Complement control protein

Last updated

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

Contents

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

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.

Further reading

Related Research Articles

<span class="mw-page-title-main">Complement system</span> Part of the immune system that enhances the ability of antibodies and phagocytic cells

The complement system, also known as complement cascade, is a part of the immune system that enhances (complements) the ability of antibodies and phagocytic cells to clear microbes and damaged cells from an organism, promote inflammation, and attack the pathogen's cell membrane. It is part of the innate immune system, which is not adaptable and does not change during an individual's lifetime. The complement system can, however, be recruited and brought into action by antibodies generated by the adaptive immune system.

<span class="mw-page-title-main">Classical complement pathway</span> Aspect of the immune system

The classical complement pathway is one of three pathways which activate the complement system, which is part of the immune system. The classical complement pathway is initiated by antigen-antibody complexes with the antibody isotypes IgG and IgM.

<span class="mw-page-title-main">Alternative complement pathway</span> Type of cascade reaction of the complement system

The alternative pathway is a type of cascade reaction of the complement system and is a component of the innate immune system, a natural defense against infections.

<span class="mw-page-title-main">C3-convertase</span>

C3 convertase belongs to family of serine proteases and is necessary in innate immunity as a part of the complement system which eventuate in opsonisation of particles, release of inflammatory peptides, C5 convertase formation and cell lysis.

<span class="mw-page-title-main">Complement receptor 1</span> Protein found in humans

Complement receptor type 1 (CR1) also known as C3b/C4b receptor or CD35 is a protein that in humans is encoded by the CR1 gene.

Opsonins are extracellular proteins that, when bound to substances or cells, induce phagocytes to phagocytose the substances or cells with the opsonins bound. Thus, opsonins act as tags to label things in the body that should be phagocytosed by phagocytes. Different types of things ("targets") can be tagged by opsonins for phagocytosis, including: pathogens, cancer cells, aged cells, dead or dying cells, excess synapses, or protein aggregates. Opsonins help clear pathogens, as well as dead, dying and diseased cells.

<span class="mw-page-title-main">Complement membrane attack complex</span> Protein complex

The membrane attack complex (MAC) or terminal complement complex (TCC) is a complex of proteins typically formed on the surface of pathogen cell membranes as a result of the activation of the host's complement system, and as such is an effector of the immune system. Antibody-mediated complement activation leads to MAC deposition on the surface of infected cells. Assembly of the MAC leads to pores that disrupt the cell membrane of target cells, leading to cell lysis and death.

<span class="mw-page-title-main">Complement component 3</span> Protein found in humans

Complement component 3, often simply called C3, is a protein of the immune system that is found primarily in the blood. It plays a central role in the complement system of vertebrate animals and contributes to innate immunity. In humans it is encoded on chromosome 19 by a gene called C3.

<span class="mw-page-title-main">C5-convertase</span> Serine protease that plays key role in innate immunity.

C5 convertase is an enzyme belonging to a family of serine proteases that play key role in the innate immunity. It participates in the complement system ending with cell death.

<span class="mw-page-title-main">Properdin</span> Protein-coding gene in the species Homo sapiens

Properdin is a protein that in humans is encoded by the CFP gene.

Co-stimulation is a secondary signal which immune cells rely on to activate an immune response in the presence of an antigen-presenting cell. In the case of T cells, two stimuli are required to fully activate their immune response. During the activation of lymphocytes, co-stimulation is often crucial to the development of an effective immune response. Co-stimulation is required in addition to the antigen-specific signal from their antigen receptors.

<span class="mw-page-title-main">MASP1 (protein)</span> Protein-coding gene in the species Homo sapiens

Mannan-binding lectin serine protease 1 also known as mannose-associated serine protease 1 (MASP-1) is an enzyme that in humans is encoded by the MASP1 gene.

<span class="mw-page-title-main">Factor D</span> Class of enzymes

Factor D is a protein which in humans is encoded by the CFD gene. Factor D is involved in the alternative complement pathway of the complement system where it cleaves factor B.

C4b-binding protein (C4BP) is a protein complex involved in the complement system where it acts as inhibitor. C4BP has an octopus-like structure with a central stalk and seven branching alpha-chains. The main form of C4BP in human blood is composed of 7 identical alpha-chains and one unique beta-chain, which in turn binds anticoagulant, vitamin K-dependent protein S.

<span class="mw-page-title-main">Decay-accelerating factor</span> Mammalian protein found in Homo sapiens

Complement decay-accelerating factor, also known as CD55 or DAF, is a protein that, in humans, is encoded by the CD55 gene.

<span class="mw-page-title-main">Factor H</span> Protein found in humans

Factor H (FH) is a member of the regulators of complement activation family and is a complement control protein. It is a large, soluble glycoprotein that circulates in human plasma. Its principal function is to regulate the alternative pathway of the complement system, ensuring that the complement system is directed towards pathogens or other dangerous material and does not damage host tissue. Factor H regulates complement activation on self cells and surfaces by possessing both cofactor activity for the Factor I mediated C3b cleavage, and decay accelerating activity against the alternative pathway C3-convertase, C3bBb. Factor H exerts its protective action on self cells and self surfaces but not on the surfaces of bacteria or viruses. There are however, important exceptions, such as for example the bacterial pathogen, Neisseria meningitidis. This human pathogen has evolved mechanisms to recruit human FH and down-regulate the alternative pathway. Binding of FH permits the bacteria to proliferate in the bloodstream and cause disease.

<span class="mw-page-title-main">C3b</span>

C3b is the larger of two elements formed by the cleavage of complement component 3, and is considered an important part of the innate immune system. C3b is potent in opsonization: tagging pathogens, immune complexes (antigen-antibody), and apoptotic cells for phagocytosis. Additionally, C3b plays a role in forming a C3 convertase when bound to Factor B, or a C5 convertase when bound to C4b and C2b or when an additional C3b molecule binds to the C3bBb complex.

<span class="mw-page-title-main">C3a (complement)</span>

C3a is one of the proteins formed by the cleavage of complement component 3; the other is C3b. C3a is a 77 residue anaphylatoxin that binds to the C3a receptor (C3aR), a class A G protein-coupled receptor. It plays a large role in the immune response.

<span class="mw-page-title-main">Complement 3 deficiency</span> Medical condition

Complement 3 deficiency is a genetic condition affecting complement component 3 (C3). People can suffer from either primary or secondary C3 deficiency. Primary C3 deficiency refers to an inherited autosomal-recessive disorder that involves mutations in the gene for C3. Secondary C3 deficiency results from a lack of factor I or factor H, two proteins that are key for the regulation of C3. Both primary and secondary C3 deficiency are characterized by low levels or absence of C3.

Sushi domain is an evolutionarily conserved protein domain. It is also known as Complement control protein (CCP) modules or short consensus repeats (SCR). The name derives from the visual similarity of the domain to nigiri sushi when the primary structure is drawn showing the loops created by the disulfide bonds.

This page is based on this Wikipedia article
Text is available under the CC BY-SA 4.0 license; additional terms may apply.
Images, videos and audio are available under their respective licenses.