacterial activity against both Gram-negative and Gram-positive bacteria, which is independent of the receptor but depends on the net charge, the proportion of hydrophobic amino acids, and the amphiphilic peptide. It is indicated that the deficiency of the C4a might result in systemic lupus erythematosus and type I diabetes mellitus, and excess was associated with schizophrenia and psychotic bipolar disorder.

Fig. 1 Structure of C4a.¹

Reference

1. From Wikipedia: By Emw - Own work, CC BY-SA 3.0 https://commons.wikimedia.org/wiki/File:Protein_C4A_PDB_1hzf.png