A Human Immunoglobulin ( Ig ) A C a 3 Domain Motif Directs Polymeric Ig Receptor – mediated Secretion

Polymeric immunoglobulins provide immunological protection at mucosal surfaces to which they are specifically transported by the polymeric immunoglobulin receptor (pIgR). Using a panel of human IgA1/IgG1 constant region “domain swap” mutants, the binding site for the pIgR on dimeric IgA (dIgA) was localized to the C a 3 domain. Selection of random peptides for pIgR binding and comparison with the IgA sequence suggested amino acids 402–410 (QEPSQGTTT), in a predicted exposed loop of the C a 3 domain, as a potential binding site. Alanine substitution of two groups of amino acids in this area abrogated the binding of dIgA to pIgR, whereas adjacent substitutions in a b -strand immediately NH 2 -terminal to this loop had no effect. All pIgR binding IgA sequences contain a conserved three amino acid insertion, not present in IgG, at this position. These data localize the pIgR binding site on dimeric human IgA to this loop structure in the C a 3 domain, which directs mucosal secretion of polymeric antibodies. We propose that it may be possible to use a pIgR binding motif to deliver antigenspecific dIgA and small-molecule drugs to mucosal epithelia for therapy.