Structural basis of TRPC4 regulation by calmodulin and pharmacological agents

  1. Deivanayagabarathy Vinayagam
  2. Dennis Quentin
  3. Jing Yu-Strzelczyk
  4. Oleg Sitsel
  5. Felipe Merino
  6. Markus Stabrin
  7. Oliver Hofnagel
  8. Maolin Yu
  9. Mark W Ledeboer
  10. Georg Nagel
  11. Goran Malojcic
  12. Stefan Raunser  Is a corresponding author
  1. Max Planck Institute of Molecular Physiology, Germany
  2. Julius-Maximilians-Universität Würzburg, Germany
  3. Max Planck Institute for Molecular Physiology, Germany
  4. Goldfinch Bio Inc, United States

Abstract

Canonical transient receptor potential channels (TRPC) are involved in receptor-operated and/or store-operated Ca2+ signaling. Inhibition of TRPCs by small molecules was shown to be promising in treating renal diseases. In cells, the channels are regulated by calmodulin. Molecular details of both calmodulin and drug binding have remained elusive so far. Here we report structures of TRPC4 in complex with three pyridazinone-based inhibitors and calmodulin. The structures reveal that all the inhibitors bind to the same cavity of the voltage-sensing-like domain and allow us to describe how structural changes from the ligand binding site can be transmitted to the central ion-conducting pore of TRPC4. Calmodulin binds to the rib helix of TRPC4, which results in the ordering of a previously disordered region, fixing the channel in its closed conformation. This represents a novel calmodulin-induced regulatory mechanism of canonical TRP channels.

Data availability

The atomic coordinates and cryo-EM maps for TRPC4DR in complex with inhibitors, calmodulin and for TRPC4DR in LMNG are available at the Protein Data Bank (PDB) and Electron Microscopy Data Bank (EMDB) databases, under the accession numbers PBD 7B0S and EMD-11970 (TRPC4-GFB8438), PBD 7B16 and EMD-11979 (TRPC4-GFB9289); PBD 7B05 and EMD-11957 (TRPC4-GFB8749); PBD 7B1G and EMD-11985 (TRPC4-Calmodulin) and PBD 7B0J and EMD-11968 (TRPC4-apo in LMNG).

The following data sets were generated

Article and author information

Author details

  1. Deivanayagabarathy Vinayagam

    Department of Structural Biochemistry, Max Planck Institute of Molecular Physiology, Dortmund, Germany
    Competing interests
    No competing interests declared.
  2. Dennis Quentin

    Department of Structural Biochemistry, Max Planck Institute of Molecular Physiology, Dortmund, Germany
    Competing interests
    No competing interests declared.
  3. Jing Yu-Strzelczyk

    Department of Neurophysiology, Julius-Maximilians-Universität Würzburg, Würzburg, Germany
    Competing interests
    No competing interests declared.
  4. Oleg Sitsel

    Department of Structural Biochemistry, Max Planck Institute for Molecular Physiology, Dortmund, Germany
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-4496-7489
  5. Felipe Merino

    Department of Structural Biochemistry, Max Planck Institute of Molecular Physiology, Dortmund, Germany
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-4166-8747
  6. Markus Stabrin

    Department of Structural Biochemistry, Max Planck Institute of Molecular Physiology, Dortmund, Germany
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-0191-6419
  7. Oliver Hofnagel

    Department of Structural Biochemistry, Max Planck Institute of Molecular Physiology, Dortmund, Germany
    Competing interests
    No competing interests declared.
  8. Maolin Yu

    Research Department, Goldfinch Bio Inc, Boston, United States
    Competing interests
    Maolin Yu, The author is or was a shareholder of Goldfinch Bio..
  9. Mark W Ledeboer

    Research Department, Goldfinch Bio Inc, Boston, United States
    Competing interests
    Mark W Ledeboer, The author is or was a shareholder of Goldfinch Bio..
  10. Georg Nagel

    Department of Biology, Institute for Molecular Plant Physiology and Biophysics, Biocenter, Julius-Maximilians-Universität Würzburg, Würzburg, Germany
    Competing interests
    No competing interests declared.
  11. Goran Malojcic

    Research Department, Goldfinch Bio Inc, Boston, United States
    Competing interests
    Goran Malojcic, The author is or was a shareholder of Goldfinch Bio..
  12. Stefan Raunser

    Department of Structural Biochemistry, Max Planck Institute of Molecular Physiology, Dortmund, Germany
    For correspondence
    stefan.raunser@mpi-dortmund.mpg.de
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-9373-3016

Funding

Max-Planck-Gesellschaft

  • Stefan Raunser

Deutsche Forschungsgemeinschaft (TR240)

  • Georg Nagel

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

Reviewing Editor

  1. Leon D Islas, Universidad Nacional Autónoma de México, Mexico

Publication history

  1. Received: July 1, 2020
  2. Accepted: November 23, 2020
  3. Accepted Manuscript published: November 25, 2020 (version 1)
  4. Version of Record published: December 14, 2020 (version 2)

Copyright

© 2020, Vinayagam 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. Deivanayagabarathy Vinayagam
  2. Dennis Quentin
  3. Jing Yu-Strzelczyk
  4. Oleg Sitsel
  5. Felipe Merino
  6. Markus Stabrin
  7. Oliver Hofnagel
  8. Maolin Yu
  9. Mark W Ledeboer
  10. Georg Nagel
  11. Goran Malojcic
  12. Stefan Raunser
(2020)
Structural basis of TRPC4 regulation by calmodulin and pharmacological agents
eLife 9:e60603.
https://doi.org/10.7554/eLife.60603
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