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Jantine E Bakema, Simone de Haij, Constance F den Hartog-Jager, Johanna Bakker, Gestur Vidarsson, Marjolein van Egmond, Jan G J van de Winkel, Jeanette H W Leusen, Signaling through Mutants of the IgA Receptor CD89 and Consequences for Fc Receptor γ-Chain Interaction, The Journal of Immunology, Volume 176, Issue 6, March 2006, Pages 3603–3610, https://doi.org/10.4049/jimmunol.176.6.3603
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Abstract
The prototypic receptor for IgA (FcαRI, CD89) is expressed on myeloid cells and can trigger phagocytosis, tumor cell lysis, and release of inflammatory mediators. The functions of FcαRI and activating receptors for IgG (FcγRI and FcγRIII) are dependent on the FcR γ-chain dimer. This study increases our understanding of the molecular basis of the FcαRI-FcR γ-chain transmembrane interaction, which is distinct from that of other activatory FcRs. FcαRI is unique in its interaction with the common FcR γ-chain, because it is based on a positively charged residue at position 209, which associates with a negatively charged amino acid of FcR γ-chain. We explored the importance of the position of this positive charge within human FcαRI for FcR γ-chain association and FcαRI functioning with the use of site-directed mutagenesis. In an FcαRI R209L/A213H mutant, which represents a vertical relocation of the positive charge, proximal and distal FcR γ-chain-dependent functions, such as calcium flux, MAPK phosphorylation, and IL-2 release, were similar to those of wild-type FcαRI. A lateral transfer of the positive charge, however, completely abrogated FcR γ-chain-dependent functions in an FcαRI R209L/M210R mutant. By coimmunoprecipitation, we have demonstrated the loss of a physical interaction between FcR γ-chain and FcαRI M210R mutant, thus explaining the loss of FcR γ-chain-dependent functions. In conclusion, not only the presence of a basic residue in the transmembrane region of FcαRI, but also the orientation of FcαRI toward the FcR γ-chain dimer is essential for FcR γ-chain association. This suggests the involvement of additional amino acids in the FcαRI-FcR γ-chain interaction.
