期刊
JOURNAL OF STRUCTURAL BIOLOGY
卷 194, 期 1, 页码 78-89出版社
ACADEMIC PRESS INC ELSEVIER SCIENCE
DOI: 10.1016/j.jsb.2016.02.001
关键词
Affinity; Fc-FcR structure; Fc receptors; GASDALIE Fc; IgG Fc; SDALIE Fc
资金
- Office of Science, Office of Basic Energy Sciences, of the U.S. Department of Energy [DE-AC02-05CH11231]
- National Institute Of Allergy And Infectious Diseases of the National Institutes of Health [HIVRAD P01 AI100148]
- Molecular Observatory at Caltech - Gordon and Betty Moore Foundation
The Fc region of Immunoglobulin G (IgG) initiates inflammatory responses such as antibody-dependent cell-mediated cytotoxicity (ADCC) through binding to activating Fc receptors (Fc gamma RI, Fc gamma RIIa, Fc gamma RIIIa). These receptors are expressed on the surface of immune cells including macrophages, dendritic cells, and natural killer cells. An inhibitory receptor, Fc gamma RIIb, is expressed on macrophages and other myeloid leukocytes simultaneously with the activating receptor Fc gamma RIIa, thereby setting a threshold for cell activation. The affinity of IgG Fc for binding activating Fc receptors depends on IgG subclass and the composition of N-linked glycans attached to a conserved asparagine in the Fc C(H)2 domain. For example, Fc regions with afucosylated glycans bind more tightly to Fc gamma RIIIa than fucosylated Fc, and afucosylated Fcs exhibit enhanced ADCC activity in vivo and in vitro. Enhanced pro-inflammatory responses have also been seen for Fc regions with amino acid substitutions. GASDALIE Fc is an Fc mutant (G236A/S239D/A330L/I332E) that exhibits a higher affinity for Fc gamma RIIIa and increased effector functions in vivo compared to wild-type Fc. To explore its altered functions, we compared the affinities of GASDALIE and wild-type Fc for activating and inhibitory Fc gamma Rs. We also determined the crystal structure of GASDALIE Fc alone and bound to Fc gamma RIIIa. The overall structure of GASDALIE Fc alone was similar to wild-type Fc structures, however, increased electrostatic interactions in the GASDALIE Fc:Fc gamma RIIIa interface compared with other Fc:Fc gamma R structures suggest a mechanism for the increased affinity of GASDALIE Fc for Fc gamma RIIIa. (C) 2016 Elsevier Inc. All rights reserved.
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