Pentraxins and Fc Receptor-Mediated Immune Responses

Abstract

C-reactive protein (CRP) is a member of the pentraxin family of proteins. These proteins are highly conserved over the course of evolution being present as far back as 250 million years ago. Mammalian pentraxins are characterized by the presence of five identical non-covalently linked subunits. Each subunit has a structurally conserved site for calcium-dependent ligand binding. The biological activities of the pentraxins established over many years include the ability to mediate opsonization for phagocytosis and complement activation. Pentraxins have an important role in protection from infection from pathogenic bacteria, and regulation of the inflammatory response. It was recognized early on that some of these functions are mediated by activation of the classical complement pathway through C1q. However, experimental evidence suggested that cellular receptors for pentraxins also play a role in phagocytosis. More recent experimental evidence indicates a direct link between pentraxins and Fc receptors. The Fc receptors were first identified as the major receptors for immunoglobulins. The avidity of the interaction between IgG complexes and Fc receptors is greatly enhanced when multivalent ligands interact with the IgG binding sites and activation of signaling pathways requires Fc receptor crosslinking. Human pentraxins bind and activate human and mouse IgG receptors, FcγRI and FcγRII, and the human IgA receptor, FcαRI. The affinities of the interactions between Fc receptors and pentraxins in solution and on cell surfaces are similar to antibody binding to low affinity Fc receptors. Crystallographic and mutagenesis studies have defined the structural features of these interactions and determined the stoichiometry of binding as one-to-one. Pentraxin aggregation or binding to multivalent ligands increases the avidity of binding and results in activation of these receptors for phagocytosis and cytokine synthesis. This review will discuss the structural and functional characteristics of pentraxin Fc receptor interactions and their implications for host defense and inflammation.

Keywords: CRP; Fc receptor activation by pentraxin; SAP; pentraxin; structure and function.

Figure 1

Structure of pentraxins. (A) Pentameric structure of CRP. The ridge helix is highlighted in green and the bound phosphocholine molecules are shown in bold sticks. (B) Pentameric structure of SAP with ridge helix highlighted in red. (C) structural superposition of CRP and SAP (Protein Data Bank ID: 1B09, 1SAC).

Figure 2

A schematic representation of FcγRs and FcαRI on the cell surface. Each tyrosine residue on the cytoplasmic immuno-tyrosine activating motif (ITAM) or immune-tyrosine inhibitory motif (ITIM) are represented by a cylinder. The orientation of each Ig domain in different Fc receptors is based on the structural superposition of the second Ig domain (D2) (Protein Data Bank ID: 3RJD, 1FCG, 2FCB,3AY4, and 1UCT).

Figure 3

Binding mode between Fcγ receptors and pentraxins or IgG antibody. (A) The FcγR-IgG Fc interaction was represented by FcγRIIIA-IgG1 Fc complex structure (PDB ID: 1T83). (B) The complex structure between SAP and FcγRIIA(PDB ID: 3D5O). (C,D) Schematic representation of the interaction between pentraxin-FcγRIIa, IgG1 Fc-FcγRIIa, or FcγRIII. The interfaces are highlighted in shaded red or black circles. (E) Binding sites of FcγRIIA on SAP in crystal structure (PDB ID: 3D5O).

Figure 4

Binding mode between FcαRI and pentraxins or IgA antibody. (A) The binding sites identified by site-directed mutagenesis between CRP and FcαRI were indicated by red circles on D1 and D2 domain of FcαRI. (B) The complex structure between FcαRI and IgA Fc(PDB ID: 1OW0). (C) Schematic representation of the interaction between pentraxin-FcαRI based on site-directed mutagenesis and docking studies. (D) Schematic representation of the interaction between IgA Fc-FcαRI in crystal structure (PDB ID: 1OW0). The interfaces are highlighted in shaded red or black circles.