期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2015
卷号：112
期号：3
页码：833-838
DOI：10.1073/pnas.1418812112
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：SignificanceFc gamma receptor I (Fc{gamma}RI) contributes to protective immunity against bacterial infections, but exacerbates certain autoimmune diseases. It is the sole high-affinity receptor for IgG and plays a significant role in immunotherapy. To date, there is no structural information available on how the receptor recognizes its antibody ligands, however. Consequently, the mechanism of its high-affinity IgG binding remains unclear. We report the first structure of the high-affinity Fc receptor in complex with IgG-Fc. The structural work reveals a direct receptor recognition of Fc glycan as a major factor in receptor affinity. This is the first example of Fc receptor making direct glycan contact through protein residues. The results have implications for the use of glycan engineering in immunotherapy. Fc gamma receptor I (Fc{gamma}RI) contributes to protective immunity against bacterial infections, but exacerbates certain autoimmune diseases. The sole high-affinity IgG receptor, Fc{gamma}RI plays a significant role in immunotherapy. To elucidate the molecular mechanism of its high-affinity IgG binding, we determined the crystal structure of the extracellular domains of human Fc{gamma}RI in complex with the Fc domain of human IgG1. Fc{gamma}RI binds to the Fc in a similar mode as the low-affinity Fc{gamma}RII and Fc{gamma}RIII receptors. In addition to many conserved contacts, Fc{gamma}RI forms additional hydrogen bonds and salt bridges with the lower hinge region of Fc. Unique to the high-affinity receptor-Fc complex, however, is the conformation of the receptor D2 domain FG loop, which enables a charged KHR motif to interact with proximal carbohydrate units of the Fc glycans. Both the length and the charge of the Fc{gamma}RI FG loop are well conserved among mammalian species. Ala and Glu mutations of the FG loop KHR residues showed significant contributions of His-174 and Arg-175 to antibody binding, and the loss of the FG loop-glycan interaction resulted in an [~]20- to 30-fold decrease in Fc{gamma}RI affinity to all three subclasses of IgGs. Furthermore, deglycosylation of IgG1 resulted in a 40-fold loss in Fc{gamma}RI binding, demonstrating involvement of the receptor FG loop in glycan recognition. These results highlight a unique glycan recognition in Fc{gamma}RI function and open potential therapeutic avenues based on antibody glycan engineering or small molecular glycan mimics to target Fc{gamma}RI for certain autoimmune diseases.
