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Abstract
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.
Highlights
Huntington disease (HD)2 is a dominantly inherited disorder caused by the expansion of polyglutamine in exon 1 of the huntingtin (Htt) protein [1]
Cooperative Interaction of the Tandem WW Domains of HYPA with the proline-rich region (PRR) Motif of Htt—It was reported that Htt interacts with HYPA through the N-terminal PRR and the tandem WW domains (Fig. 1A) [24]
To better understand how the tandem WW domains of HYPA interact with the Htt PRR motif, we used GST pulldown experiments to characterize the interactions between N-terminal Htt and different GST-fused WW domains (Fig. 1B)
Summary
Huntington disease (HD)2 is a dominantly inherited disorder caused by the expansion of polyglutamine (polyQ) in exon 1 of the huntingtin (Htt) protein [1]. 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 PRR motif of Htt consists of almost 40 amino acid residues, whereas HYPA contains two WW domains in a tandem array (see Fig. 1A).
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