Structural requirements for the interaction of human IgM and IgA with the human Fc alpha/mu receptor

Ashfaq Ghumra, Jianguo Shi, Richard S. Mcintosh, Ingunn B. Rasmussen, Ranveig Braathen, Finn-Eirik Johansen, Inger Sandlie, Patricia K. Mongini, Thomas Areschoug, Gunnar Lindahl, Melanie J. Lewis, Jennifer M. Woof (Lead / Corresponding author), Richard J. Pleass (Lead / Corresponding author)

    Research output: Contribution to journalArticlepeer-review

    31 Citations (Scopus)

    Abstract

    Here we unravel the structural features of human IgM and IgA that govern their interaction with the human Fc alpha/mu receptor (hFc alpha/mu R). Ligand polymerization status was crucial for the interaction, because hFc alpha/mu R binding did not occur with monomeric Ab of either class. hFc alpha/mu R bound IgM with an affinity in the nanomolar range, whereas the affinity for dimeric IgA (dIgA) was tenfold lower. Panels of mutant IgM and dIgA were used to identify regions critical for hFc alpha/mu R binding. IgM binding required contributions from both C mu 3 and C mu 4 Fc domains, whereas for dIgA, an exposed loop in the C alpha 3 domain was crucial. This loop, comprising residues Pro440-Phe443, lies at the Fc domain interface and has been implicated in the binding of host receptors Fc alpha RI and polymeric Ig receptor (pIgR), as well as IgA-binding proteins produced by certain pathogenic bacteria. Substitutions within the Pro440-Phe443 loop resulted in loss of hFc alpha/mu R binding. Furthermore, secretory component (SC, the extracellular portion of pIgR) and bacterial IgA-binding proteins were shown to inhibit the dIgA-hFc alpha/mu R interaction. Therefore, we have identified a motif in the IgA-Fc inter-domain region critical for hFc alpha/mu R interaction, and highlighted the multi-functional nature of a key site for protein-protein interaction at the IgA Fc domain interface.

    Original languageEnglish
    Pages (from-to)1147-1156
    Number of pages10
    JournalEuropean Journal of Immunology
    Volume39
    Issue number4
    DOIs
    Publication statusPublished - Apr 2009

    Keywords

    • Human Fc alpha/mu receptor
    • IgA
    • IgM
    • POLYMERIC IMMUNOGLOBULIN RECEPTOR
    • J-CHAIN
    • BINDING-SITE
    • EPITHELIAL TRANSPORT
    • DOMAIN
    • PROTEINS
    • ANTIBODIES
    • INTERFACE
    • REGION
    • CD89

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