Role of Oligosaccharide Residues of IgG1-Fc in FcγRIIb Binding*

By Y. Mimura, P. Sondermann, R. Ghirlando, J. Lund, S. Young, M. Goodall, R. Jefferis. Journal of Biological Chemistry, 2001

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Engagement of Fcγ receptors (FcγRs) with the Fc region of IgG elicits immune responses by leukocytes. The recent crystal structure of FcγRIII in complex with IgG-Fc has provided details of molecular interactions between these components (Sondermann, P., Huber, R., Oosthuizen, V., and Jacob, U. (2000) Nature406, 267–273). One of the most intriguing issues is that glycosylation of IgG-Fc is essential for the recognition by FcγRs although the carbohydrate moieties are on the periphery of the FcγRIII-Fc interface. To better understand the role of Fc glycosylation in FcγR binding we prepared homogeneous glycoforms of IgG-Fc (Cri) and investigated the interactions with a soluble form of FcγRIIb (sFcγRIIb). A 1:1 complex stoichiometry was observed in solution at 30 °C (K d , 0.94 μm; ΔG, −8.4 kcal mol−1; ΔH, −6.5 kcal mol−1; TΔS, 1.9 kcal mol−1; ΔC p , −160 cal mol−1 K−1). Removal of terminal galactose residues did not alter the thermodynamic parameters significantly. Outer-arm GlcNAc residues contributed significantly to thermal stability of the CH2 domains but only slightly to sFcγRIIb binding. Truncation of 1,3- and 1,6-arm mannose residues generates a linear trisaccharide core structure and resulted in a significantly decreased affinity, a less exothermic ΔH, and a more negative ΔC p for sFcγRIIb binding, which may result from a conformational change coupled to complex formation. Deglycosylation of the CH2 domains abrogated sFcγRIIb binding and resulted in the lowest thermal stability accompanied with noncooperative unfolding. These results suggest that truncation of the oligosaccharides of IgG-Fc causes disorder and a closed disposition of the two CH2 domains, impairing sFcγRIIb binding.

Subfields: Molecular Biology, Radiology, Nuclear Medicine and Imaging

View Paper: https://www.semanticscholar.org/paper/cc348cea7ca3ba25ec48774b872e8ca08618339b

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