Journal Article

Huntingtin Interacts with a Family of WW Domain Proteins

Peter W. Faber, Glenn T. Barnes, Jayalakshmi Srinidhi, Jianmin Chen, James F. Gusella and Marcy E. MacDonald

in Human Molecular Genetics

Volume 7, issue 9, pages 1463-1474
Published in print September 1998 | ISSN: 0964-6906
Published online September 1998 | e-ISSN: 1460-2083 | DOI: http://dx.doi.org/10.1093/hmg/7.9.1463
Huntingtin Interacts with a Family of WW Domain Proteins

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The hallmark neuropathology of Huntington's disease (HD) is due to elongation of a polyglutamine segment in huntingtin, a novel ∼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.

Journal Article.  7645 words.  Illustrated.

Subjects: Genetics and Genomics

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