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.
SciCrunch is a data sharing and display platform. Anyone can create a custom portal where they can select searchable subsets of hundreds of data sources, brand their web pages and create their community. SciCrunch will push data updates automatically to all portals on a weekly basis. User communities can also add their own data to scicrunch, however this is not currently a free service.