Faber P W, Barnes G T, Srinidhi J, Chen J, Gusella J F, MacDonald M E
Molecular Neurogenetics Unit, Massachusetts General Hospital East, Building 149, 13th Street, Charlestown, MA 02129, USA.
Hum Mol Genet. 1998 Sep;7(9):1463-74. doi: 10.1093/hmg/7.9.1463.
The hallmark neuropathology of Huntington's disease (HD) is due to elongation of a polyglutamine segment in huntingtin, a novel approximately 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, HYPB 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 HYPB 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.
亨廷顿舞蹈病（HD）的标志性神经病理学特征是由于亨廷素中多聚谷氨酰胺片段的延长，亨廷素是一种功能未知的约350 kDa的新型蛋白质。我们利用酵母双杂交相互作用分子筛选来鉴定那些在致病过程中与亨廷素的结合可能发生改变的蛋白质。令人惊讶的是，未发现与亨廷素的内部和C末端片段相互作用的分子。相反，亨廷素的N末端检测到13种不同的蛋白质，其中7种是新发现的，6种是先前已报道的。在这些蛋白质中，我们鉴定出一个主要的相互作用分子类别，包括三种不同的WW结构域蛋白，即HYPA、HYPB和HYPC，它们在HD淋巴母细胞提取物中与正常和突变型亨廷素结合。这种相互作用由亨廷素富含脯氨酸的区域介导，并通过延长相邻的谷氨酰胺序列而增强。虽然HYPB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质。这类蛋白质作为亨廷素的相互作用伙伴的出现表明，一个由WW结构域介导的过程，如非受体信号传导、蛋白质降解或前体mRNA剪接，可能参与了HD的发病机制。
