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Pentraxins and IgA share a binding hot-spot on Fc?RI.

ABSTRACT: The pentraxins, C-reactive protein (CRP), and serum amyloid P component (SAP) have previously been shown to function as innate opsonins through interactions with Fc? receptors. The molecular details of these interactions were elucidated by the crystal structure of SAP in complex with Fc?RIIA. More recently, pentraxins were shown to bind and activate Fc?RI (CD89), the receptor for IgA. Here, we used mutations of the receptor based on a docking model to further examine pentraxin recognition by Fc?RI. The solution binding of pentraxins to six Fc?RI alanine cluster mutants revealed that mutations Y35A and R82A, on the C-and F-strands of the D1 domain, respectively, markedly reduced receptor binding to CRP and SAP. These residues are in the IgA-binding site of the receptor, and thus, significantly affected receptor binding to IgA. The shared pentraxin and IgA-binding site on Fc?RI is further supported by the results of a solution binding competition assay. In addition to the IgA-binding site, pentraxins appear to interact with a broader region of the receptor as the mutation in the C'-strand (R48A/E49A) enhanced pentraxin binding. Unlike Fc? receptors, the H129A/I130A and R178A mutations on the BC- and FG-loops of D2 domain, respectively, had little effect on Fc?RI binding to the pentraxins. In conclusion, our data suggest that the pentraxins recognize a similar site on Fc?RI as IgA.

SUBMITTER: Lu J

PROVIDER: S-EPMC3970889 | biostudies-literature | 2014 Apr

REPOSITORIES: biostudies-literature

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Pentraxins and IgA share a binding hot-spot on FcαRI.

Lu Jinghua J Marjon Kristopher D KD Mold Carolyn C Marnell Lorraine L Du Clos Terry W TW Sun Peter P

Protein science : a publication of the Protein Society 20140128 4

The pentraxins, C-reactive protein (CRP), and serum amyloid P component (SAP) have previously been shown to function as innate opsonins through interactions with Fcγ receptors. The molecular details of these interactions were elucidated by the crystal structure of SAP in complex with FcγRIIA. More recently, pentraxins were shown to bind and activate FcαRI (CD89), the receptor for IgA. Here, we used mutations of the receptor based on a docking model to further examine pentraxin recognition by Fcα ...[more]

PMID: 24407959

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Project description: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.

Dataset Information

Pentraxins and IgA share a binding hot-spot on Fc?RI.

Publications

Pentraxins and IgA share a binding hot-spot on FcαRI.

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