The Phospholipid-binding Protein SESTD1 Is a Novel Regulator of the Transient Receptor Potential Channels TRPC4 and TRPC5
The Phospholipid-binding Protein SESTD1 Is a Novel Regulator of the Transient Receptor Potential Channels TRPC4 and TRPC5
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DOI：
10.1074/jbc.m109.068304
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发表时间：
2010-04-16
影响因子：
4.8
通讯作者：
Struebing, Carsten
中科院分区：
文献类型：
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作者：
Miehe, Susanne;Bieberstein, Andrea;Struebing, Carsten
TRPC 4和TRPC 5是哺乳动物瞬时受体电位阳离子通道家族的两个密切相关的成员，其涉及重要的生理功能，例如生长锥引导和平滑肌收缩。为了进一步阐明TRPC 4和TRPC 5在体内这些过程中的作用，需要关于天然通道复合物的分子组成及其与细胞信号网络的关联的详细信息。因此，我们使用改良的酵母双杂交法在人主动脉cDNA文库中寻找新的TRPC 4相互作用蛋白。该筛选鉴定了SESTD 1，一种先前未表征的蛋白质，其含有脂质结合SEC 14样结构域以及血影蛋白型细胞骨架相互作用结构域。SESTD 1被发现通过通道的钙调素和肌醇1，4，5-三磷酸受体结合结构域与TRPC 4和TRPC 5结合。在功能研究中，我们证明了SESTD 1在体外结合几种磷脂物质，并且对于TRPC 5的有效受体介导的活化是必不可少的。值得注意的是，磷脂结合SESTD 1是Ca 2+依赖性的。由于TRPC 4和-5传导Ca 2+，SESTD 1通道信号可能是双向的，并且还通过SESTD 1将TRPC活性偶联到脂质信号。TRPC通道功能的调制由特定的脂质结合蛋白，如SESTD 1，增加了另一个方面，这些通道的复杂的调节互补的直接通道-磷脂相互作用的影响，前面描述的。
TRPC4 and TRPC5 are two closely related members of the mammalian transient receptor potential cation channel family that have been implicated in important physiological functions, such as growth cone guidance and smooth muscle contraction. To further unravel the role of TRPC4 and TRPC5 in these processes in vivo, detailed information about the molecular composition of native channel complexes and their association with cellular signaling networks is needed. We therefore searched a human aortic cDNA library for novel TRPC4-interacting proteins using a modified yeast two-hybrid assay. This screen identified SESTD1, a previously uncharacterized protein containing a lipid-binding SEC14-like domain as well as spectrin-type cytoskeleton interaction domains. SESTD1 was found to associate with TRPC4 and TRPC5 via the channel's calmodulin-and inositol 1,4,5-trisphosphate receptor-binding domain. In functional studies, we demonstrate that SESTD1 binds several phospholipid species in vitro and is essential for efficient receptor-mediated activation of TRPC5. Notably, phospholipid binding to SESTD1 was Ca2+-dependent. Because TRPC4 and -5 conduct Ca2+, SESTD1-channel signaling may be bidirectional and also couple TRPC activity to lipid signaling through SESTD1. The modulation of TRPC channel function by specific lipid-binding proteins, such as SESTD1, adds another facet to the complex regulation of these channels complementary to the previously described effects of direct channel-phospholipid interaction.