Modulation of Polyglutamine Conformations and Associations by C-Terminal Proline Rich Regions from Exon 1 of Huntingtin

Abstract

Huntington's disease (HD) is associated with CAG repeats within exon 1 that lead to polyglutamine (polyQ) expansions in the protein huntingtin (htt). Proteolysis of htt leads to products that can be trafficked into the nucleus and form neuronal intranuclear inclusions. The presence / absence of flanking sequences namely, the N-terminal 17-residue amphipathic stretch (Nt17h-htt) and the C-terminal 38-residue proline-rich stretch (Ct38h-htt) in products of proteolysis have a profound effect on the HD phenotype in animal models (where h-htt denotes human-htt). The biophysical basis for the effects of these flanking sequences remains unresolved. Here, we focus on the influence of different proline-rich C-terminal sequences on the conformations of and intermolecular associations through the polyQ tract. The flanking sequences include Ct38h-htt and Ct31m-htt (the mouse 31-residue C-terminal proline-rich region).We used atomistic simulations based on the ABSINTH implicit solvation model and underlying forcefield paradigm to quantify the nature of the coupling between C-terminal flanking sequences and polyQ tracts for different polyQ lengths. There are clear differences between the intrinsic and context dependent properties of Ct31m-htt and Ct38h-htt. Detailed analyses of the monomer conformations and intermolecular associations of polyQ in cis with different synthetic and naturally occurring C-terminal proline-rich stretches identify how flanking sequences modulate aggregation mechanisms. These results might be important for recent studies in animal models that show different toxicity profiles between transgenic animals expressing different C-terminal proline-rich sequences.This work was supported by grant 5R01NS056114 from the National Institutes of Health.