Direct Binding between Pre-S1 and TRP-like Domains in TRPP Channels Mediates Gating and Functional Regulation by PIP2.
Direct Binding between Pre-S1 and TRP-like Domains in TRPP Channels Mediates Gating and Functional Regulation by PIP2.
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TRPP 通道中 Pre-S1 和 TRP 样结构域之间的直接结合介导 PIP2 的门控和功能调节。
DOI：
10.1016/j.celrep.2018.01.042
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发表时间：
2018-02-06
期刊：
影响因子：
8.8
通讯作者：
Chen XZ
中科院分区：
文献类型：
--
作者：
Zheng W;Cai R;Hofmann L;Nesin V;Hu Q;Long W;Fatehi M;Liu X;Hussein S;Kong T;Li J;Light PE;Tang J;Flockerzi V;Tsiokas L;Chen XZ
瞬时受体电位（TRP）通道受包括热、化学和机械形式的多种刺激调节。它们也通常由磷脂酰肌醇-4，5-二磷酸（PIP 2）调节，其潜在机制在很大程度上未知。我们在这里揭示了TRPP 3 N和C末端（N-C）的分子内相互作用，这是功能上必不可少的。前S1区的芳香族Trp 81和TRP样区的阳离子Lys 568介导了这种相互作用。结构-功能分析显示TRPP 2和TRPM 8/-V1/-C4通过高度保守的色氨酸和赖氨酸/精氨酸残基进行类似的N-C相互作用。PIP 2与TRPP 3中的阳离子残基结合，包括K568，从而破坏N-C相互作用并负调节TRPP 3。PIP 2对TRPP 2也有类似的负面影响。有趣的是，我们发现PIP 2促进TRPM 8/-V1中的N-C相互作用，导致通道增强。分子内N-C相互作用可能代表TRP通道门控和PIP 2调节的共同机制。Zheng等人表明，前S1中的芳香族Trp残基和TRP多囊蛋白通道的TRP样结构域中的阳离子Lys残基介导N-C结合，这是TRPPs门控和PIP 2调节的基础。这些残基的保守性表明，这可能是TRP通道门控的一个共同机制。
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. Zheng et al. show that an aromatic Trp residue in pre-S1 and a cationic Lys residue in the TRP-like domain of TRP polycystin channels mediate N-C binding, which underlies TRPPs gating and PIP2 regulation. The conservation of these residues suggests that this may be a shared mechanism of TRP channel gating.
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影响因子：
64.8
作者：
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