Complement Receptors

Robert Graham Quinton Leslie, University of Southern Denmark, Odense, Denmark
Søren Hansen, University of Southern Denmark, Odense, Denmark

Published online: March 2009

DOI: 10.1002/9780470015902.a0000512.pub2

Complement receptors are membrane proteins, expressed on cells involved in the immune response, which bind a wide range of the protein fragments generated in the course of complement activation. Through these cellular interactions, the complement system plays a crucial role combating infection. Thus, complement is instrumental in the recruitment of blood leucocytes to a site of inflammation, in promoting phagocytosis and/or extracellular killing of the microorganisms by these cells and in clearance of particulate and soluble immune complexes (ICs) generated at the infected site or released in the circulation. Furthermore, complement is intimately involved in the development of an acquired immune response towards invading pathogens both through the induction of primary B-cell responses and through shaping of T-cell responses towards the antigen. This article presents a systematic account of the complement receptors in terms of their structure, cellular distribution and biological and signalling functions.

Key concepts:

  • Structural diversity of receptors reflecting the diversity of the complement fragments engaged.
  • Functional diversity, depending on the type of complement fragment involved and/or the type of cells expressing the appropriate receptor.

Keywords: complement receptor; CR; C3; C5; C1q

Figure 1. Structure and function of CR1 and CR2. (a) The most prevalent allele of CR1 is comprised of 30 short consensus repeats (SCRs) arranged in four long homologous regions (LHRs), where the ligand-binding sites are contained in the three N-terminal SCRs of each of the first three LHRs, whereas the ligand-binding site of the 15 (or 16) SCR CR2 is located in SCR1/2. On B cells, CR1 and CR2 are found in noncovalent association with each other. As a cofactor for factor I, CR1 promotes degradation of C3b to iC3b and then C3c+C3dg, thus providing CR2 with its ligand. It also promotes the decay of classical pathway convertases and the degradation of C4b to C4c and C4d. (b) The association of CR2 with CD19 ensures recruitment of the latter to the B-cell receptor (BCR) complex upon BCR/CR2 crosslinking by opsonized antigen. This crosslinking promotes and protracts BCR complex association with the lipid rafts and thereby with the protein tyrosine kinase Lyn, which initiates the signal cascade by phosphorylating tyrosine residues within cytoplasmic domains (ITAMs) of the BCR complex. By virtue of its ability to bind PLC-2 (phospholipase C 2), PI3 kinase and Vav, CD19 supplements the signalling transduced through BCR upon antigen engagement.
Figure 2. Structure and function of CR3. In its resting state (a), CR3 is retained in a crouching configuration by interaction of the N-terminal ‘head’ (A) of the subunit (CD18, in red) with the subunit's membrane-proximal ‘foot’ (TD). In this configuration, CR3 displays only low affinity for its ligand. Signalling from within the cell (b) releases A from TD, allowing the head to rise slightly and engage, through its MIDAS (blue asterisk), the A-head of the subunit (CD11b, in blue). This serves to stabilize the A MIDAS (red asterisk) in a high affinity configuration for its ligand. Binding of the ligand (c), stabilizes the A–A interaction, and initiates opening at the ‘knee’ joints and separation of the ‘legs’ (d), thereby transforming CR3 into a fully functional signal transducer. This research was originally published in Blood. Gupta et al. (2007). © The American Society of Hematology.
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 References
    Cherukuri A, Cheng PC, Sohn HW and Pierce SK (2001) The CD19/CD21 complex functions to prolong B cell antigen receptor signaling from lipid rafts. Immunity 14: 169–179.
    Crass T, Raffetseder U, Martin U et al. (1996) Expression and cloning of the human C3a anaphylatoxin receptor (C3aR) from differentiated U937 cells. European Journal of Immunology 26: 1944–1950.
    Dempsey PW, Allison MED, Srinivas A, Goodnow CC and Fearon DT (1996) C3d of complement as a molecular adjuvant: bridging innate and acquired immunity. Science 271: 348–350.
    Edelson BT, Stricker TP, Li Z et al. (2006) Novel collectin/C1q receptor mediates mast cell activation and innate immunity. Blood 107: 143–150.
    Emsley J, Knight CG, Farndale RW, Barnes MJ and Liddington RC (2000) Structural basis of collagen recognition by integrin alpha2beta1. Cell 101: 47–56.
    Fleming SD, Shea-Donohue T, Guthridge JM et al. (2002) Mice deficient in complement receptors 1 and 2 lack a tissue injury-inducing subset of the natural antibody repertoire. Journal of Immunology 169: 2126–2133.
    Gelebart P, Opas M and Michalak M (2005) Calreticulin, a Ca2+-binding chaperone of the endoplasmic reticulum. International Journal of Biochemistry & Cell Biology 37: 260–266.
    Gupta V, Gylling A, Alonso JL et al. (2007) The -tail domain (TD) regulates physiologic ligand binding to integrin CD11b/CD18. Blood 109: 3513–3520.
    Józsi M, Prechl J, Baitay Z and Erdei A (2002) Complement type 1 (CD35) mediates inhibitory signals in human B lymphocytes. Journal of Immunology 168: 2782–2788.
    Kim CH, Lee KH, Lee CT et al. (2004) Aggregation of beta2 integrins activates human neutrophils through the IB/-NF-B pathway. Journal of Leukocyte Biology 75: 286–292.
    McGreal EP, Ikewaki N, Akatsu H, Morgan BP and Gasque P (2002) Human C1qRp is identical with CD93 and the mNI-11 antigen but does not bind C1q. Journal of Immunology 168: 5222–5232.
    Mongini PK and Inman JK (2001) Cytokine dependency of human B cell cycle progression elicited by ligands which co-engage BCR and the CD21/Cd19/CD81 co-stimulatory complex. Cellular Immunology 207: 127–140.
    Naik N, Giannini E, Brouchon L and Boulay F (1997) Internalisation and recycling of the C5a anaphylatoxin receptor: evidence that the agonist-mediated internalization is modulated by phosphorylation of the C-terminal domain. Journal of Cell Science 110: 2381–2390.
    Nakayama H, Yoshizaki F, Prinetti A et al. (2008) Lyn-coupled LacCer-enriched lipid rafts are required for CD11b/CD18-mediated neutrophil phagocytosis of non-opsonized micro-organisms. Journal of Leukocyte Biology 83: 728–741.
    Nielsen CH, Antonsen S, Matthiesen SH and Leslie RGQ (1997) The roles of complement receptors type 1 (CR1, CD35) and type 3 (CR3, CD11b/CD18) in the regulation of the immune complex-elicited respiratory burst of polymorphonuclear leukocytes in whole blood. European Journal of Immunology 27: 2914–2919.
    Nikiforovich GV, Marshall GR and Baranski TJ (2008) Modeling molecular mechanisms of binding of the anaphylatoxin C5a to the C5a receptor. Biochemistry 47: 3117–3130.
    Peerschke EI and Ghebrehiwet B (2007) The contribution of gC1qR/p33 in infection and inflammation. Immunobiology 212: 333–342.
    Pettit EJ and Hallett MB (1998) Two distinct storage and release sites in human neutrophils. Journal of Leukocyte Biology 63: 225–232.
    Raffetseder U, Roper D, Mery L et al. (1996) Site-directed mutagenesis of conserved charged residues in the helical region of the human C5a receptor. Arg206 determines high-affinity binding sites of C5a receptor. European Journal of Biochemistry 235: 82–90.
    Reid RR, Woodcock S, Shimabukuro-Vornhagen A et al. (2002) Functional activity of natural antibody is altered in Cr2-deficient mice. Journal of Immunology 169: 5433–5440.
    Richter M, Ray SJ, Chapman TJ et al. (2007) Collagen distribution and expression of collagen-binding 11 (VLA-1) and 21 (VLA-2) integrins on CD4 and CD8T cells during influenza infection. Journal of Immunology 178: 4506–4516.
    Roberts T and Snow EC (1999) Cutting edge: recruitment of the CD19/CD21 co-receptor to B cell antigen receptor is required for antigen-mediated expression of Bcl-2 by resting and cycling hen egg lysozyme transgenic B cells. Journal of Immunology 162: 4377–4380.
    Smith BO, Mallin RL, Krych-Goldberg M et al. (2002) Structure of the C3b binding site of CR1 (CD35), the immune adherence receptor. Cell 108: 769–780.
    Vegh Z, Goyarts EC, Rozengarten K et al. (2003) Maturation-dependent expression of C1q-binding proteins on the cell surface of human monocyte-derived dendritic cells. International Immunopharmacology 3: 39–51.
    Waggoner SN, Hall CH and Hahn YS (2007) HCV core protein interaction with gC1q receptor inhibits Th1 differentiation of CD4+ T cells via suppression of dendritic cell IL-12 production. Journal of Leukocyte Biology 82: 1407–1419.
    Wagner C, Ochmann C, Geise T et al. (2006) The complement receptor 1, CR1 (CD35) mediates inhibitory signals to T lymphocytes. Molecular Immunology 43: 643–651.
    Wills-Karp M and Köhl J (2005) New insights into the role of the complement pathway in allergy and asthma. Current Allergy and Asthma Reports 5: 362–329.
    Xia Y, Borland G, Huang J et al. (2002) Function of the lectin domain of Mac-1/complement receptor type 3 (CD11b/CD18) in regulating neutrophil adhesion. Journal of Immunology 169: 6417–6426.
    Zen K, Utech M, Liu Y et al. (2004) Association of BAP31 with CD11b/CD18. Potential role in intracellular trafficking of CD11b/CD18 in neutrophils. The Journal of Biological Chemistry 279: 44924–44930.
 Further Reading
    Ehlers MR (2000) CR3: a general purpose adhesion-recognition receptor essential for innate immunity. Microbes and Infection 2: 289–294.
    Ghebrehiwet B and Peerschke EIB (2004) cC1q-R (calreticulin) and gC1q-R/p33: ubiquitously expressed multi-ligand binding cellular proteins involved in inflammation and infection. Molecular Immunology 41: 173–183.
    Holers VM and Kulik L (2007) Complement receptor 2, natural antibodies and innate immunity: inter-relationships in B cell selection and activation. Molecular Immunology 44: 64–72.
    Hourcade D, Holers VM and Aktinson JP (1989) The regulators of complement activation (RCA) gene cluster. Advances in Immunology 45: 381–416.
    Monk PN, Scola A-M, Madala P and Fairlie DP (2007) Function, structure and therapeutic potential of complement C5a receptors Brit. Journal of Pharmacology 152: 429–448.
    Petty HR, Worth RG and Todd RF 3rd (2002) Interactions of integrins with their partner proteins in leukocyte membranes. Immunological Research 25: 75–95.
    Rickert RC (2005) Regulation of B lymphocyte activation by complement C3 and the B cell co-receptor complex. Current Opinion in Immunology 17: 237–243.
    Speth C, Kacani L and Dierich MP (1997) Complement receptors and HIV infection. Immunological Reviews 159: 49–67.
    Zutter MM and Edelson BT (2007) The alpha2beta1 integrin: a novel collectin/C1q receptor. Immunobiology 212: 343–353.

Related Sub-Topics:

Cells of the Immune System | Complement
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Article Title: Complement Receptors
 
How to Cite close
Leslie, Robert Graham Quinton, and Hansen, Søren(Mar 2009) Complement Receptors. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0000512.pub2]