FcγRIIB-I232T polymorphic change allosterically suppresses ligand binding

  1. Wei Hu
  2. Yong Zhang
  3. Xiaolin Sun
  4. Tongtong Zhang
  5. Liling Xu
  6. Hengyi Xie
  7. Zhanguo Li
  8. Wanli Liu  Is a corresponding author
  9. Jizhong Lou  Is a corresponding author
  10. Wei Chen  Is a corresponding author
  1. Zhejiang University School of Medicine, China
  2. Institute of Biophysics, Chinese Academy of Sciences, China
  3. Peking University People's Hospital, China
  4. Tsinghua University, China

Abstract

FcγRIIB binding to its ligand suppresses immune cell activation. A single-nucleotide polymorphic (SNP) change, I232T, in the transmembrane (TM) domain of FcγRIIB loses its suppressive function, which is clinically associated with systemic lupus erythematosus (SLE). Previously, we reported that I232T tilted FcγRIIB's TM domain. In this study, combining with molecular dynamics simulations and single-cell FRET assay, we further reveal that such tilting by I232T unexpectedly bends the FcγRIIB's ectodomain towards plasma membrane to allosterically impede FcγRIIB's ligand association. I232T substitution reduces in-situ two-dimensional binding affinities and association rates of FcγRIIB to interact with its ligands, IgG1, IgG2 and IgG3 by three to four folds. This allosteric regulation by a SNP provides an intrinsic molecular mechanism for the functional loss of FcγRIIB-I232T in SLE patients.

Data availability

All data generated or analysed during this study are included in the manuscript and supporting files.

Article and author information

Author details

  1. Wei Hu

    Department of Neurobiology, Institute of Neuroscience, Zhejiang University School of Medicine, Zhejiang, China
    Competing interests
    The authors declare that no competing interests exist.
  2. Yong Zhang

    CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China
    Competing interests
    The authors declare that no competing interests exist.
  3. Xiaolin Sun

    Department of Rheumatology and Immunology, Peking University People's Hospital, Beijing, China
    Competing interests
    The authors declare that no competing interests exist.
  4. Tongtong Zhang

    Department of Neurobiology, Institute of Neuroscience, Zhejiang University School of Medicine, Zhejiang, China
    Competing interests
    The authors declare that no competing interests exist.
  5. Liling Xu

    Institute for Immunology, Tsinghua University, Beijing, China
    Competing interests
    The authors declare that no competing interests exist.
  6. Hengyi Xie

    Institute for Immunology, Tsinghua University, Beijing, China
    Competing interests
    The authors declare that no competing interests exist.
  7. Zhanguo Li

    Department of Rheumatology and Immunology, Peking University People's Hospital, Beijing, China
    Competing interests
    The authors declare that no competing interests exist.
  8. Wanli Liu

    School of Life Sciences, Tsinghua University, Beijing, China
    For correspondence
    liulab@tsinghua.edu.cn
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-0395-2800
  9. Jizhong Lou

    CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China
    For correspondence
    jlou@ibp.ac.cn
    Competing interests
    The authors declare that no competing interests exist.
  10. Wei Chen

    Department of Neurobiology, Institute of Neuroscience, Zhejiang University School of Medicine, Zhejiang, China
    For correspondence
    jackweichen@zju.edu.cn
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-5366-7253

Funding

Natural Basic Research Program of China (2015CB910800)

  • Wei Chen

Natural Science Foundation of China (31470900)

  • Wei Chen

Natural Science Foundation of China (31522021)

  • Wei Chen

Natural Science Foundation of China (11672317)

  • Jizhong Lou

Natural Science Foundation of China (11772348)

  • Yong Zhang

Fundamental Research Founds for the Central Universities (2015XZZX004-32)

  • Wei Chen

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Ethics

Human subjects: The ethics committee of Peking University People's Hospital approved this study and informed consents were obtained from each patient and healthy volunteer. All the human cell associated experimental guidelines were approved by the Medical Ethics Committee of Peking University People's Hospital (approval no. 2014PHB116-01) and by the Medical Ethics Committee of Tsinghua University (approval no. 20180029).

Reviewing Editor

  1. Tomohiro Kurosaki, Osaka University, Japan

Publication history

  1. Received: March 22, 2019
  2. Accepted: July 25, 2019
  3. Accepted Manuscript published: July 25, 2019 (version 1)
  4. Version of Record published: August 27, 2019 (version 2)

Copyright

© 2019, Hu et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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  1. Wei Hu
  2. Yong Zhang
  3. Xiaolin Sun
  4. Tongtong Zhang
  5. Liling Xu
  6. Hengyi Xie
  7. Zhanguo Li
  8. Wanli Liu
  9. Jizhong Lou
  10. Wei Chen
(2019)
FcγRIIB-I232T polymorphic change allosterically suppresses ligand binding
eLife 8:e46689.
https://doi.org/10.7554/eLife.46689

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