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FcγRI FG-loop functions as a pH sensitive switch for IgG binding and release.

Jinghua Lu1, Matthew Spencer1, Zhongcheng Zou1

  • 1Structural Immunology Section, Lab of Immunogenetics, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, MD, United States.

Frontiers in Immunology
|February 23, 2023
PubMed
Summary

The Fc gamma receptor I (FcγRI) uses its FG-loop as a pH-sensing switch to control binding to IgG antibodies. This mechanism is crucial for immune complex uptake and release, impacting therapeutic antibody engineering.

Keywords:
Fc-glycan recognitionantibody recognitionhuman FcγRIlive cell tracking of FcγRI-antibody endocytosispH sensitive bindingreceptor FG-loop

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Area of Science:

  • Immunology
  • Structural Biology
  • Biochemistry

Background:

  • Understanding Fc gamma receptor (FcγR) and IgG antibody interactions is vital for therapeutic antibody development.
  • Previous FcγRI-Fc complex structures proposed conflicting binding mechanisms.
  • The role of FcγRI in immune complex dynamics requires further elucidation.

Purpose of the Study:

  • To resolve the molecular mechanism of FcγRI-IgG binding.
  • To investigate the role of the FcγRI FG-loop in IgG interaction.
  • To explore the pH-dependent binding states of FcγRI.

Main Methods:

  • High-resolution crystal structure determination of FcγRI-Fc complexes.
  • Biochemical analysis of FcγRI-IgG interactions.
  • Live cell imaging to observe FcγRI-mediated immune complex uptake and release.

Main Results:

  • Confirmed the critical role of the FG loop-Fc interaction in high-affinity IgG binding.
  • Demonstrated the FcγRI D2-domain FG-loop acts as a pH-sensing switch.
  • Observed pH-sensitive temporal-spatial dynamics of immune complex uptake and release.
  • Identified distinct high-affinity (neutral pH) and low-affinity (acidic pH) binding states.

Conclusions:

  • FcγRI utilizes a pH-sensitive FG-loop mechanism for regulating IgG binding affinity.
  • This pH-switch mechanism facilitates antigen delivery via immune complex uptake and release.
  • Fc glycan is important for antibody binding to FcγRI, offering insights for antibody engineering.