Abstract
Most cells active in the immune system express receptors for antibodies which mediate a variety of defensive mechanisms. These receptors interact with the Fc portion of the antibody and are therefore collectively called Fc receptors. Here, using high-speed atomic force microscopy, we observe interactions of human, humanized, and mouse/human-chimeric immunoglobulin G1 (IgG1) antibodies and their cognate Fc receptor, FcγRIIIa. Our results demonstrate that not only Fc but also Fab positively contributes to the interaction with the receptor. Furthermore, hydrogen/deuterium exchange mass spectrometric analysis reveals that the Fab portion of IgG1 is directly involved in its interaction with FcγRIIIa, in addition to the canonical Fc-mediated interaction. By targeting the previously unidentified receptor-interaction sites in IgG-Fab, our findings could inspire therapeutic antibody engineering.
Highlights
The Fc portion of immunoglobulin G (IgG) provides interaction sites for effector molecules such as complement[1,2,3,4]
The interaction modes of human IgG1 and FcγRIII molecules have been structurally characterized by X-ray crystallography using the Fc fragments and the soluble forms of FcγRIII molecules, comprising the D1 and D2 domains[20,21,22,23,24,25]
A large gulf exists between the structural views obtained and the functional and therapeutic insights gained from observations under physiologically realistic conditions where IgG1 interacts with FcγRIIIa anchored on the cell surfaces through a C-terminal transmembrane segment
Summary
The Fc portion of immunoglobulin G (IgG) provides interaction sites for effector molecules such as complement[1,2,3,4]. Most of the cells working in the immune system express receptors for IgG, possessing extracellular regions comprising Ig-fold domains and interacting with the Fc portion of IgG6–11. They are collectively termed Fcγ receptors (FcγRs). The interaction modes of human IgG1 and FcγRIII molecules have been structurally characterized by X-ray crystallography using the Fc fragments and the soluble forms of FcγRIII (sFcγRIII) molecules, comprising the D1 and D2 domains[20,21,22,23,24,25]. The interaction modes of these IgGs with sFcγRIIIa have been characterized by hydrogen-deuterium exchange mass spectrometry (HDX-MS) in solution
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