한빛사논문
Minjoo Kim1,2,5, Nicholas J. Sisco1,2,5, Jacob K. Hilton1,2, Camila M. Montano2, Manuel A. Castro1, Brian R. Cherry3, Marcia Levitus1,4 & Wade D. Van Horn1,2,*
1School of Molecular Sciences, Arizona State University, 551 E. University Drive, Tempe, AZ 85287, USA. 2The Biodesign Institute Virginia G. Piper Center for Personalized Diagnostics, Arizona State University, Tempe, AZ 85287, USA. 3The Magnetic Resonance Research Center, Arizona State University, Tempe, AZ 85287, USA. 4The Biodesign Institute Center for Single Molecule Biophysics, Arizona State University, Tempe, AZ 85287, USA.
5These authors contributed equally: Minjoo Kim, Nicholas J. Sisco.
*Corresponding author
Abstract
Sensing and responding to temperature is crucial in biology. The TRPV1 ion channel is a well-studied heat-sensing receptor that is also activated by vanilloid compounds, including capsaicin. Despite significant interest, the molecular underpinnings of thermosensing have remained elusive. The TRPV1 S1-S4 membrane domain couples chemical ligand binding to the pore domain during channel gating. Here we show that the S1-S4 domain also significantly contributes to thermosensing and couples to heat-activated gating. Evaluation of the isolated human TRPV1 S1-S4 domain by solution NMR, far-UV CD, and intrinsic fluorescence shows that this domain undergoes a non-denaturing temperature-dependent transition with a high thermosensitivity. Further NMR characterization of the temperature-dependent conformational changes suggests the contribution of the S1-S4 domain to thermosensing shares features with known coupling mechanisms between this domain with ligand and pH activation. Taken together, this study shows that the TRPV1 S1-S4 domain contributes to TRPV1 temperature-dependent activation.
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