Complement Receptors

Abstract

Complement receptors are membrane proteins, expressed either on or in the cells that drive or regulate immune responses. They bind a wide range of the protein fragments generated in the course of canonical and non‐canonical complement activation. Interaction of such fragments with their cognate receptors activates and regulates the function of immune and stromal cells. Through these pathways, complement receptors control the recruitment of blood leucocytes to the sites of inflammation, promote phagocytosis and/or extra‐cellular killing of microorganisms by immune cells and clearance of particulate and soluble immune complexes generated during infectious or non‐infectious inflammatory events. Furthermore, complement receptor activation drives and controls the development of adaptive immune responses towards pathogens, allergens, auto‐antigens and altered self‐molecules through the induction of primary B and T lymphocyte responses. This article provides basic insights into the structure, cellular distribution as well as biological and signalling functions of the different complement receptors.

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.
  • Intra‐cellular expression and function of anaphylatoxin receptors.
  • Homo‐ and heterodimerisation of anaphylatoxin receptors that alter their biologic functions.
  • Cross‐talk of complement receptors with several other receptor classes.

Keywords: complement receptor; CR; C3; C5; C3aR; C5aR1; C5aR2; C1qR; CD46; CRIg

Figure 1. Anaphylatoxin receptors. Depicted are the sequences and domain structures of (a) the two C5a receptors and (b) the C3a receptor. Potential intra‐cellular loops formed by S‐acylation of cysteine residues are shown for C5aR2 and C3aR. Glycosylation sites are denoted by pink circles; phosphorylation sites at the intra‐cellular domains of the receptors are highlighted by pink and tyrosine sulfation sites at the extra‐cellular domains by blue circles. The ligand‐binding sites located at the extra‐cellular domains are highlighted by green circles. Adapted from Klos et al. 2013.
Figure 2. Structure and function of CR1 and CR2. (a) The most prevalent allele of CR1 is comprised of 30 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 non‐covalent association with each other. As a co‐factor 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 cross‐linking by opsonised antigen. This cross‐linking 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‐γ2 (phospholipase C γ2), PI3 kinase and Vav, CD19 supplements the signalling transduced through BCR upon antigen engagement.
Figure 3. Model detailing the structure and conformational change of CR3 upon iC3b binding. In its resting state (1), CR3 is retained in a crouching configuration by interaction of the N‐terminal ‘head’ (βA) of the β sub‐unit (CD18, in blue) with the membrane‐proximal ‘foot’ (βTD) of the sub‐unit. In this configuration, CR3 displays only low affinity for its ligand. The metal‐ion‐dependent adhesion site (MIDAS) within the αA head (CD11b in yellow) is occupied by a metal ion (black asterisk). Signals from within the cell (2) release βA from βTD, allowing the head to rise slightly and engage, through its MIDAS (red asterisk), the αA‐head of the CD11b sub‐unit. This serves to stabilise αA in a high‐affinity configuration for its ligand (open semi‐circle in αA). Binding of iC3b (3) stabilises the αA–βA interaction and initiates opening at the ‘knee’ joints and separation of the ‘legs’ (4), thereby transforming CR3 into a fully functional signal transducer. Modified from a figure kindly provided by Dr. Vineet Gupta, Rush University, Chicago; Gupta et al. 2007.
Figure 4. CD46 protein structure. The extra‐cellular domain of CD46 is common to all isoforms and composed of four complement control protein (CCP) domains which bind C3b and C4b. CCPs are followed by a heavily O‐glycosylated STP region (which differs in length depending on the alternative splicing of the corresponding ‘B’ and ‘C’ gene regions) and a domain of currently unknown function (‘U’). The transmembrane (TM) region is then followed by one of two alternatively spliced cytoplasmic tails termed CYT‐1 or CYT‐2, composed of 16 and 23 amino acids, respectively. Alternative splicing of the CD46 gene thus can give rise to four different isoforms designated C1, BC1, C2 and BC2. The arrows indicate extra‐cellular cleavage of CD46 by metalloproteases (MMPs) or a‐disintegrin and metalloproteinase domain‐containing proteins (ADAMs) and intra‐cellularly by γ‐secretase, with the exact cleavage sites within CD46 for both events not yet defined. The amino‐acid sequence of CYT‐1 and CYT‐2 is depicted below the structure with putative tyrosine phosphorylation sites (‘Y’) marked in bold. Candidate kinases include casein kinase 2 (CK‐2) and protein kinase C (PKC) for CYT‐1, and src kinases and CK‐2 for CYT‐2 (Wang et al., ).
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Further Reading

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Verschoor, Admar, Kemper, Claudia, and Köhl, Jörg(Sep 2017) Complement Receptors. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0000512.pub3]