Complement component 4

complement component 4A (Rodgers blood group)
Identifiers
Symbol C4A
Entrez 720
HUGO 1323
OMIM 120810
RefSeq NM_007293
UniProt P0C0L4
Other data
Locus Chr. 6 p21.3
complement component 4B
(Chido blood group)
Identifiers
Symbol C4B
Entrez 721
HUGO 1324
OMIM 120820
RefSeq NM_000592
UniProt P0C0L5
Other data
Locus Chr. 6 p21.3

Complement component 4 (C4) is a protein involved in the complement system in human, primate, and other animals.[1] It serves a number of critical functions in the complement system, including contributing component C4B, which bears a reactive thionolactone ring which covalently modifies the cell surfaces of infecting pathogens, and which is a part of the C3 convertase which readies the C3 protein for its role in the complement system. C4 defines the Chido/Rodgers blood group system,[2] and it, and the gene encoding it, are being investigated for its possible role in schizophrenia risk and development.[3]

Complement system

The 25-25 proteins of the complement system work together to "complement" the function of the separate immune system effort (involving antibodies), together to destroy foreign invaders such as bacteria. Circulating in blood in inactive forms, complement proteins activated (e.g., by interaction with an antibody-antigen complex) set in motion a domino effect, a precise chain of steps, the complement cascade (see image). The product of the cascade is a cylindrical pore inserted into the cell membrane allowing water to flow in, resulting in the cell's swelling and eventual bursting.[4][5]

Structure, role, and mechanism

Main article: Complement system
Two pathways of the complement cascade.[4] Components and enzymes of the classical and alternative pathways of the complement cascade, which provides a complementary means for human and other systems to defend against foreign pathogens (see text). Not shown are elements of the lectin pathway.[5] Note, while the appended letters in this figure are lower cases, they are synonymous with the same designations appearing in upper case in the text.

As noted, C4 participates in all three of the complement pathways (classical, alternative, and lectin); the alternative pathway is "triggered spontaneously," while the classical and alternative pathways are elicited in response to the recognition of particular microbes.[5] All three pathways converge at a step in which compliment protein C3 is cleaved into proteins C3A and C3B, which results in a lytic pathway and formation of a macromolecular assembly of multiple proteins, termed the membrane-attack complex (MAC), which serves as a pore in the membrane of the targeted pathogen, leading to invading cell disruption and eventual lysis.[5]

In the classical pathway, the complement component—hereafter abbreviated by the "C" preceding the protein number— termed C1s, a serine protease, is activated by upstream steps of the pathway, resulting in its cleavage of the native, parent ~200 kilodalton (kDa) C4 protein—composed of three chains, a 97 kDa alpha, a 75 kDa beta, and a 33 kDa gamma chain (where these are generally referred to by the single Greek letters α, β, and γ).[5]:288 The C4 is cleaved by the protease into two parts, a peptide C4A (small at ~9 kDa, and anaphylotoxic), and the higher molecular weight protein C4B, at about 190 kDa.[6] The cleavage of the C4 results in C4B bearing a thioester functional group [-S-C(O)-]: work in the 1980s on C3, and then on C4, indicated the presence, within the parent C3 and C4 structures, of a unique protein modification, a 15-atom (15-membered) thionolactone ring serving to connect the thiol side chain of the amino acid cysteine (Cys) in a -Cys-Gly-Glu-Glx- sequence with a side chain acyl group of what began as a glutamine side chain (Glx, here) that resided three amino acid residues downstream (where the remaining atoms of the 15 were backbone and side chain atoms);[6][7] upon cleavage, this unique thionolactone ring structure becomes exposed at the surface of the new C4B protein.[5][6][7] Because of proximity to the microbial surface, some portion of the released C4B proteins, with this reactive thionolactone, react with nucelophilic amino acid side chains and other groups on the foreign microbe's cell surface, resulting in covalent attachment of the slightly modified C4B protein to the cell surface, via the original Glx residue of C4.[5][6][7]

C4B has further functions. It interacts with protein C2; the same protease invoked earlier, C1s, then cleaves C2 into two parts, termed C2A and C2B, with C2B being released, and C2A remaining in association with C4B; the C4B-C2A complex of the two proteins then exhibits a further system-associated protease activity toward protein C3 (cleaving it), with subsequent release of both proteins, C4B and C2A, from their complex (whereupon C4B can bind another protein C2, and conduct these steps again).[5] Because C4B is regenerated, and a cycle is created, the C4B-C2A complex with protease activity has been termed the C3 convertase.[5] Protein 4B can be further cleaved into 4C and 4D.[8]

Clinical significance

Complement component 4 is responsible for the Chido/Rodgers blood group system.[2][9] C4d may be a biomarker for systemic lupus erythematosus.[10] The gene that codes for C4 is being investigated for the role it may play in schizophrenia risk and development.[11][12][13]

Complement deficiency is associated with a syndrome that resembles systemic lupus erythematosus that is a result of a failure to clear circulating immune complexes from tissues.[14][15]

See also

References

  1. ↑ Nonaka M, Kimura A (2006). "Genomic view of the evolution of the complement system". Immunogenetics 58 (9): 701–13. doi:10.1007/s00251-006-0142-1. PMC 2480602. PMID 16896831.
  2. 1 2 Mougey R (2010). "A review of the Chido/Rodgers blood group" (PDF). Immunohematology / American Red Cross 26 (1): 30–8. PMID 20795316.
  3. ↑ Mayilyan KR, Weinberger DR, Sim RB (2008). "The complement system in schizophrenia". Drug News & Perspectives 21 (4): 200–10. doi:10.1358/dnp.2008.21.4.1213349. PMC 2719487. PMID 18560619.
  4. 1 2 "Understanding the Immune System: How It Works" (PDF). NIH Publication No. 03–5423. U.S. Department Of Health And Human Services National Institutes of Health, National Institute of Allergy and Infectious Diseases, National Cancer Institute. September 2003. pp. 17–18.
  5. 1 2 3 4 5 6 7 8 9 Biedzka-Sarek M, Skurnik M (2012). "Chapter 13: Bacterial Escape from the Complement System". In Locht C, Simonet M. Bacterial Pathogenesis: Molecular and Cellular Mechanisms. Norfolk, UK: Caister Academic Press. pp. 287–304. ISBN 978-1-904455-91-2.
  6. 1 2 3 4 Law SK, Dodds AW (Feb 1997). "The internal thioester and the covalent binding properties of the complement proteins C3 and C4" (print, online review). Protein Science 6 (2): 263–74. doi:10.1002/pro.5560060201. PMC 2143658. PMID 9041627.
  7. 1 2 3 Sepp A, Dodds AW, Anderson MJ, Campbell RD, Willis AC, Law SK (May 1993). "Covalent binding properties of the human complement protein C4 and hydrolysis rate of the internal thioester upon activation" (print, online review). Protein Science 2 (5): 706–16. doi:10.1002/pro.5560020502. PMC 2142499. PMID 8495193.
  8. ↑ MacConmara MP (2013). "Recognition and Management of Antibody-Mediated Rejection" (PDF). The Immunology Report 10 (1): 6–10.
  9. ↑ "dbRBC - BGMUT - System - Chido/Rodgers". Ncbi.nlm.nih.gov. 2011-11-13. Retrieved 2016-02-19.
  10. ↑ Liu CC, Ahearn JM (2009). "The search for lupus biomarkers". Best Practice & Research. Clinical Rheumatology 23 (4): 507–23. doi:10.1016/j.berh.2009.01.008. PMC 2727983. PMID 19591781.
  11. ↑ "Genetic study provides first-ever insight into biological origin of schizophrenia | Broad Institute of MIT and Harvard". Broadinstitute.org. 2016-01-26. Retrieved 2016-02-19.
  12. ↑ "Schizophrenia’s strongest known genetic risk deconstructed". National Institutes of Health (NIH). Retrieved 2016-02-20.
  13. ↑ Sekar A, Bialas AR, de Rivera H, Davis A, Hammond TR, Kamitaki N, et al. (Feb 2016). "Schizophrenia risk from complex variation of complement component 4". primary. Nature 530 (7589): 177–83. doi:10.1038/nature16549. PMID 26814963.
  14. ↑ Pettigrew HD, Teuber SS, Gershwin ME (Sep 2009). "Clinical significance of complement deficiencies". Annals of the New York Academy of Sciences 1173 (1): 108–23. doi:10.1111/j.1749-6632.2009.04633.x. PMID 19758139.
  15. ↑ "Complement Deficiencies. What are complement deficiencies? | Patient". Patient. Retrieved 2016-02-20.

Further reading

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