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

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.

The following data sets were generated

Article and author information

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

Version 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)
  5. Version of Record published: September 29, 2021 (version 2)

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.

Metrics

  • 2,031
    Page views
  • 403
    Downloads
  • 18
    Citations

Article citation count generated by polling the highest count across the following sources: Crossref, PubMed Central, Scopus.

Download links

A two-part list of links to download the article, or parts of the article, in various formats.

Downloads (link to download the article as PDF)

Open citations (links to open the citations from this article in various online reference manager services)

Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)

  1. Yao Rong
  2. Jinghui Jiang
  3. Yiwei Gao
  4. Jianli Guo
  5. Danfeng Song
  6. Wenhao Liu
  7. Mingmin Zhang
  8. Yan Zhao
  9. Bailong Xiao
  10. Zhenfeng Liu
(2021)
TMEM120A contains a specific coenzyme A-binding site and might not mediate poking- or stretch-induced channel activities in cells
eLife 10:e71474.
https://doi.org/10.7554/eLife.71474

Share this article

https://doi.org/10.7554/eLife.71474

Further reading

    1. Neuroscience
    Daichi Sasaki, Ken Imai ... Ko Matsui
    Research Article

    The presence of global synchronization of vasomotion induced by oscillating visual stimuli was identified in the mouse brain. Endogenous autofluorescence was used and the vessel ‘shadow’ was quantified to evaluate the magnitude of the frequency-locked vasomotion. This method allows vasomotion to be easily quantified in non-transgenic wild-type mice using either the wide-field macro-zoom microscopy or the deep-brain fiber photometry methods. Vertical stripes horizontally oscillating at a low temporal frequency (0.25 Hz) were presented to the awake mouse, and oscillatory vasomotion locked to the temporal frequency of the visual stimulation was induced not only in the primary visual cortex but across a wide surface area of the cortex and the cerebellum. The visually induced vasomotion adapted to a wide range of stimulation parameters. Repeated trials of the visual stimulus presentations resulted in the plastic entrainment of vasomotion. Horizontally oscillating visual stimulus is known to induce horizontal optokinetic response (HOKR). The amplitude of the eye movement is known to increase with repeated training sessions, and the flocculus region of the cerebellum is known to be essential for this learning to occur. Here, we show a strong correlation between the average HOKR performance gain and the vasomotion entrainment magnitude in the cerebellar flocculus. Therefore, the plasticity of vasomotion and neuronal circuits appeared to occur in parallel. Efficient energy delivery by the entrained vasomotion may contribute to meeting the energy demand for increased coordinated neuronal activity and the subsequent neuronal circuit reorganization.

    1. Medicine
    2. Neuroscience
    Flora Moujaes, Jie Lisa Ji ... Alan Anticevic
    Research Article

    Background:

    Ketamine has emerged as one of the most promising therapies for treatment-resistant depression. However, inter-individual variability in response to ketamine is still not well understood and it is unclear how ketamine’s molecular mechanisms connect to its neural and behavioral effects.

    Methods:

    We conducted a single-blind placebo-controlled study, with participants blinded to their treatment condition. 40 healthy participants received acute ketamine (initial bolus 0.23 mg/kg, continuous infusion 0.58 mg/kg/hr). We quantified resting-state functional connectivity via data-driven global brain connectivity and related it to individual ketamine-induced symptom variation and cortical gene expression targets.

    Results:

    We found that: (i) both the neural and behavioral effects of acute ketamine are multi-dimensional, reflecting robust inter-individual variability; (ii) ketamine’s data-driven principal neural gradient effect matched somatostatin (SST) and parvalbumin (PVALB) cortical gene expression patterns in humans, while the mean effect did not; and (iii) behavioral data-driven individual symptom variation mapped onto distinct neural gradients of ketamine, which were resolvable at the single-subject level.

    Conclusions:

    These results highlight the importance of considering individual behavioral and neural variation in response to ketamine. They also have implications for the development of individually precise pharmacological biomarkers for treatment selection in psychiatry.

    Funding:

    This study was supported by NIH grants DP5OD012109-01 (A.A.), 1U01MH121766 (A.A.), R01MH112746 (J.D.M.), 5R01MH112189 (A.A.), 5R01MH108590 (A.A.), NIAAA grant 2P50AA012870-11 (A.A.); NSF NeuroNex grant 2015276 (J.D.M.); Brain and Behavior Research Foundation Young Investigator Award (A.A.); SFARI Pilot Award (J.D.M., A.A.); Heffter Research Institute (Grant No. 1–190420) (FXV, KHP); Swiss Neuromatrix Foundation (Grant No. 2016–0111) (FXV, KHP); Swiss National Science Foundation under the framework of Neuron Cofund (Grant No. 01EW1908) (KHP); Usona Institute (2015 – 2056) (FXV).

    Clinical trial number:

    NCT03842800