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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Membrane association of myotubularin-related protein 2 is mediated by a pleckstrin homology-GRAM domain and a coiled-coil dimerization module.
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Membrane association of myotubularin-related protein 2 is mediated by a pleckstrin homology-GRAM domain and a coiled-coil dimerization module.

机译：肌微管蛋白相关蛋白2的膜缔合是由pleckstrin同源性-GRAM域和卷曲螺旋二聚化模块介导的。

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摘要

Mutations in the myotubularin (MTM)-related protein 2 (MTMR2) gene are responsible for the severe autosomal recessive neuropathy Charcot-Marie-Tooth disease type 4B1. MTMR2 belongs to the MTM family of dual-specific phosphatases that use phosphatidylinositol (PI) 3,5-bisphosphate [PI(3,5)P2] and PI 3-phosphate [PI(3)P] as their substrate. Because these substrates are localized in the membrane bilayer, membrane targeting of Mtmr2 is an important regulatory mechanism. In hypoosmotically stressed COS cells with increased levels of PI(3,5)P2, Mtmr2 is bound to the membrane of vacuoles formed under these conditions. Using several mutant forms of Mtmr2, we identified two domains that are necessary for membrane association: (i) A pleckstrin homology-GRAM domain; and (ii) a coiled-coil module. Protein-lipid overlay assays show that the pleckstrin homology-GRAM domain binds to PI(3,5)P2 and PI(5)P, a substrate and a product of the Mtmr2 enzyme, respectively. We also demonstrate that Mtmr2 forms a dimer and thatthe C-terminal coiled-coil is responsible for homodimerization, in addition to membrane association. Our data indicate that phosphoinositide-protein interactions, as well as protein-protein interactions, are necessary for the correct regulation of MTMR2.
机译：肌管蛋白（MTM）相关蛋白2（MTMR2）基因的突变是造成严重的常染色体隐性神经病Charcot-Marie-Tooth疾病类型4B1的原因。 MTMR2属于MTM系列的双特异性磷酸酶，其使用磷脂酰肌醇（PI）3,5-双磷酸[PI（3,5）P2]和PI 3-磷酸[PI（3）P]作为底物。由于这些底物位于膜双层中，因此Mtmr2的膜靶向是重要的调节机制。在具有较高水平的PI（3,5）P2的低渗压力COS细胞中，Mtmr2结合到在这些条件下形成的液泡膜上。使用Mtmr2的几种突变形式，我们确定了膜缔合所必需的两个域：（i）pleckstrin同源性-GRAM域； （ii）盘绕线圈模块。蛋白质-脂质覆盖测定表明，pleckstrin同源性-GRAM域分别与PI（3,5）P2和PI（5）P（Mtmr2酶的底物和产物）结合。我们还证明，Mtmr2形成二聚体，C末端卷曲螺旋负责除膜缔合以外的均二聚作用。我们的数据表明，磷酸肌醇-蛋白质相互作用以及蛋白质-蛋白质相互作用对于正确调节MTMR2是必需的。

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