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Structural requirements for the interaction of human IgM and IgA with the human Fcα/μ receptor
Author(s) -
Ghumra Ashfaq,
Shi Jianguo,
Mcintosh Richard S.,
Rasmussen Ingunn B.,
Braathen Ranveig,
Johansen FinnEirik,
Sandlie Inger,
Mongini Patricia K.,
Areschoug Thomas,
Lindahl Gunnar,
Lewis Melanie J.,
Woof Jenny M.,
Pleass Richard J.
Publication year - 2009
Publication title -
european journal of immunology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.272
H-Index - 201
eISSN - 1521-4141
pISSN - 0014-2980
DOI - 10.1002/eji.200839184
Subject(s) - biology , receptor , mutant , microbiology and biotechnology , plasma protein binding , extracellular , binding site , protein–protein interaction , immunoglobulin domain , secretory component , antibody , biochemistry , biophysics , immunology , gene
Abstract Here we unravel the structural features of human IgM and IgA that govern their interaction with the human Fcα/μ receptor (hFcα/μR). Ligand polymerization status was crucial for the interaction, because hFcα/μR binding did not occur with monomeric Ab of either class. hFcα/μR 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 hFcα/μR binding. IgM binding required contributions from both Cμ3 and Cμ4 Fc domains, whereas for dIgA, an exposed loop in the Cα3 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 FcαRI 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 hFcα/μR binding. Furthermore, secretory component (SC, the extracellular portion of pIgR) and bacterial IgA‐binding proteins were shown to inhibit the dIgA–hFcα/μR interaction. Therefore, we have identified a motif in the IgA–Fc inter‐domain region critical for hFcα/μR interaction, and highlighted the multi‐functional nature of a key site for protein–protein interaction at the IgA Fc domain interface.