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.
- 48 -
