Division of Life Science, Molecular Neuroscience Center, State Key Laboratory of Molecular Neuroscience, Hong Kong University of Science and Technology, Clear Water Bay, Kowloon, Hong Kong.
Cell. 2011 Jun 24;145(7):1088-101. doi: 10.1016/j.cell.2011.05.015.
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 ∼330 mV. Acidification, potentially mediated via light and PLCβ-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.
INAD 是一种支架蛋白，可调节果蝇光感受器中的信号转导。它的一个 PDZ 结构域 PDZ5 可响应光在还原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，我们表明 PDZ5 的氧化还原电位通过其与另一个 INAD 结构域 PDZ4 的相互作用被别构调节。虽然分离的 PDZ5 在氧化状态下稳定，但 PDZ45“超模块”的形成通过将其 Cys606/Cys645 二硫键的氧化还原电位提高约 330 mV，将 PDZ5 锁定在还原状态。酸化，可能通过光和 PLCβ 介导的 PIP(2)水解来介导，破坏 PDZ4 与 PDZ5 之间的相互作用，导致 PDZ5 氧化并从 TRP Ca(2+)通道（飞视觉信号的关键组成部分）解离。这些结果表明，支架蛋白可以主动调节其二硫键的固有氧化还原电位，以在信号转导中发挥调节作用。
