Structural recognition and functional activation of FcγR by innate pentraxins

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Abstract

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, which are two of the acute-phase proteins synthesized in response to infection1,2. Both recognize microbial pathogens and activate the classical complement pathway through C1q (refs 3 and 4). More recently, members of the pentraxin family were found to interact with cell-surface Fcγ receptors (FcγR) and activate leukocyte-mediated phagocytosis5,6,7,8. Here we describe the structural mechanism for pentraxin’s 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 for 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 antibody-like functions for pentraxins in the FcγR pathway, suggest an evolutionary overlap between the innate and adaptive immune systems, and have new therapeutic implications for autoimmune diseases.

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Figure 1: Activation of FcγR by pentraxin results in phagocytosis and cytokine release.
Figure 2: Crystal structure of SAP–FcγRIIa complex.
Figure 3: The binding interfaces between SAP and FcγRIIa.
Figure 4: Competition between human IgG1 and SAP or CRP for binding to Fcγ receptors.

Accession codes

Primary accessions

Protein Data Bank

Data deposits

Atomic coordinates for the SAP–FcγRIIa complex have been deposited in the PDB data bank under accession number 3D5O.

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Acknowledgements

We thank D. Klinman, G. Cheng, P. W. Dempsey and S. Bolland for providing the bone marrow from the Myd88-/-, RIP2-/- and wild-type C57BL/6 mice, respectively; M. Pancera and B. Dey for technical support in the isothermal titration calorimetry experiments; V. Deretic and S. Master for assistance with confocal microscopy; and B. Bottazzi for providing PTX-3. The X-ray SER-CAT beamlines (www.ser-cat.org/members.html) at the Advanced Photon Source is supported by the US Department of Energy, Basic Energy Sciences, Office of Science, under contract no. W-31-109-Eng-38. This work was supported by intramural research funding from the National Institute of Allergy and Infectious Diseases, National Institutes of Health, and by RO1 AI28358 and by the Department of Veterans Affairs.

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Correspondence to Peter D. Sun.

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Lu, J., Marnell, L., Marjon, K. et al. Structural recognition and functional activation of FcγR by innate pentraxins. Nature 456, 989–992 (2008) doi:10.1038/nature07468

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