Crystal structure of sialylated IgG Fc: Implications for the mechanism of intravenous immunoglobulin therapy

Abstract

Intravenous Ig consists of pooled human serum IgG and is widely used as an anti-inflammatory agent. The fraction of IgG that is α2,6-sialylated exhibits anti-inflammatory activity and sialylation is proposed to enable binding to the cell surface lectin, dendritic cell-specific intercellular adhesion molecule-3-grabbing nonintegrin (DC-SIGN) (1). In a recent article in PNAS, Sondermann et al. propose a mechanism to explain the putative sialic acid-dependent binding of IgG Fc to DC-SIGN, as well as to the IgE receptor, CD23 (2). The core of their hypothesis is that sialylation of IgG Fc leads to a conformational change, which triggers DC-SIGN binding. To directly assess this hypothesis, we have generated α2,6-sialylated IgG1 Fc (sFc) that we both chemically verified by HPLC analysis (Fig. 1A) and structurally characterized by X-ray crystallographic analysis to a resolution of 2.3 A (Fig. 1 B and C, and Table 1).