Complement Receptors Structure which with closely a subunit.CR3 also binds zymosan (Z)via a B-glucan- binding lectin site remote from the I domain (Thornton pl of 5 5-60 The et a CR3 calreticulin(CRT):a 475 amino acid 52-kDa polypeptide o ROM and.in the case of neutrophils,release of the specific granules.CR3 pHoimaeucifPC nd is also involved in the IgE antibody-dependent cytotoxic its C.terminal KDEL sequence.the means of attachment of cCIqR to the cell membrane remains unclear. ophages.Both CR3 and CR4,along with LFA-1.are intimately involved in leucocyte ad esion to endothelial cells and their migration to sites of inflammation drate-recognition domain,five EGF-like domains.a 25 1 5)of (p Signalling cellula The taining a 13 cid leade that prior PKC-dependent phosphorylation of the B yothefhmnctionsini relatively hy quired and that ma s such as the20 mino acids in mature ClaR.73 are charged ve 0 esidues,with an acid:base ratio of 2:1,while no putative transmembrane sequence is discernible FeyRIII(CD16).Stimulation of CR3,in its primed state, resul s in tyrosine phosphorylation of s ev Cellular distribution NADPH biphasic fashion,with an initial release of Ca? from stores,located just under the plasma membrane,followed gingival fibroblasts (Tables 2and3).as well as on mveloid pre-B and B-cell lines.The level of expression varies widel localizad to the 6106 cell types, global mobilization are accomnanied by changes in cell morphology,indicating an intimate connection between rgulated by receptor shedding upon activation with PMA cClqR on gingival fibroblasts,on the other hand,is CR3 sand reorganization of the cyt by the cuvatio IL-1b o paxillin becomes phosphorylated upon stimulation via the calciun CR3. U937 cells. ClqRp is also expressed on myeloid leucocytes,en dothelial cells, s (Nepomuceno and Ienner ymphoi The C1q Receptors he c acity of fMLPand PMA to up e this re on neutrophils.while the expression on rat microglial cells may be by IFNg. en nophil dmast cel collagen.fibrinogen or fibronectin (Table 2).Although that has similar ligand specificity,and gClqR,a 33-kDa gClqR is not expressed on the surface of endothelial cells ound in asso with thei mitochondria,as it is in 99 ENCYCLOPEDIA OF LIFE SCIENCES/e 2001 Nature Publishing Group /www.els.net 1 lipopolysaccharide (LPS) and neutrophil inhibition factor (NIF) from the hookworm Ancylostoma caninum; all of which react with closely related sites in the I domain of the a subunit. CR3 also binds zymosan (Z) via a b-glucan￾binding lectin site remote from the I domain (Thornton et al., 1996). Stimulation of neutrophils and monocytes via CR3 or CR4 results in phagocytosis, production of ROM and, in the case of neutrophils, release of the specific granules. CR3 is also involved in the IgE antibody-dependent cytotoxic response of eosinophils towards parasites and their elaboration of ROM, and in the induction of nitric oxide synthesis by monocytes/macrophages. Both CR3 and CR4, along with LFA-1, are intimately involved in leucocyte adhesion to endothelial cells and their migration to sites of inflammation. Signalling The extent to which CR3 and CR4 act as independent signal transducers is uncertain. Current evidence suggests that prior PKC-dependent phosphorylation of the b2 subunit is required and that many of the functions initiated by CR3 involve cooperation with other receptors such as the glycosylphosphatidylinositol (GPI) anchored proteins, urokinase plasminogen activator receptor (CD87) and FcgRIII (CD16). Stimulation of CR3, in its primed state, results in tyrosine phosphorylation of several endogenous proteins, activation of phospholipases A2 and D and NADPH oxidase. Calcium ions are also mobilized in a biphasic fashion, with an initial release of Ca2+ from stores, located just under the plasma membrane, followed by global mobilization driven by influx of extracellular Ca2+ (Pettit and Hallet, 1998). Both the initial Ca2+ burst, which is localized to the sites of CR3 engagement, and the global mobilization are accompanied by changes in cell morphology, indicating an intimate connection between signalling via CR3 and reorganization of the cytoskeleton. The role of CR3 in cytoskeleton rearrangement is further emphasized by the fact that the cytoskeletal protein paxillin becomes phosphorylated upon stimulation via CR3. The C1q Receptors Three cell-associated proteins with affinity for C1q have been described: cC1qR, a 56-kDa protein closely resem￾bling calreticulin which binds the collagen-like tail of C1q; C1qRp, a phagocytosis-promoting receptor of 126 kDa that has similar ligand specificity, and gC1qR, a 33-kDa protein, which recognizes the globular head regions of C1q. Structure cC1qR is a relatively hydrophobic protein consisting of 42% hydrophobic and 12.6% hydrophilic residues, with a pI of 5.5–6.0. The amino acid sequence of cC1qR displays near identity with the Ca2+-binding intracellular protein, calreticulin (CRT); a 475 amino acid 52-kDa polypeptide containing three zinc-finger motifs, a leucine zipper and a ret finger protein (rfp)-like domain. While CRT is anchored to the endoplasmic reticulum via its C-terminal KDEL sequence, the means of attachment of cC1qR to the cell membrane remains unclear. The primary C1qRp gene product is a 641 amino acid protein, consisting of a 21 amino acid leader sequence, a 156 amino acid segment resembling a C-type carbohy￾drate-recognition domain, five EGF-like domains, a 25 amino acid transmembrane segment and a short (47 amino acid) C-terminal cytoplasmic tail. gC1qR is an acid protein (pI= 4.5) of 33 kDa at the cell membrane and 88–90 kDa in neutrophil intracellular granules. The gene for gC1qR encodes a 282 amino acid protein containing a 13 amino acid putative leader sequence followed by a relatively hydrophobic 60 amino acid segment which is not present in the mature protein. Of the 209 amino acids in mature gC1qR, 73 are charged residues, with an acid:base ratio of 2:1, while no putative transmembrane sequence is discernible. Cellular distribution cC1qR is expressed on monocytes, neutrophils, B cells, murine mast cells, endothelial and epithelial cells, human gingival fibroblasts (Tables 2 and 3), as well as on myeloid, pre-B and B-cell lines. The level of expression varies widely between cell types, from 8000 per cell on the B-cell line Raji to 1.6´106 per cell on U937 cells and 3´106 per cell on gingival fibroblasts. Expression of cC1qR on neutrophils is down￾regulated by receptor shedding upon activation with PMA. cC1qR on gingival fibroblasts, on the other hand, is upregulated by 30–60% upon activation with IL-1b or transforming growth factor b (TGFb), while the calcium ionophore, A23187, increases expression of the receptor on U937 cells. C1qRp is also expressed on myeloid leucocytes, en￾dothelial cells, platelets (Nepomuceno and Tenner, 1998) and rat microglial cells, but not on lymphoid or epithelial cells (Tables2and 3). There are conflicting reports regarding the capacity of fMLP and PMA to upregulate this receptor on neutrophils, while the expression on rat microglial cells may be upregulated by IFNg. gC1qR is found on neutrophils, eosinophils, mast cells and B cells, as well as on platelets, following adhesion to collagen, fibrinogen or fibronectin (Table 2). Although gC1qR is not expressed on the surface of endothelial cells, it is found in association with their mitochondria, as it is in fetal mouse tissue (Dedio et al., 1998). Complement Receptors ENCYCLOPEDIA OF LIFE SCIENCES / & 2001 Nature Publishing Group / www.els.net 7