Complement control protein are proteins that interact with components of the complement system.

The complement system is tightly regulated by a network of proteins known as "regulators of complement activation (RCA)" that help distinguish target cells as "self" or "non-self." A subset of this family of proteins, complement control proteins (CCP), are characterized by domains of conserved repeats that direct interaction with components of the complement system.[1] These "Sushi" domains have been used to identify other putative members of the CCP family. There are many other RCA proteins that do not fall into this family.

Most CCPs prevent activation of the complement system on the surface of host cells and protect host tissues against damage caused by autoimmunity. Because of this, these proteins play important roles in autoimmune disorders and cancers.[2]

Members

Most of the well-studied proteins within this family can be categorized in two classes:

Membrane-bound complement regulators

  • Membrane Cofactor Protein, MCP (CD46)
  • Decay Accelerating Factor, DAF (CD55)
  • Protectin (CD59)
  • Complement C3b/C4b Receptor 1, CR1 (CD35)
  • Complement Regulator of the Immunoglobulin Superfamily, CRIg

Soluble complement regulators

Other proteins with characteristic CCP domains have been identified including members of the sushi domain containing (SUSD) protein family and Human CUB and sushi multiple domains family (CSMD).[3]

Mechanisms of protection

Every cell in the human body is protected by one or more of the membrane-associated RCA proteins, CR1, DAF or MCP. Factor H and C4BP circulate in the plasma and are recruited to self-surfaces through binding to host-specific polysaccharides such as the glycosaminoglycans.[4]

Most CCPs function by preventing convertase activity. Convertases, specifically the C3 convertases C3b.Bb and C4b.2a, are the enzymes that drive complement activation by activating C3b, a central component of the complement system. Some CCPs, such as CD46, recruit other RCAs to proteolytically inactivate developing convertases. CD55 and other CCPs promote the rapid dissociation of active enzymes. Other CCPs prevent the activity of terminal effectors of the complement system, CD59 for example blocks oligomerization of the complement peptide C9 stalling the formation of the Membrane Attack Complex (MAC).[5]

For example, C3b.Bb is an important convertase that is part of the alternative pathway, and it is formed when factor B binds C3b and is subsequently cleaved. To prevent this from happening, factor H competes with factor B to bind C3b; if it manages to bind, then the convertase is not formed. Factor H can bind C3b much more easily in the presence of sialic acid, which is a component of most cells in the human body; conversely, in the absence of sialic acid, factor B can bind C3b more easily. This means that if C3b is bound to a "self" cell, the presence of sialic acid and the binding of factor H will prevent the complement cascade from activating; if C3b is bound to a bacterium, factor B will bind and the cascade will be set off as normal. This mechanism of immune regulation using Factor H has been exploited by several bacterial pathogens.[6]

Structure

RCA proteins typically possess CCP domains, also termed Sushi domains or Short Consensus Repeats (SCR). Such beta-sandwich domains contain about 60 amino acid residues, each with 4 conserved cysteines arranged in two conserved disulfide bonds (oxidized in 'abab' manner), and a conserved tryptophan, but otherwise can vary greatly in sequence. Recently, it has been demonstrated that the order, spatial relationship, and structure of these domains is essential for determining function.[7]

The first CCP structure determined was a solution structure of the 16th module of factor H (pdb:1hcc).[8] Since then, other CCP domains have been solved either by NMR-spectroscopy (also relaxation studies, e.g. module 2 and 3 from CD55 (pdb:1nwv))[9] or by X-ray diffraction (also with co-crystallized partner, e.g. CR2 CCP modules complexed with C3d (pdb:1ghq)).[10]

Clinical significance

Complement has been implicated in many diseases associated with inflammation and autoimmunity.[11] Efforts to develop therapeutics that target the interactions between the RCA network, CCPs, and components of the complement system have led to the development of successful drugs including Eculizumab.

There are two primary mechanisms by which dysfunction of complement can contribute to tissue damage:[12]

  1. Decreased protection of host tissues from complement activation due to the absence or lack of function of CCPs
  2. Exhaustion of CRAs due to exposure of host cells that activate complement (either through direct damage or dysfunction) or prolonged attack by a potential pathogen such as during sepsis

The importance of complement regulation for good health is highlighted by recent work that seems to imply that individuals carrying point mutations or single nucleotide polymorphisms in their genes for factor H may be more susceptible to diseases including atypical hemolytic uremic syndrome,[13] dense deposit diseases (or membranoproliferative glomerulonephritis type 2) and - most notably because of its prevalence in the elderly - age-related macular degeneration.[14] Transgenic pigs that express human complement regulation factors were some of the first transgenic pigs used for xenotransplantation.[15][16]

Complement control proteins also play a role in malignancy. Complement proteins protect against malignant cells- both by direct complement attack and through initiation of Complement-dependent cytotoxicity, which synergises with specific monoclonal antibody therapies. However, some malignant cells have been shown to have increased expression of membrane-bound complement control proteins, especially CD46, DAF and CD59.[17] This mechanism allows some tumours to evade complement action.

CCPs have been exploited extensively by pathogenic microbes.[18] Neisseria gonorhoeae and Neisseria meningitidis, the bacteria responsible for gonorrhea and meningitis have many well-studied evasion strategies involving CCPs, including binding soluble regulators like Factor H and C4bp. Many viruses, such as Vaccinia incorporate mimics of CCPs into their envelope for the purposes of evading the complement system. Still other microbes such as the measles virus use CCPs as receptors to gain entry to cells during infection. Each of these strategies may provide targets for the development of vaccines, as with the case of N. meningitidis.

Certain forms of schizophrenia are characterised by an underlying biological mechanism of excessive synaptic pruning, mediated by a dysregulated complement system in the brain.[19] Accordingly, genetic variants of a brain-specific complement inhibitor, CSMD1, are associated with the risk of developing schizophrenia.[20] [21]

Sources

  1. ↑ McLure CA, Dawkins RL, Williamson JF, Davies RA, Berry J, Natalie LJ, et al. (August 2004). "Amino acid patterns within short consensus repeats define conserved duplicons shared by genes of the RCA complex". Journal of Molecular Evolution. 59 (2): 143–57. Bibcode:2004JMolE..59..143M. doi:10.1007/s00239-004-2609-8. PMID 15486690. S2CID 25038346.
  2. ↑ Pangburn MK, Ferreira VP, Cortes C (December 2008). "Discrimination between host and pathogens by the complement system". Vaccine. 26 (Suppl 8): I15-21. doi:10.1016/j.vaccine.2008.11.023. PMC 2673523. PMID 19388159.
  3. ↑ Gialeli C, Gungor B, Blom AM (October 2018). "Novel potential inhibitors of complement system and their roles in complement regulation and beyond". Molecular Immunology. Special Issue: 2018 International Complement Workshop. 102: 73–83. doi:10.1016/j.molimm.2018.05.023. PMID 30217334. S2CID 52278070.
  4. ↑ Langford-Smith A, Day AJ, Bishop PN, Clark SJ (2015-02-02). "Complementing the Sugar Code: Role of GAGs and Sialic Acid in Complement Regulation". Frontiers in Immunology. 6: 25. doi:10.3389/fimmu.2015.00025. PMC 4313701. PMID 25699044.
  5. ↑ Zipfel PF, Skerka C (October 2009). "Complement regulators and inhibitory proteins". Nature Reviews. Immunology. 9 (10): 729–40. doi:10.1038/nri2620. PMID 19730437. S2CID 1723316.
  6. ↑ Józsi M (2017-05-18). "Factor H Family Proteins in Complement Evasion of Microorganisms". Frontiers in Immunology. 8: 571. doi:10.3389/fimmu.2017.00571. PMC 5435753. PMID 28572805.
  7. ↑ Ojha H, Ghosh P, Singh Panwar H, Shende R, Gondane A, Mande SC, Sahu A (December 2019). "Spatially conserved motifs in complement control protein domains determine functionality in regulators of complement activation-family proteins". Communications Biology. 2 (1): 290. doi:10.1038/s42003-019-0529-9. PMC 6683126. PMID 31396570.
  8. ↑ Norman DG, Barlow PN, Baron M, Day AJ, Sim RB, Campbell ID (June 1991). "Three-dimensional structure of a complement control protein module in solution". Journal of Molecular Biology. 219 (4): 717–25. doi:10.1016/0022-2836(91)90666-t. PMID 1829116.
  9. ↑ Uhrinova S, Lin F, Ball G, Bromek K, Uhrin D, Medof ME, Barlow PN (April 2003). "Solution structure of a functionally active fragment of decay-accelerating factor". Proceedings of the National Academy of Sciences of the United States of America. 100 (8): 4718–23. Bibcode:2003PNAS..100.4718U. doi:10.1073/pnas.0730844100. PMC 153622. PMID 12672958.
  10. ↑ Szakonyi G, Guthridge JM, Li D, Young K, Holers VM, Chen XS (June 2001). "Structure of complement receptor 2 in complex with its C3d ligand". Science. 292 (5522): 1725–8. Bibcode:2001Sci...292.1725S. doi:10.1126/science.1059118. PMID 11387479. S2CID 45893794.
  11. ↑ Wong EK, Kavanagh D (January 2018). "Diseases of complement dysregulation-an overview". Seminars in Immunopathology. 40 (1): 49–64. doi:10.1007/s00281-017-0663-8. PMC 5794843. PMID 29327071.
  12. ↑ Pangburn MK, Ferreira VP, Cortes C (December 2008). "Discrimination between host and pathogens by the complement system". Vaccine. 26 (Suppl 8): I15-21. doi:10.1016/j.vaccine.2008.11.023. PMC 2673523. PMID 19388159.
  13. ↑ Buddles MR, Donne RL, Richards A, Goodship J, Goodship TH (May 2000). "Complement factor H gene mutation associated with autosomal recessive atypical hemolytic uremic syndrome". American Journal of Human Genetics. 66 (5): 1721–2. doi:10.1086/302877. PMC 1378030. PMID 10762557.
  14. ↑ Hageman GS, Anderson DH, Johnson LV, Hancox LS, Taiber AJ, Hardisty LI, et al. (May 2005). "A common haplotype in the complement regulatory gene factor H (HF1/CFH) predisposes individuals to age-related macular degeneration". Proceedings of the National Academy of Sciences of the United States of America. 102 (20): 7227–32. doi:10.1073/pnas.0501536102. PMC 1088171. PMID 15870199.
  15. ↑ Eisenson DL, Hisadome Y, Yamada K (2022). "Progress in Xenotransplantation: Immunologic Barriers, Advances in Gene Editing, and Successful Tolerance Induction Strategies in Pig-To-Primate Transplantation". Frontiers in Immunology. 13: 899657. doi:10.3389/fimmu.2022.899657. PMC 9157571. PMID 35663933.
  16. ↑ Lu T, Yang B, Wang R, Qin C (2020). "Xenotransplantation: Current Status in Preclinical Research". Frontiers in Immunology. 10: 3060. doi:10.3389/fimmu.2019.03060. PMC 6989439. PMID 32038617.
  17. ↑ Ricklin D, Hajishengallis G, Yang K, Lambris JD (September 2010). "Complement: a key system for immune surveillance and homeostasis". Nature Immunology. 11 (9): 785–97. doi:10.1038/ni.1923. PMC 2924908. PMID 20720586.
  18. ↑ Zipfel PF, Hallström T, Riesbeck K (December 2013). "Human complement control and complement evasion by pathogenic microbes--tipping the balance". Molecular Immunology. 14th European Meeting on Complement in Human Disease, Jena, August 17–21, 2013. 56 (3): 152–60. doi:10.1016/j.molimm.2013.05.222. PMID 23810413.
  19. ↑ Baum, Matthew L. (2018-09-16). "The Schizophrenia-Associated Gene, CSMD1, Encodes a Brain-Specific Complement Inhibitor". {{cite journal}}: Cite journal requires |journal= (help)
  20. ↑ Liu Y, Fu X, Tang Z, Li C, Xu Y, Zhang F, et al. (April 2019). "Altered expression of the CSMD1 gene in the peripheral blood of schizophrenia patients". BMC Psychiatry. 19 (1): 113. doi:10.1186/s12888-019-2089-4. PMC 6466712. PMID 30987620.
  21. ↑ Håvik B, Le Hellard S, Rietschel M, Lybæk H, Djurovic S, Mattheisen M, et al. (July 2011). "The complement control-related genes CSMD1 and CSMD2 associate to schizophrenia". Biological Psychiatry. 70 (1): 35–42. doi:10.1016/j.biopsych.2011.01.030. PMID 21439553. S2CID 26368229.

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