6eaq
Glycosylated FCGR3B / CD16b in complex with afucosylated IgG1 Fc
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 PubMedTherapeutic mAbs engage Fc gamma receptor III (CD16) to elicit a protective cell-mediated response and destroy the target tissue. Newer drugs designed to bind CD16a with increased affinity surprisingly also elicit protective CD16b-mediated responses. However, it is unclear why immunoglobulin G (IgG) binds CD16a with more than 10-fold higher affinity than CD16b even though these receptors share > 97% identity. Here, we identified one residue, Gly129, that contributes to the greater IgG-binding affinity of CD16a. The CD16b variant D129G bound IgG1 Fc with two-fold higher affinity than CD16a and with 90-fold higher affinity than WT. Conversely, the binding affinity of CD16a-G129D was decreased 128-fold relative to WT CD16a and comparably to that of WT CD16b. The interaction of IgG1 Fc with CD16a, but not with CD16b, is known to be sensitive to the composition of the asparagine-linked carbohydrates (N-glycans) attached to the receptor. CD16a and CD16b-D129G displaying minimally processed oligomannose N-glycans bound to IgG1 Fc with about 5.2-fold increased affinity compared with variants with highly processed complex-type N-glycans. CD16b and the CD16a-G129D variant exhibited a smaller 1.9-fold affinity increase with oligomannose N-glycans. A model of glycosylated CD16b bound to IgG1 Fc determined to 2.2 A resolution combined with a 250-ns all-atom molecular dynamics simulation showed that the larger Asp129 residue deformed the Fc-binding surface. These results reveal how Asp-129 in CD16b affects its binding affinity for IgG1 Fc and suggest that antibodies engineered to engage CD16b with high affinity must accommodate the Asp-129 sidechain. A single amino acid distorts the Fc gamma receptor IIIb / CD16b structure upon binding immunoglobulin G1 and reduces affinity relative to CD16a.,Roberts JT, Barb AW J Biol Chem. 2018 Oct 25. pii: RA118.005273. doi: 10.1074/jbc.RA118.005273. PMID:30361439[4] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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