Interaction with Polyglutamine-expanded Huntingtin Alters Cellular Distribution and RNA Processing of Huntingtin Yeast Two-hybrid Protein A (HYPA)
Interaction with Polyglutamine-expanded Huntingtin Alters Cellular Distribution and RNA Processing of Huntingtin Yeast Two-hybrid Protein A (HYPA)
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DOI：
10.1074/jbc.m110.216333
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发表时间：
2011-07-15
影响因子：
4.8
通讯作者：
Hu, Hong-Yu
中科院分区：
文献类型：
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作者：
Jiang, Ya-Jun;Che, Mei-Xia;Hu, Hong-Yu
亨廷顿病(HD)是一种常染色体遗传性疾病，导致脑细胞退化。亨廷顿蛋白(Htt)的多聚谷氨酰胺(PolyQ)扩张通过与RNA剪接因子Htt酵母双杂交蛋白A/形成结合蛋白11(HYPA/FBP11)的相互作用参与HD的发病。除了致病多聚Q的扩展外，Htt还含有一个富含脯氨酸的区域(PRR)，该区域正好位于多聚Q区的C末端。然而，多聚Q的扩展如何影响PRR介导的蛋白质相互作用以及这种异常相互作用如何导致生物学后果仍然是未知的。我们的核磁共振结构分析表明，Htt的PRR基序通过WW1在WW2上的结构域伴侣作用于HYPA的串联WW结构域。多聚Q-扩展的Htt将HYPA隔离到胞浆位置，从而显著降低了前mRNA剪接的效率。我们认为，多聚Q扩展的Htt的毒性功能增强导致细胞RNA处理功能障碍，参与了HD的发病机制。
Huntington disease (HD) is an autosomal inherited disorder that causes the deterioration of brain cells. The polyglutamine (polyQ) expansion of huntingtin (Htt) is implicated in the pathogenesis of HD via interaction with an RNA splicing factor, Htt yeast two-hybrid protein A/forming-binding protein 11 (HYPA/FBP11). Besides the pathogenic polyQ expansion, Htt also contains a proline-rich region (PRR) located exactly in the C terminus to the polyQ tract. However, how the polyQ expansion influences the PRR-mediated protein interaction and how this abnormal interaction leads to the biological consequence remain elusive. Our NMR structural analysis indicates that the PRR motif of Htt cooperatively interacts with the tandem WW domains of HYPA through domain chaperoning effect of WW1 on WW2. The polyQ-expanded Htt sequesters HYPA to the cytosolic location and then significantly reduces the efficiency of pre-mRNA splicing. We propose that the toxic gain-of-function of the polyQ-expanded Htt that causes dysfunction of cellular RNA processing contributes to the pathogenesis of HD.