Evidence that the TRPV1 S1-S4 membrane domain contributes to thermosensing
Evidence that the TRPV1 S1-S4 membrane domain contributes to thermosensing
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DOI：
10.1038/s41467-020-18026-2
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发表时间：
2020-08-20
影响因子：
16.6
通讯作者：
Van Horn, Wade D.
中科院分区：
文献类型：
--
作者：
Kim, Minjoo;Sisco, Nicholas J.;Van Horn, Wade D.
对温度的感知和反应在生物学中至关重要。TRPV 1离子通道是一种研究充分的热敏受体，也被香草素化合物（包括辣椒素）激活。尽管有很大的兴趣，热敏的分子基础仍然难以捉摸。TRPV 1 S1-S4膜结构域在通道门控期间将化学配体结合偶联到孔结构域。在这里，我们表明，S1-S4域也显着有助于热敏和热激活门控夫妇。通过溶液NMR、远紫外CD和固有荧光对分离的人TRPV 1 S1-S4结构域进行的评价表明，该结构域经历了具有高热敏性的非变性温度依赖性转变。温度依赖性构象变化的进一步NMR表征表明，S1-S4结构域对热敏的贡献与该结构域与配体和pH活化之间的已知耦合机制共享特征。总之，这项研究表明，TRPV 1 S1-S4结构域有助于TRPV 1温度依赖性激活。
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.