Complement receptor 4 (CR4) is a heterodimer of α (CD11c) and β (CD18) transmembrane glycoproteins and shows specificity for the iC3b fragment. CR3 and CR4 are members of the integrin superfamily of adhesion proteins. They are termed β2 integrins because, in common with leucocyte function-associated molecule 1 (LFA-1, CD11a/CD18), they contain the same β subunit; α 95-kDa transmembrane glycoprotein, encoded by a gene in the q22 region of human chromosome 21 and in chromosome 10 in mice.
The human β2 is comprised of a 678 amino acid extracellular domain containing 57 Cys residues, of which 24 occur in three repeating units each with eight residues, a 23 amino acid transmembrane segment and a 46 amino acid cytoplasmic tail. The subunit contains a putative metal ion-dependent adhesion site (MIDAS) involving the residues Asp134, Ser136, Asp232 and Glu235, which contributes to the ligand-binding activity of the intact receptor.
The α subunit of CR3 is a 155-kDa glycoprotein, comprising a 1092 amino acid extracellular domain, a 26 amino acid transmembrane segment and a 19 amino acid cytoplasmic tail. The CR3 α subunit shows 63% sequence identity with that of complement receptor (CR4), a 150-kDa glycoprotein, in which the extracellular domain, transmembrane segment and cytoplasmic tail consist of 1081, 26 and 29 amino acids, respectively.
Like complement receptor 3 (CR3), CR4 are both present on neutrophils, eosinophils, basophils, monocytes/macrophages, NK cells, Kupffer cells, microglial cells and platelets.
The extent to which complement receptor 3 (CR3) and complement receptor 4 (CR4) act as independent signal transducers is uncertain. Current evidence suggests that prior PKC-dependent phosphorylation of the β2 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 FcγRIII (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+. 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.
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