5yc5
Crystal structure of human IgG-Fc in complex with aglycan and optimized Fc gamma receptor IIIa
Structural highlights
FunctionIGG1_HUMAN Immunoglobulins, also known as antibodies, are membrane-bound or secreted glycoproteins produced by B lymphocytes. In the recognition phase of humoral immunity, the membrane-bound immunoglobulins serve as receptors which, upon binding of a specific antigen, trigger the clonal expansion and differentiation of B lymphocytes into immunoglobulins-secreting plasma cells. Secreted immunoglobulins mediate the effector phase of humoral immunity, which results in the elimination of bound antigens (PubMed:22158414, PubMed:20176268). The antigen binding site is formed by the variable domain of one heavy chain, together with that of its associated light chain. Thus, each immunoglobulin has two antigen binding sites with remarkable affinity for a particular antigen. The variable domains are assembled by a process called V-(D)-J rearrangement and can then be subjected to somatic hypermutations which, after exposure to antigen and selection, allow affinity maturation for a particular antigen (PubMed:20176268, PubMed:17576170).[1] [2] [3] Publication Abstract from PubMedThe N-glycan moiety of IgG-Fc has a significant impact on multifaceted properties of antibodies such as in their effector function, structure, and stability. Numerous studies have been devoted to understanding its biological effect since the exact composition of the Fc N-glycan modulates the magnitude of effector functions such as the antibody-dependent cell mediated cytotoxicity (ADCC), and the complement-dependent cytotoxicity (CDC). To date, systematic analyses of the properties and influence of glycan variants have been of great interest. Understanding the principles on how N-glycosylation modulates those properties is important for the molecular design, manufacturing, process optimization, and quality control of therapeutic antibodies. In this study, we have separated a model therapeutic antibody into three fractions according to the composition of the N-glycan by using a novel FcgammaRIIIa chromatography column. Notably, Fc galactosylation was a major factor influencing the affinity of IgG-Fc to the FcgammaRIIIa immobilized on the column. Each antibody fraction was employed for structural, biological, and physicochemical analysis, illustrating the mechanism by which galactose modulates the affinity to FcgammaRIIIa. In addition, we discuss the benefits of the FcgammaRIIIa chromatography column to assess the heterogeneity of the N-glycan. Assessing the Heterogeneity of the Fc-Glycan of a Therapeutic Antibody Using an engineered FcgammaReceptor IIIa-Immobilized Column.,Kiyoshi M, Caaveiro JMM, Tada M, Tamura H, Tanaka T, Terao Y, Morante K, Harazono A, Hashii N, Shibata H, Kuroda D, Nagatoishi S, Oe S, Ide T, Tsumoto K, Ishii-Watabe A Sci Rep. 2018 Mar 2;8(1):3955. doi: 10.1038/s41598-018-22199-8. PMID:29500371[4] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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