1. Neuroscience
  2. Structural Biology and Molecular Biophysics
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TMEM120A contains a specific coenzyme A-binding site and might not mediate poking- or stretch-induced channel activities in cells

  1. Yao Rong
  2. Jinghui Jiang
  3. Yiwei Gao
  4. Jianli Guo
  5. Danfeng Song
  6. Wenhao Liu
  7. Mingmin Zhang
  8. Yan Zhao  Is a corresponding author
  9. Bailong Xiao  Is a corresponding author
  10. Zhenfeng Liu  Is a corresponding author
  1. Institute of Biophysics, Chinese Academy of Sciences, China
  2. School of Pharmaceutical Sciences, Tsinghua University, China
  3. Tsinghua University, China
Research Article
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Cite this article as: eLife 2021;10:e71474 doi: 10.7554/eLife.71474

Abstract

TMEM120A, a member of the Transmembrane protein 120 (TMEM120) family, has pivotal function in adipocyte differentiation and metabolism, and may also contribute to sensing mechanical pain by functioning as an ion channel named TACAN. Here we report that expression of TMEM120A is not sufficient in mediating poking- or stretch-induced currents in cells, and have solved cryo-EM structures of human TMEM120A (HsTMEM120A) in complex with an endogenous metabolic cofactor (coenzyme A, CoASH) and in the apo form. HsTMEM120A forms a symmetrical homodimer with each monomer containing an amino-terminal coiled-coil motif followed by a transmembrane domain with six membrane-spanning helices. Within the transmembrane domain, a CoASH molecule is hosted in a deep cavity and forms specific interactions with nearby amino acid residues. Mutation of a central tryptophan residue involved in binding CoASH dramatically reduced the binding affinity of HsTMEM120A with CoASH. HsTMEM120A exhibits distinct conformations at the states with or without CoASH bound. Our results suggest that TMEM120A may have alternative functional roles potentially involved in CoASH transport, sensing or metabolism.

Data availability

The structural models have been deposited in the Protein Data Bank under accession codes of 7F3T (https://www.rcsb.org/structure/7F3T) for HsTMEM120A-CoASH complex in nanodisc and 7F3U (https://www.rcsb.org/structure/7F3U) for HsTMEM120A in detergent. The cryo-EM density maps of HsTMEM120A-CoASH complex in nanodisc and HsTMEM120A in detergent have been deposited in the Electron Microscopy Data Bank under accession codes of EMD-31440 (https://www.emdataresource.org/EMD-31440) and EMD-31441 (https://www.emdataresource.org/EMD-31441), respectively.The source data files for Figure 1, Figure 1-figure supplement 1, Figure 2-figure supplement 1A, Figure 4D and Figure 4-figure supplement 3 have been provided.

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Author details

  1. Yao Rong

    National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-5590-2939
  2. Jinghui Jiang

    School of Pharmaceutical Sciences, Tsinghua University, Beijing, China
    Competing interests
    The authors declare that no competing interests exist.
  3. Yiwei Gao

    National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-8169-9332
  4. Jianli Guo

    National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China
    Competing interests
    The authors declare that no competing interests exist.
  5. Danfeng Song

    National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China
    Competing interests
    The authors declare that no competing interests exist.
  6. Wenhao Liu

    School of Pharmaceutical Sciences, Tsinghua University, Beijing, China
    Competing interests
    The authors declare that no competing interests exist.
  7. Mingmin Zhang

    School of Pharmaceutical Sciences, Tsinghua University, Beijing, China
    Competing interests
    The authors declare that no competing interests exist.
  8. Yan Zhao

    National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China
    For correspondence
    zhaoy@ibp.ac.cn
    Competing interests
    The authors declare that no competing interests exist.
  9. Bailong Xiao

    State Key Laboratory of Membrane Biology, Tsinghua University, Beijing, China
    For correspondence
    xbailong@mail.tsinghua.edu.cn
    Competing interests
    The authors declare that no competing interests exist.
  10. Zhenfeng Liu

    National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China
    For correspondence
    liuzf@ibp.ac.cn
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-5502-9474

Funding

National Natural Science Foundation of China (31925024 and 31670749)

  • Zhenfeng Liu

National Natural Science Foundation of China (31825014 and 31630090)

  • Bailong Xiao

the Strategic Priority Research Program of CAS (XDB37020101)

  • Zhenfeng Liu

the Strategic Priority Research Program of CAS (XDB37030304)

  • Yan Zhao

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

Reviewing Editor

  1. Andrés Jara-Oseguera, University of Texas at Austin, United States

Publication history

  1. Preprint posted: June 17, 2021 (view preprint)
  2. Received: June 20, 2021
  3. Accepted: August 16, 2021
  4. Accepted Manuscript published: August 19, 2021 (version 1)

Copyright

© 2021, Rong 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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