Structural recognition and functional activation of FcγR by innate pentraxins

Pentraxins are a family of ancient innate immune mediators conserved throughout evolution. The classical pentraxins include serum amyloid P component (SAP) and C-reactive protein (CRP), that are part of acute phase proteins synthesized in response to infection1, 2. Both recognize microbial pathogens and activate the classical complement pathway through C1q3,4. More recently, members of the pentraxin family were found to interact with cell surface Fcγ receptors (FcγR) and activate leukocyte-mediated phagocytosis5-8. We now describe the structural mechanism for pentraxin binding to FcγR and its functional activation of FcγR-mediated phagocytosis and cytokine secretion. The complex structure between human SAP and FcγRIIa reveals a diagonally bound receptor on each SAP pentamer with both D1 and D2 domains of the receptor contacting the ridge helices from two SAP subunits. The 1:1 stoichiometry between SAP and FcγRIIa infers the requirement for multivalent pathogen binding for receptor aggregation. Mutational and binding studies show that pentraxins are diverse in their binding specificity to FcγR isoforms but conserved in their recognition structure. The shared binding site for SAP and IgG results in competition for FcγR binding and the inhibition of immune complex-mediated phagocytosis by soluble pentraxins. These results establish the antibody-like functions for pentraxins in the FcγR pathway, suggest an evolutionary overlap between the innate and adaptive immune systems, and have novel therapeutic implications for autoimmune diseases.