FcyR Structure Distribution And Function

FcyRIIa is a member of a family of structurally related glycoproteins (GPs), many of which are expressed on hematopoietic cells (Table 1). Twelve different transcripts have been reported, derived from eight genes grouped into three different classes: I, II, and III (van de Winkel and Capel, 1993; Rascu et al., 1997; Gessner et al., 1998). Allelic polymorphic variants add yet another level of diversity for FcyRIIa, FcyRIIIa, and FcyRIIIb. The genomic organization of the FcyR genes on chromosome lq23 was resolved by Su and coworkers (2002). The multigenic region at 1q21-23 is approximately 1 mb in size and is in the following gene order and orientation: centromere—FCGR2A(5'-3')—FCGR3A(3'-5')—FCGR2C(3'-5')— FCGR3B(3' -5')—FCGR2B(5'-3')—telomere.

The affinity for IgG varies among isoforms and variants. FcyRIIa-His131 has a higher affinity for human IgG2 than FcyRIIa-Arg131 (Warmerdam et al., 1991). Furthermore, FcyRIIIa-Val158 and FcyRIIIb-NAl bind nearly twice as much IgG as FcyRIIIa-Phe158 and FcyRIIIb-NA2, respectively (Salmon et al., 1990; Koene et al., 1997). One nonfunctional FcyRIIc variant has a nonsense codon, which results in a null phenotype (Metes et al., 1998). When cross-linked, each isoform participates in biological activities through distinct signal transduction pathways that affect cell functions including antigen presentation, immune complex clearance, phagocytosis and the oxidative burst, release of cytokines and intracellular granular mediators, antibody-dependent cellular cytotoxicity (ADCC), and downregulation of antibody production or phagocytosis.

Only FcyRIIa is expressed on platelets (Rosenfeld et al., 1985; Kelton et al., 1987). The receptor is a single a-chain, 40-kDa GP, with an extracellular region consisting of two immunoglobulin-like, disulfide-linked domains responsible for ligand binding, a transmembrane region, and an intracellular domain that incorporates an immunoreceptor tyrosine-based activation motif (ITAM) essential for intracellular signal transduction (Qiu et al., 1990; Brooks et al., 1989). A soluble form of the receptor is produced by alternative splicing of primary RNA transcripts to exclude exon 5 containing the transmembrane region (Rappaport et al., 1993).

The extracellular domain of FcyRIIa shares 96% amino acid identity with FcyRIIb and FcyRIIc (Brooks et al., 1989). AG ! A polymorphism at nucleotide position 519 of the cDNA (position 535 in Genbank Reference Sequence NM_021642) is responsible for the Arg/His131 functional variants (Clark et al., 1989). An additional polymorphism, an A ! G at nucleotide 207 of the cDNA, results in a Gln-Trp27 substitution in the mature polypeptide (Warmerdam et al., 1991). However, the Arg-His131 position is near or within the binding region for IgG Fc (Hulett et al., 1995), and it is this polymorphism that is associated with the affinity differences for human IgG2 (Warmerdam et al., 1991). More recently, another polymorphism proximal to Arg131 that affects IgG2 binding has been found in a single healthy individual (Norris et al., 1998): A lysine substitution for glutamine at position 127 demonstrated a significant increase in FcyR-mediated phagocytosis in this homozygous FcyRIIa-Arg 31 individual.

TABLE 1 The Family of Fcy Receptors: Molecular and Structural Characteristics and Tissue Distribution
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