Toxic PRn poly-dipeptides encoded by the C9orf72 repeat expansion block nuclear import and export
Toxic PRn poly-dipeptides encoded by the C9orf72 repeat expansion block nuclear import and export
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DOI：
10.1073/pnas.1620293114
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发表时间：
2017-02-14
影响因子：
11.1
通讯作者：
McKnight, Steven L.
中科院分区：
文献类型：
--
作者：
Shi, Kevin Y.;Mori, Eiichiro;McKnight, Steven L.
有毒的脯氨酸：由C9 orf 72型遗传性肌萎缩侧索硬化症（ALS）中的（GGGGCC）（n）重复扩增编码的精氨酸（PRn）聚二肽与核孔的中央通道结合并抑制大分子进出核的运动。PRn多聚二肽与苯丙氨酸：甘氨酸（FG）重复结构域的聚合形式结合，该结构域由核孔复合物的几种蛋白质（包括中央通道中的蛋白质）共享。使用化学足迹法来表征由Nup 54蛋白的FG结构域形成的不稳定的交叉β聚合物。Nup 54聚合物足迹区域内的突变阻断了聚合和PRn聚二肽的结合。脂肪醇1，6-己二醇在体外熔化FG结构域聚合物并逆转PRn介导的核孔渗透性屏障增强。这些数据表明，PRn聚二肽的毒性部分是由于其将核孔蛋白的FG重复锁定在聚合状态的能力。我们的研究提供了一个机制的解释PRn聚二肽毒性的背景下，一个突出的形式ALS。
The toxic proline: arginine (PRn) poly-dipeptide encoded by the (GGGGCC) (n) repeat expansion in the C9orf72 form of heritable amyotrophic lateral sclerosis (ALS) binds to the central channel of the nuclear pore and inhibits the movement of macromolecules into and out of the nucleus. The PRn poly-dipeptide binds to polymeric forms of the phenylalanine: glycine (FG) repeat domain, which is shared by several proteins of the nuclear pore complex, including those in the central channel. A method of chemical foot-printing was used to characterize labile, cross-beta polymers formed from the FG domain of the Nup54 protein. Mutations within the footprinted region of Nup54 polymers blocked both polymerization and binding by the PRn poly-dipeptide. The aliphatic alcohol 1,6-hexanediol melted FG domain polymers in vitro and reversed PRn-mediated enhancement of the nuclear pore permeability barrier. These data suggest that toxicity of the PRn poly-dipeptide results in part from its ability to lock the FG repeats of nuclear pore proteins in the polymerized state. Our study offers a mechanistic interpretation of PRn poly-dipeptide toxicity in the context of a prominent form of ALS.