National "111" Center for Cellular Regulation and Molecular Pharmaceutics, Hubei University of Technology, Wuhan, Hubei 430068, China; Membrane Protein Disease Research Group, Department of Physiology, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB T6G 2H7, Canada.
Membrane Protein Disease Research Group, Department of Physiology, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB T6G 2H7, Canada.
Cell Rep. 2018 Feb 6;22(6):1560-1573. doi: 10.1016/j.celrep.2018.01.042.
Transient receptor potential (TRP) channels are regulated by diverse stimuli comprising thermal, chemical, and mechanical modalities. They are also commonly regulated by phosphatidylinositol-4,5-bisphosphate (PIP2), with underlying mechanisms largely unknown. We here revealed an intramolecular interaction of the TRPP3 N and C termini (N-C) that is functionally essential. The interaction was mediated by aromatic Trp81 in pre-S1 domain and cationic Lys568 in TRP-like domain. Structure-function analyses revealed similar N-C interaction in TRPP2 as well as TRPM8/-V1/-C4 via highly conserved tryptophan and lysine/arginine residues. PIP2 bound to cationic residues in TRPP3, including K568, thereby disrupting the N-C interaction and negatively regulating TRPP3. PIP2 had similar negative effects on TRPP2. Interestingly, we found that PIP2 facilitates the N-C interaction in TRPM8/-V1, resulting in channel potentiation. The intramolecular N-C interaction might represent a shared mechanism underlying the gating and PIP2 regulation of TRP channels.
瞬时受体电位 (TRP) 通道受多种刺激调节，包括热、化学和机械方式。它们还通常受磷脂酰肌醇-4,5-二磷酸 (PIP2) 调节，但其潜在机制在很大程度上尚不清楚。我们在这里揭示了 TRPP3 N 和 C 末端（N-C）之间的分子内相互作用，该相互作用在功能上是必不可少的。这种相互作用由前 S1 结构域中的芳香性色氨酸 81 和 TRP 样结构域中的阳离子赖氨酸 568 介导。结构功能分析表明，TRPP2 以及 TRPM8/-V1/-C4 也存在类似的 N-C 相互作用，这是通过高度保守的色氨酸和赖氨酸/精氨酸残基实现的。PIP2 与阳离子残基结合，包括 K568，从而破坏 N-C 相互作用并负调节 TRPP3。PIP2 对 TRPP2 也有类似的负作用。有趣的是，我们发现 PIP2 促进了 TRPM8/-V1 中的 N-C 相互作用，导致通道增强。这种分子内的 N-C 相互作用可能代表了 TRP 通道门控和 PIP2 调节的共同机制。
