A Unique Redox-sensing Sensor II Motif in TorsinA Plays a Critical Role in Nucleotide and Partner Binding*
A Unique Redox-sensing Sensor II Motif in TorsinA Plays a Critical Role in Nucleotide and Partner Binding*
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DOI：
10.1074/jbc.m110.123471
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发表时间：
2010-09
期刊：
影响因子：
--
通讯作者：
Li Zhu;L. Millen;J. Mendoza;P. Thomas
中科院分区：
文献类型：
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作者：
Li Zhu;L. Millen;J. Mendoza;P. Thomas
早发性肌张力障碍通常与位于内质网管腔的AAA+蛋白家族（与多种细胞活动相关的atp酶）成员torsinA C端附近的一对谷氨酸残基中的一个（ΔE302/303）的缺失有关。致病突变ΔE的功能后果目前尚不清楚。与其他AAA+蛋白相比，torsin蛋白在c端结构域含有两个保守的半胱氨酸残基，其中一个位于核苷酸传感器II基序中。根据氧化还原状态，torsinA的ATP水解突变体与层相关多肽1 （LAP1）和管腔结构域如LAP1 （LULL1）相互作用。传感器II中半胱氨酸的替代减少了氧化还原调节的torsinA与这些底物的相互作用。值得注意的是，引起肌张力障碍的突变ΔE改变了torsinA介导氧化还原调节的与LAP1和LULL1相互作用的能力。有限的蛋白水解实验揭示了torsinA局部构象的氧化还原和突变依赖变化是核苷酸结合的功能。这些结果表明，含半胱氨酸的传感器II在氧化还原传感、torsinA的核苷酸和伴侣结合功能中起着关键作用，并表明torsinA的这种功能的丧失有助于DYT1肌张力障碍的发展。
Early onset dystonia is commonly associated with the deletion of one of a pair of glutamate residues (ΔE302/303) near the C terminus of torsinA, a member of the AAA+ protein family (ATPases associated with a variety of cellular activities) located in the endoplasmic reticulum lumen. The functional consequences of the disease-causing mutation, ΔE, are not currently understood. By contrast to other AAA+ proteins, torsin proteins contain two conserved cysteine residues in the C-terminal domain, one of which is located in the nucleotide sensor II motif. Depending on redox status, an ATP hydrolysis mutant of torsinA interacts with lamina-associated polypeptide 1 (LAP1) and lumenal domain like LAP1 (LULL1). Substitution of the cysteine in sensor II diminishes the redox-regulated interaction of torsinA with these substrates. Significantly, the dystonia-causing mutation, ΔE, alters the ability of torsinA to mediate the redox-regulated interactions with LAP1 and LULL1. Limited proteolysis experiments reveal redox- and mutation-dependent changes in the local conformation of torsinA as a function of nucleotide binding. These results indicate that the cysteine-containing sensor II plays a critical role in redox sensing and the nucleotide and partner binding functions of torsinA and suggest that loss of this function of torsinA contributes to the development of DYT1 dystonia.