Huntingtin interacts with a family of WW domain proteins
Huntingtin interacts with a family of WW domain proteins
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DOI：
10.1093/hmg/7.9.1463
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发表时间：
1998-09-01
影响因子：
3.5
通讯作者：
MacDonald, ME
中科院分区：
文献类型：
--
作者：
Faber, PW;Barnes, GT;MacDonald, ME
亨廷顿氏病（HD）的标志性神经病理学是由于亨廷顿蛋白中聚谷氨酰胺片段的延伸，这是一种类似于功能未知的350 kDa蛋白的新蛋白。我们使用酵母双杂交相互作用筛选来鉴定在致病过程中可能改变与亨廷顿蛋白关联的蛋白。令人惊讶的是，在亨廷顿蛋白的内部和c端没有发现相互作用物，相反，亨廷顿蛋白的n端检测到13种不同的蛋白质，其中7种是新的，6种是以前报道的。在这些相互作用物中，我们发现了一个主要的相互作用物类，包括三种不同的WW结构域蛋白，HYPA， HYPE和HYPC，它们与HD淋巴母细胞样细胞提取物中的正常和突变亨廷顿蛋白结合。这种相互作用是由亨廷顿蛋白富含脯氨酸的区域介导的，并通过延长邻近的谷氨酰胺束而增强。尽管HYPE和HYPC是新发现的，但HYPA是人类FBP-11，一种与剪接体功能有关的蛋白。这类蛋白作为亨廷顿蛋白的伴侣蛋白的出现表明，WW结构域介导的过程，如非受体信号传导、蛋白降解或mrna前剪接，可能参与了HD的发病机制。
The hallmark neuropathology of Huntington's disease (HD) is due to elongation of a polyglutamine segment in huntingtin, a novel similar to 350 kDa protein of unknown function. We used a yeast two-hybrid interactor screen to identify proteins whose association with huntingtin might be altered in the pathogenic process. Surprisingly, no interactors were found with internal and C-terminal segments of huntingtin, In contrast, huntingtin's N-terminus detected 13 distinct proteins, seven novel and six reported previously, Among these, we identified a major interactor class, comprising three distinct WW domain proteins, HYPA, HYPE and HYPC, that bind normal and mutant huntingtin in extracts of HD lymphoblastoid cells. This interaction is mediated by huntingtin's proline-rich region and is enhanced by lengthening the adjacent glutamine tract. Although HYPE and HYPC are novel, HYPA is human FBP-11, a protein implicated in spliceosome function, The emergence of this class of proteins as huntingtin partners argues that a WW domain-mediated process, such as non-receptor signaling, protein degradation or pre-mRNA splicing, may participate in HD pathogenesis.