Complement component 5a

C5a is a protein fragment released from complement component C5. In humans, the polypeptide contains 74 amino acids. NMR spectroscopy proved that the molecule is composed of four helices and loops connecting the helices. On the N terminus a short 1.5 turn helix is also present. 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-Arg.



Functions

 * C5a is an anaphylatoxin, causing the release of histamine from mast cells; C5a des-Arg is a much less potent anaphylatoxin.


 * 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. (See also Chemotaxis.)


 * C5a activates white blood cells by increasing avidity for white blood cell integrins and upregulating the Lipoxygenase pathway for arachidonic acid metabolism.


 * C5a is a powerful inflammatory mediator, and seems to be a key factor in the development of pathology of many inflammatory diseases involving the complement system.


 * C5a modulates balance between activating versus inhibitory IgG Fc receptors on leukocytes, thereby enhancing autoimmune response.

Binding process
C5a binds to a receptor protein on the surface of target cells, C5aR or CD88. This is a member of the G-protein-coupled receptor superfamily of proteins, predicted to have seven transmembrane helical domains of largely hydrophobic amino acid residues, forming three intra- and three extra-cellular loops, with an extracellular N-terminus and an intracellular C-terminus. 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 domains. 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 GNAI2.