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Structural basis for the transmembrane signaling and antidepressant-induced activation of the receptor tyrosine kinase TrkB

Author

Listed:
  • Erik F. Kot

    (Shenzhen MSU-BIT University
    Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry)

  • Sergey A. Goncharuk

    (Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry)

  • María Luisa Franco

    (Instituto de Biomedicina de Valencia-CSIC)

  • Daniel M. McKenzie

    (Johns Hopkins University)

  • Alexander S. Arseniev

    (Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry)

  • Andrea Benito-Martínez

    (Instituto de Biomedicina de Valencia-CSIC)

  • Mario Costa

    (Scuola Normale Superiore Laboratory of Biology BIO@SNS
    CNR Neuroscience Institute)

  • Antonino Cattaneo

    (Scuola Normale Superiore Laboratory of Biology BIO@SNS)

  • Kalina Hristova

    (Johns Hopkins University)

  • Marçal Vilar

    (Instituto de Biomedicina de Valencia-CSIC)

  • Konstantin S. Mineev

    (Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry
    Frankfurt am Main)

Abstract

Neurotrophin receptors of the Trk family are involved in the regulation of brain development and neuroplasticity, and therefore can serve as targets for anti-cancer and stroke-recovery drugs, antidepressants, and many others. The structures of Trk protein domains in various states upon activation need to be elucidated to allow rational drug design. However, little is known about the conformations of the transmembrane and juxtamembrane domains of Trk receptors. In the present study, we employ NMR spectroscopy to solve the structure of the TrkB dimeric transmembrane domain in the lipid environment. We verify the structure using mutagenesis and confirm that the conformation corresponds to the active state of the receptor. Subsequent study of TrkB interaction with the antidepressant drug fluoxetine, and the antipsychotic drug chlorpromazine, provides a clear self-consistent model, describing the mechanism by which fluoxetine activates the receptor by binding to its transmembrane domain.

Suggested Citation

  • Erik F. Kot & Sergey A. Goncharuk & María Luisa Franco & Daniel M. McKenzie & Alexander S. Arseniev & Andrea Benito-Martínez & Mario Costa & Antonino Cattaneo & Kalina Hristova & Marçal Vilar & Konsta, 2024. "Structural basis for the transmembrane signaling and antidepressant-induced activation of the receptor tyrosine kinase TrkB," Nature Communications, Nature, vol. 15(1), pages 1-16, December.
    • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-53710-7
    DOI: 10.1038/s41467-024-53710-7
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    References listed on IDEAS

    as
    1. Sarvenaz Sarabipour & Kalina Hristova, 2016. "Mechanism of FGF receptor dimerization and activation," Nature Communications, Nature, vol. 7(1), pages 1-12, April.
    2. F. D. Kornilov & A. V. Shabalkina & Cong Lin & P. E. Volynsky & E. F. Kot & A. L. Kayushin & V. A. Lushpa & M. V. Goncharuk & A. S. Arseniev & S. A. Goncharuk & Xiaohui Wang & K. S. Mineev, 2023. "The architecture of transmembrane and cytoplasmic juxtamembrane regions of Toll-like receptors," Nature Communications, Nature, vol. 14(1), pages 1-12, December.
    3. Vassiliki Nikoletopoulou & Heiko Lickert & José Maria Frade & Chantal Rencurel & Patrizia Giallonardo & Lixin Zhang & Miriam Bibel & Yves-Alain Barde, 2010. "Neurotrophin receptors TrkA and TrkC cause neuronal death whereas TrkB does not," Nature, Nature, vol. 467(7311), pages 59-63, September.
    4. Christian Wiesmann & Mark H. Ultsch & Steven H. Bass & Abraham M. de Vos, 1999. "Crystal structure of nerve growth factor in complex with the ligand-binding domain of the TrkA receptor," Nature, Nature, vol. 401(6749), pages 184-188, September.
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