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-Chain Interaction1
,
* Immunotherapy Laboratory, Department of Immunology, University Medical Center Utrecht, Utrecht, The Netherlands;
Department Experimental Immunohematology, Sanquin Research at CLB and Landsteiner Laboratory of the Academic Medical Centre, University of Amsterdam, Amsterdam, The Netherlands;
Department of Molecular Cell Biology and Immunology, Free University Medical Center, Amsterdam, The Netherlands;
Department of Surgical Oncology, Free University Medical Center, Amsterdam, The Netherlands; and
¶ Genmab, Utrecht, The Netherlands
The prototypic receptor for IgA (Fc
RI, CD89) is expressed on myeloid cells and can trigger phagocytosis, tumor cell lysis, and release of inflammatory mediators. The functions of FcRI and activating receptors for IgG (Fc
RI and FcRIII) are dependent on the FcR -chain dimer. This study increases our understanding of the molecular basis of the FcRI-FcR -chain transmembrane interaction, which is distinct from that of other activatory FcRs. FcRI is unique in its interaction with the common FcR -chain, because it is based on a positively charged residue at position 209, which associates with a negatively charged amino acid of FcR -chain. We explored the importance of the position of this positive charge within human FcRI for FcR -chain association and FcRI functioning with the use of site-directed mutagenesis. In an FcRI R209L/A213H mutant, which represents a vertical relocation of the positive charge, proximal and distal FcR -chain-dependent functions, such as calcium flux, MAPK phosphorylation, and IL-2 release, were similar to those of wild-type FcRI. A lateral transfer of the positive charge, however, completely abrogated FcR -chain-dependent functions in an FcRI R209L/M210R mutant. By coimmunoprecipitation, we have demonstrated the loss of a physical interaction between FcR -chain and FcRI M210R mutant, thus explaining the loss of FcR -chain-dependent functions. In conclusion, not only the presence of a basic residue in the transmembrane region of FcRI, but also the orientation of FcRI toward the FcR -chain dimer is essential for FcR -chain association. This suggests the involvement of additional amino acids in the FcRI-FcR -chain interaction.
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