A pentameric TRPV3 channel with a dilated pore

Shifra Lansky, John Michael Betancourt, Jingying Zhang, Yining Jiang, Elizabeth D. Kim, Navid Paknejad, Crina M. Nimigean, Peng Yuan and Simon Scheuring ()
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Shifra Lansky: Weill Cornell Medicine
John Michael Betancourt: Weill Cornell Medicine
Jingying Zhang: Washington University School of Medicine
Yining Jiang: Weill Cornell Medicine
Elizabeth D. Kim: Weill Cornell Medicine
Navid Paknejad: Memorial Sloan Kettering Cancer Center
Crina M. Nimigean: Weill Cornell Medicine
Peng Yuan: Washington University School of Medicine
Simon Scheuring: Weill Cornell Medicine

Nature, 2023, vol. 621, issue 7977, 206-214

Abstract: Abstract Transient receptor potential (TRP) channels are a large, eukaryotic ion channel superfamily that control diverse physiological functions, and therefore are attractive drug targets1–5. More than 210 structures from more than 20 different TRP channels have been determined, and all are tetramers4. Despite this wealth of structures, many aspects concerning TRPV channels remain poorly understood, including the pore-dilation phenomenon, whereby prolonged activation leads to increased conductance, permeability to large ions and loss of rectification6,7. Here, we used high-speed atomic force microscopy (HS-AFM) to analyse membrane-embedded TRPV3 at the single-molecule level and discovered a pentameric state. HS-AFM dynamic imaging revealed transience and reversibility of the pentamer in dynamic equilibrium with the canonical tetramer through membrane diffusive protomer exchange. The pentamer population increased upon diphenylboronic anhydride (DPBA) addition, an agonist that has been shown to induce TRPV3 pore dilation. On the basis of these findings, we designed a protein production and data analysis pipeline that resulted in a cryogenic-electron microscopy structure of the TRPV3 pentamer, showing an enlarged pore compared to the tetramer. The slow kinetics to enter and exit the pentameric state, the increased pentamer formation upon DPBA addition and the enlarged pore indicate that the pentamer represents the structural correlate of pore dilation. We thus show membrane diffusive protomer exchange as an additional mechanism for structural changes and conformational variability. Overall, we provide structural evidence for a non-canonical pentameric TRP-channel assembly, laying the foundation for new directions in TRP channel research.

Date: 2023
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DOI: 10.1038/s41586-023-06470-1

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