Pentraxins and Fc receptors

Pentraxins are a family of secreted pattern recognition proteins containing a homologous pentraxin (PTX) domain of approximately 200 amino acids (Fig. 1). Members of the family, such as C-reactive protein (CRP) (also called PTX1) and serum amyloid P component (SAP) (also called PTX2) containing only a PTX domain, are termed short chain pentraxins, while others, such as pentraxin member 3 (PTX3), and neuronal pentraxins 1 and 2, have an additional N-terminal domain preceding the PTX domain and are referred as long chain pentraxins. The structure and function of short chain pentraxins have been studied more extensively compared to the members of long chain pentraxins (1-5). Both CRP and SAP are part of acute phase proteins expressed by hepatocytes in response to inflammatory cytokine stimulation during infections (6-8). CRP recognizes phosphorylcholine moieties associated with microbial polysaccharides or necrotic cells in a calcium-dependent manner (9, 10). In addition, CRP also recognizes some nuclear antigens, such as small nuclear ribonucleoprotein and chromatin subunits (11-15). SAP is known to recognize phosphorylethanolamine (PE) and other microbial associated molecules as well as nuclear antigens in a calcium-dependent manner (11, 16-18). Both CRP and SAP can opsonize microbial pathogens or apoptotic cells and effectively clear them through complement activation (19-22). Fig. 1 Domain structure of pentraxins. The structure of a pentraxin domain displays a conserved β-sandwich fold with two opposing β-sheets each consisting of 7 β-strands (2, 23, 24) (Fig. 2A). A three turn α-helix from residue 168-176 of CRP, termed ridge helix, is situated on top of the β-sandwich. Both CRP and SAP subunits display a similar donut-shaped pentameric structure, with all five ridge helices on one face and microbial ligand binding sites on the opposite face. Calcium ions form part of the phosphorylcholine-binding site (23). The face with ridge helices is shown to contain C1q-binding sites by mutational analysis (25). Fig. 2 Structural recognition between pentraxins and Fc receptors Immunoglobulin Fc receptors (FcRs) are broadly expressed on hematopoietic cells and are important for antibody-mediated humoral and cellular immunity. Binding of immune complexes to Fc receptors activates effector cells leading to phagocytosis, endocytosis of IgG-opsonized particles, the release of inflammatory mediators, and antibody-dependent cellular cytotoxicity (ADCC) (26-28). The most well studied Fc receptors are FcγR and neonatal FcR (FcRn) for immunoglobulin G (IgG), FceR for IgE, and FcαR for IgA. Fc receptors belong to the immunoglobulin superfamily, except for the FcRn and FceRII, which are structurally related to class I major histocompatibility antigens and C-type lectins, respectively. FcγRI, FceRI, and FcαRI display higher binding affinities to their cognate immunoglobulins than the low affinity FcγRII and FcγRIII. In addition to the affinity variations among the receptors, Fcγ receptors also display distinct IgG subtype specificities. For example, FcγRIII binds IgG1 and IgG3 better than IgG2 and IgG4 (29). All Fcγ receptors are type I transmembrane or GPI-anchored glycoproteins consisting of two or three C2-type immunoglobulin-like domains. All Fcγ receptors show a high degree of sequence identity in their extracellular portion (50-96%) but differ significantly in their cytoplasmic domains (28). Activating Fcγ receptors either contain or associate with a common signaling γ-chain that contains the immunoreceptor tyrosine-based activation motifs (ITAMs), while the inhibitory FcγRIIB contains the immunoreceptor tyrosine-based inhibitory motif (ITIM) in its cytoplasmic tail. Several structures of the extracellular portion of Fc receptors have been published (30-34). They can be divided into two structural groups depending on their relative orientation between D1 and D2 domains (Fig. 2B). Group I receptors include all Fcγ receptors and FceRI, and group II includes FcαRI. The D1-D2 domain juxtaposition of group I receptors is opposite to that of group II, which displays natural killer cell immunoglobulin-like receptor (KIR) domain juxtaposition. The antibody-binding affinities of Fc receptors vary substantially between 10-5 and 10-9 M (26, 27, 29). Among them, FceRI and FcγRI display high affinity IgE and IgG binding, respectively, and are presumed preoccupied with their antibodies in circulation. Others, including FcγRII, FcγRIII, and FcαRI, display intermediate and low binding affinities toward their antibodies and thus can only recognize antigen-bound immune complexes. Despite differences in antibody affinities, both the high affinity FceRI and the lower affinity FcγRs have been shown to recognize their antibody Fc domains in similar structure modes in which one Fc receptor interacts with both heavy chains of Fc in the lower hinge region, between CH1 and CH2 domains in IgG or between Ce2 and Ce3 in IgE, near the conserved Fc glycosylation site (35-39). Aside from their well-established functions in antibody-mediated immune activations, Fc receptors were not known to recognize soluble innate pentraxins until recently.