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Extracellular cap domain is an essential component of the TRPV1 gating mechanism

Author

Listed:
  • Kirill D. Nadezhdin

    (Columbia University)

  • Arthur Neuberger

    (Columbia University)

  • Yury A. Nikolaev

    (Yale University School of Medicine)

  • Lyle A. Murphy

    (Yale University School of Medicine)

  • Elena O. Gracheva

    (Yale University School of Medicine
    Yale University School of Medicine
    Yale University School of Medicine)

  • Sviatoslav N. Bagriantsev

    (Yale University School of Medicine)

  • Alexander I. Sobolevsky

    (Columbia University)

Abstract

Transient receptor potential (TRP) channels are polymodal molecular sensors involved in numerous physiological processes and implicated in a variety of human diseases. Several structures of the founding member of the TRP channel family, TRPV1, are available, all of which were determined for the protein missing the N- and C-termini and the extracellular S5-P-loop. Here, we present structures of the full-length thirteen-lined ground squirrel TRPV1 solved by cryo-EM. Our structures resolve the extracellular cap domain formed by the S5-P-loops and the C-terminus that wraps around the three-stranded β-sheet connecting elements of the TRPV1 intracellular skirt. The cap domain forms a dome above the pore’s extracellular entrance, with four portals leading to the ion conductance pathway. Deletion of the cap increases the TRPV1 average conductance, reduces the open probability and affects ion selectivity. Our data show that both the termini and the cap domain are critical determinants of TRPV1 function.

Suggested Citation

  • Kirill D. Nadezhdin & Arthur Neuberger & Yury A. Nikolaev & Lyle A. Murphy & Elena O. Gracheva & Sviatoslav N. Bagriantsev & Alexander I. Sobolevsky, 2021. "Extracellular cap domain is an essential component of the TRPV1 gating mechanism," Nature Communications, Nature, vol. 12(1), pages 1-8, December.
    • Handle: RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-22507-3
    DOI: 10.1038/s41467-021-22507-3
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    Cited by:

    1. Ruth A. Pumroy & Anna D. Protopopova & Tabea C. Fricke & Iris U. Lange & Ferdinand M. Haug & Phuong T. Nguyen & Pamela N. Gallo & Bárbara B. Sousa & Gonçalo J. L. Bernardes & Vladimir Yarov-Yarovoy & , 2022. "Structural insights into TRPV2 activation by small molecules," Nature Communications, Nature, vol. 13(1), pages 1-12, December.
    2. Liying Zhang & Charlotte Simonsen & Lucie Zimova & Kaituo Wang & Lavanya Moparthi & Rachelle Gaudet & Maria Ekoff & Gunnar Nilsson & Ute A. Hellmich & Viktorie Vlachova & Pontus Gourdon & Peter M. Zyg, 2022. "Cannabinoid non-cannabidiol site modulation of TRPV2 structure and function," Nature Communications, Nature, vol. 13(1), pages 1-18, December.
    3. Kirill D. Nadezhdin & Irina A. Talyzina & Aravind Parthasarathy & Arthur Neuberger & David X. Zhang & Alexander I. Sobolevsky, 2023. "Structure of human TRPV4 in complex with GTPase RhoA," Nature Communications, Nature, vol. 14(1), pages 1-11, December.
    4. Arthur Neuberger & Mai Oda & Yury A. Nikolaev & Kirill D. Nadezhdin & Elena O. Gracheva & Sviatoslav N. Bagriantsev & Alexander I. Sobolevsky, 2023. "Human TRPV1 structure and inhibition by the analgesic SB-366791," Nature Communications, Nature, vol. 14(1), pages 1-10, December.

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