Printor, a Novel TorsinA-interacting Protein Implicated in Dystonia Pathogenesis
Printor, a Novel TorsinA-interacting Protein Implicated in Dystonia Pathogenesis
复制标题
DOI：
10.1074/jbc.m109.004838
复制
发表时间：
2009-08-07
影响因子：
4.8
通讯作者：
Chin, Lih-Shen
中科院分区：
文献类型：
--
作者：
Giles, Lisa M.;Li, Lian;Chin, Lih-Shen
早发性全身性肌张力障碍（DYT 1）是一种常染色体显性遗传神经系统疾病，由AAA（+）（与多种细胞活动相关的ATP酶）蛋白torsinA C-末端区域的单个谷氨酸残基（torsinA Delta E）缺失引起。torsinA Delta E突变导致肌张力障碍的致病机制尚不清楚。在这里，我们报告的628个氨基酸的新蛋白质，打印机，与torsinA相互作用的鉴定和表征。打印机共分布与torsinA在多个脑区和共定位与torsinA在内质网。有趣的是，打印机选择性地结合到ATP-自由形式，但不是ATP-结合形式的torsinA，支持打印机作为辅因子，而不是基板的torsinA的作用。张力障碍相关的torsinA Delta E突变完全消除了printor与torsinA的相互作用。我们的研究结果表明，打印机是DYT 1致病途径的一个新的组成部分，并为肌张力障碍的治疗干预提供了一个潜在的分子靶点。
Early onset generalized dystonia (DYT1) is an autosomal dominant neurological disorder caused by deletion of a single glutamate residue (torsinA Delta E) in the C-terminal region of the AAA(+) (ATPases associated with a variety of cellular activities) protein torsinA. The pathogenic mechanism by which torsinA Delta E mutation leads to dystonia remains unknown. Here we report the identification and characterization of a 628-amino acid novel protein, printor, that interacts with torsinA. Printor co-distributes with torsinA in multiple brain regions and colocalizes with torsinA in the endoplasmic reticulum. Interestingly, printor selectively binds to the ATP-free form but not to the ATP-bound form of torsinA, supporting a role for printor as a cofactor rather than a substrate of torsinA. The interaction of printor with torsinA is completely abolished by the dystonia-associated torsinA Delta E mutation. Our findings suggest that printor is a new component of the DYT1 pathogenic pathway and provide a potential molecular target for therapeutic intervention in dystonia.