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首页> 美国卫生研究院文献>The Journal of Biological Chemistry >The Region Adjacent to the C-end of the Inner Gate in Transient Receptor Potential Melastatin 8 (TRPM8) Channels Plays a Central Role in Allosteric Channel Activation
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The Region Adjacent to the C-end of the Inner Gate in Transient Receptor Potential Melastatin 8 (TRPM8) Channels Plays a Central Role in Allosteric Channel Activation

机译：瞬态受体电位Melastatin 8（TRPM8）通道内门C端附近的区域在变构通道激活中起核心作用

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The ability of transient receptor potential (TRP) channels to sense and respond to environmental and endogenous cues is crucial in animal sensory physiology. The molecular mechanism of channel gating is yet elusive. The TRP box, a conserved region in the N-end of the C terminus domain, has been signaled as pivotal for allosteric activation in TRP channels. Here, we have examined the role of the linker region between the TRPM8 inner gate and the TRP box (referred to as the S6-TRP box linker) to identify structural determinants of channel gating. Stepwise substitutions of segments in the S6-TRP box linker of TRPM8 channel with the cognate TRPV1 channel sequences produced functional chimeric channels, and identified Tyr981 as a central molecular determinant of channel function. Additionally, mutations in the 986–990 region had a profound impact on channel gating by voltage and menthol, as evidenced by the modulation of the conductance-to-voltage (G-V) relationships. Simulation of G-V curves using an allosteric model for channel activation revealed that these mutations altered the allosteric constants that couple stimuli sensing to pore opening. A molecular model of TRPM8, based on the recently reported TRPV1 structural model, showed that Tyr981 may lie in a hydrophobic pocket at the end of the S6 transmembrane segment and is involved in inter-subunit interactions with residues from neighbor subunits. The 986–990 region holds intrasubunit interactions between the TRP domain and the S4–S5 linker. These findings substantiate a gating mechanism whereby the TRP domain acts as a coupling domain for efficient channel opening. Furthermore, they imply that protein-protein interactions of the TRP domain may be targets for channel modulation and drug intervention.
机译：瞬态受体电位（TRP）通道感知并响应环境和内源线索的能力在动物的感觉生理学中至关重要。通道门控的分子机理尚不清楚。 TRP盒是C末端域N端的保守区域，已被信号指示为TRP通道中的变构激活的关键。在这里，我们检查了TRPM8内门和TRP盒之间的连接区域（称为S6-TRP盒连接器）的作用，以确定通道门控的结构决定因素。用同源的TRPV1通道序列逐步取代TRPM8通道的S6-TRP盒连接子中的片段，产生了功能性嵌合通道，并将Tyr 981 确定为通道功能的中心分子。另外，电压和薄荷醇对986-990区域的突变也对通道门控产生了深远的影响，如电导率与电压（G-V）关系的调制所证明。使用变构模型进行通道激活的G-V曲线模拟显示，这些突变改变了变构常数，该常数将刺激感测与开孔耦合。基于最近报道的TRPV1结构模型的TRPM8分子模型显示，Tyr 981 可能位于S6跨膜段末端的疏水口袋中，并参与亚基与残基的相互作用来自邻居亚单位。 986–990区域保留了TRP域和S4–S5接头之间的亚基内部相互作用。这些发现证实了门控机制，其中TRP域充当有效通道开放的耦合域。此外，他们暗示，TRP域的蛋白质相互作用可能是通道调节和药物干预的目标。

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