Bivalent binding of IgA1 to FcalphaRI suggests a mechanism for cytokine activation of IgA phagocytosis.
FcalphaRI, the receptor specific for the Fc region of immunoglobulin A (IgA), is responsible for IgA-mediated phagocytosis, oxidative burst, and antibody-dependent cellular cytotoxicity. Using the techniques of analytical ultracentrifugation and equilibrium gel-filtration, we show that two FcalphaRI molecules bind to a single Fcalpha homodimer. Surface plasmon resonance studies confirm the 2:1 stoichiometry of binding, with equilibrium dissociation constants of 176 nM and 431 nM for the first and second binding events, respectively. The binding affinity decreases at acidic pH in a manner consistent with protonation of a single histidine residue in the binding site. A thermodynamic analysis indicates that the histidine residue does not participate in a salt-bridge in the complex; in fact, less than 10% of the free energy of binding was contributed by electrostatic interactions. The bivalent, pH-dependent interaction between FcalphaRI and IgA has important implications for cytokine-dependent phagocytosis of IgA and the FcalphaRI-mediated degradation or recycling of IgA.
Herr
Andrew B
AB
Division of Biology, California Institute of Technology, Pasadena, CA 91125, USA.
White
Clinton L
CL
Milburn
Christina
C
Wu
Carol
C
Bjorkman
Pamela J
PJ
D015703:Antigens, CD / Q000737:chemistry* / Q000378:metabolism; D001665:Binding Sites; D002850:Chromatography, Gel; D016207:Cytokines / Q000378:metabolism; D004789:Enzyme Activation; D005822:Genetic Vectors; D006639:Histidine / Q000737:chemistry; D006801:Humans; D006863:Hydrogen-Ion Concentration; D007070:Immunoglobulin A / Q000737:chemistry* / Q000378:metabolism; D007700:Kinetics; D010587:Phagocytosis; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D011961:Receptors, Fc / Q000737:chemistry* / Q000378:metabolism; D020349:Surface Plasmon Resonance; D013816:Thermodynamics; D013997:Time Factors; D014162:Transfection; D014461:Ultracentrifugation
D015703:Antigens, CD; D016207:Cytokines; C036832:Fc(alpha) receptor; D007070:Immunoglobulin A; D011961:Receptors, Fc; D006639:Histidine