Disordered Motifs and Domains in Cell Control - October 11-15, 2014

Disordered Motifs and Domains in Cell Control Wednesday Speaker Abstracts

Modulation of Huntingtin Exon 1 Interactions through Synergy between Polyglutamine Tracts and Flanking Sequence Motifs Rohit V. Pappu . Washington University in St. Louis, St. Louis, USA. Polyglutamine expansions in the huntingtin protein cause Huntington’s disease. N- and C- terminal segments that include a 17-residue amphipathic stretch N17 and a 38-residue proline- stretch C38 flank the polyglutamine tract in huntingtin. Mutant transcripts of the huntingtin gene are aberrantly spliced and yield toxic N-terminal fragments that span the exon 1 encoded region of huntingtin. Our in vitro biophysical and computational studies demonstrate that N17 and C38 act as gatekeeping linear sequence motifs. They modulate the driving forces for and mechanisms of polyglutamine-mediated aggregation of exon 1 spanning fragments of huntingtin. Additionally, C38 interacts directly with profilin and its affinity for profilin is enhanced by polyglutamine-mediated aggregation. Our results come from a combination of in vitro, in silico, and in cell investigations. They highlight the importance of polyglutamine aggregation-mediated enhancement in C38-proflin interactions for wild type polyglutamine lengths. These results also suggest a model for the interplay between protein-aggregation that has functional relevance for wild type polyglutamine lengths versus pathological aggregation for expanded polyglutamine tracts.

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