TRPV4 channel activity is modulated by direct interaction of the ankyrin domain to PI(4,5)P2
TRPV4 channel activity is modulated by direct interaction of the ankyrin domain to PI(4,5)P2
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DOI：
10.1038/ncomms5994
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发表时间：
2014-09-01
影响因子：
16.6
通讯作者：
Suetsugu, Shiro
中科院分区：
文献类型：
--
作者：
Takahashi, Nobuaki;Hamada-Nakahara, Sayaka;Suetsugu, Shiro
TRPV 4的锚蛋白重复结构域（ARD）中的突变是导致几种通道病的原因，包括Charcot-Marie-Tooth病2C型和先天性远端和肩胛腓侧脊髓性肌萎缩症。然而，这些突变介导的分子发病机制仍然难以捉摸，主要是由于对TRPV 4 ARD功能的了解有限。在这里，我们表明，磷酸肌醇结合TRPV 4 ARD导致抑制通道活性。在磷酸肌醇中，磷脂酰肌醇-4，5-二磷酸（PI（4，5）P-2）最有效地结合TRPV 4 ARD。TRPV 4 ARD与肌醇-1，4，5-三磷酸（PI（4，5）P-2的头基）复合的晶体结构和分子动力学模拟揭示了PI（4，5）P-2结合的氨基酸残基。通过滴定或水解膜PI（4，5）P-2增加TRPV 4通道活性。值得注意的是，导致功能获得性表型的疾病相关TRPV 4突变消除了PI（4，5）P-2结合和PI（4，5）P-2敏感性。这些发现将TRPV 4 ARD鉴定为脂质结合结构域，其中与PI（4，5）P-2的相互作用使TRPV 4中的通道活性正常化。
Mutations in the ankyrin repeat domain (ARD) of TRPV4 are responsible for several channelopathies, including Charcot-Marie-Tooth disease type 2C and congenital distal and scapuloperoneal spinal muscular atrophy. However, the molecular pathogenesis mediated by these mutations remains elusive, mainly due to limited understanding of the TRPV4 ARD function. Here we show that phosphoinositide binding to the TRPV4 ARD leads to suppression of the channel activity. Among the phosphoinositides, phosphatidylinositol-4,5-bisphosphate (PI(4,5)P-2) most potently binds to the TRPV4 ARD. The crystal structure of the TRPV4 ARD in complex with inositol-1,4,5-trisphosphate, the head-group of PI(4,5)P-2, and the molecular-dynamics simulations revealed the PI(4,5)P-2-binding amino-acid residues. The TRPV4 channel activities were increased by titration or hydrolysis of membrane PI(4,5)P-2. Notably, disease-associated TRPV4 mutations that cause a gain-of-function phenotype abolished PI(4,5)P-2 binding and PI(4,5)P-2 sensitivity. These findings identify TRPV4 ARD as a lipid-binding domain in which interactions with PI(4,5)P-2 normalize the channel activity in TRPV4.