Complement component 5a

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complement component 5
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C5a is a protein fragment released from cleavage of

membrane attack complex (MAC), one of the most basic weapons of the innate immune system, formed as an automatic response to intrusions from foreign particles and microbial invaders. It essentially pokes microscopic pinholes in these foreign objects, causing loss of water and sometimes death. C5a, the other cleavage product of C5, acts as a highly inflammatory peptide, encouraging complement activation, formation of the MAC, attraction of innate immune cells, and histamine release involved in allergic responses. The origin of C5 is in the hepatocyte, but its synthesis can also be found in macrophages, where it may cause local increase of C5a. C5a is a chemotactic agent and an anaphylatoxin; it is essential in the innate immunity but it is also linked with the adaptive immunity. The increased production of C5a is connected with a number of inflammatory diseases.[1]

Structure

Human polypeptide C5a contains 74 amino acids and has 11kDa. NMR spectroscopy proved that the molecule is composed of four helices and connected by peptide loops with three disulphide bonds between helix IV and II, III. There is a short 1.5 turn helix on N-terminus but all agonist activity take place in the C-terminus. C5a is rapidly metabolised by a serum enzyme carboxypeptidase B to a 72 amino acid form C5a des-Arg without C terminal arginine.[2][3]

Functions

C5a is an

TNF-α. C5a is also an effective chemoattractant,[4] initiating accumulation of complement and phagocytic cells at sites of infection or recruitment of antigen-presenting cells to lymph nodes.[5]
C5a plays a key role in increasing migration and adherence of neutrophils and monocytes to vessel walls. White blood cells are activated by upregulation of integrin avidity, the lipoxygenase pathway and arachidonic acid metabolism. C5a also modulates the balance between activating versus inhibitory IgG Fc receptors on leukocytes, thereby enhancing the autoimmune response.[1]

Binding process

C5a interact with

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.[6]

Sensitivity of C5aR1 to C5a stimulation is enhanced by lipopolysaccharides exposure. C5a, acting via C5aR1, is shown to differentially modulate lipopolysaccharides-induced inflammatory responses in primary human monocytes versus macrophages,[7] yet this is not due to C5aR1 upregulation.[8] C5L2 is another C5a receptor that is thought to regulate the C5a-C5aR1 effects. There is apparently contradictory evidence showing decoy receptor activity conferring anti-inflammatory properties and also signalling activity conferring pro-inflammatory properties.[9][1]

Diseases

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 such as sepsis, rheumatoid arthritis, inflammatory bowel disease, systemic lupus erythemotosis, psoriasis. The inhibitor of C5a that can block its effects would be helpful in medical applications. Another candidate is PMX53 or PMX205 that is highly specific for CD88 and effectively reduces inflammatory response.

ARDS)[19] and promote tumor growth and metastasis.[20]

References

  1. ^
    PMID 19464229
    .
  2. PMID 23383423
    .
  3. S2CID 22630287
    .
  4. PMID 27094554
    .
  5. S2CID 4338594
    .
  6. ^ Fujita T (14 October 1999). Boulay F (ed.). "PROW and IWHLDA present the GUIDE on: CD88". Protein Reviews on the Web. Archived from the original on 2008-07-24.
  7. S2CID 207429042
    .
  8. PMID 21630250
    .
  9. PMID 23383423
    .
  10. S2CID 9206660
    .
  11. PMID 22924972
    .
  12. PMID 12218141
    .
  13. PMID 19324972
    .
  14. PMID 21292772
    .
  15. PMID 29915941
    .
  16. PMID 23756248
    .
  17. PMID 23479227
    .
  18. PMID 32634128
    .
  19. PMID 23982144
    .
  20. S2CID 245556050
    .

External links
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