The INAD Scaffold Is a Dynamic, Redox-Regulated Modulator of Signaling in the Drosophila Eye
The INAD Scaffold Is a Dynamic, Redox-Regulated Modulator of Signaling in the Drosophila Eye
复制标题
INAD 支架是果蝇眼睛中一种动态的、氧化还原调节的信号调节器
DOI：
10.1016/j.cell.2011.05.015
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发表时间：
2011-06-24
期刊：
影响因子：
64.5
通讯作者：
Zhang, Mingjie
中科院分区：
文献类型：
--
作者：
Liu, Wei;Wen, Wenyu;Zhang, Mingjie
Inad是一种支架蛋白，调节果蝇光感受器中的信号传递。它的PDZ结构域之一，PDZ5，对光的反应在还原形式和氧化形式之间循环，但尚不清楚光如何影响其氧化还原电位。通过生化和结构研究，我们证明了PDZ5的氧化还原电位受其与另一个INAD结构域PDZ4相互作用的变构调节。虽然分离的PDZ5在氧化状态下是稳定的，但PDZ45“超模块”的形成通过提高其Cys606/Cys645二硫键的氧化还原电位而将PDZ5锁定在还原状态，其氧化还原电位与330 mV相似。通过光和PLCβ介导的PIP(2)的酸化，破坏了PDZ4和PDZ5之间的相互作用，导致PDZ5氧化和从Trp Ca(2+)通道解离，Trp Ca(2+)通道是果蝇视觉信号的关键成分。这些结果表明，支架蛋白可以主动调节其二硫键的内在氧化还原电位，在信号传递中发挥调节作用。
INAD is a scaffolding protein that regulates signaling in Drosophila photoreceptors. One of its PDZ domains, PDZ5, cycles between reduced and oxidized forms in response to light, but it is unclear how light affects its redox potential. Through biochemical and structural studies, we show that the redox potential of PDZ5 is allosterically regulated by its interaction with another INAD domain, PDZ4. Whereas isolated PDZ5 is stable in the oxidized state, formation of a PDZ45 "supramodule'' locks PDZ5 in the reduced state by raising the redox potential of its Cys606/Cys645 disulfide bond by similar to 330 mV. Acidification, potentially mediated via light and PLC beta-mediated hydrolysis of PIP(2), disrupts the interaction between PDZ4 and PDZ5, leading to PDZ5 oxidation and dissociation from the TRP Ca(2+) channel, a key component of fly visual signaling. These results show that scaffolding proteins can actively modulate the intrinsic redox potentials of their disulfide bonds to exert regulatory roles in signaling.