(544g) Elucidating the Role of N-Terminal Huntingtin Fragment in Polyglutamine Aggregation

Huntington's disease is cause by the aggregation of poly-glutamine (35-40 residues) repeats forming toxic fibrils in the neuronal cells leading to the cell death. These repeats are attached at the N-terminal of the Huntingtin protein. It has been shown that the in the presence of the 17 residues N-terminal fragment, N17 of the Huntingtin protein, the poly-glutamine repeats aggregate faster. Several mechanisms have been proposed to explain the role of N17 fragment including poly-glutamine induced unfolding of N17 (Williamson et. al., J. Mol. Bio., 2010) or a conformational change in N17 to expose hydrophobic residues (Dlugosz et. al., J. Phys. Chem. B, 2010) leading to the N17 aggregation. Aggregation of N17 fragment brings the poly-glutamine repeats closer and induces the fibril formation. Furthermore, phosphorylation of serine residues in N17 leads to changes in conformation and toxicity (Atwal et. al., Nat. Chem. Biol., 2011) In this talk, we report results from an extensive molecular dynamics simulations of both the phosphorylated and unphosphorylated N17 fragment of Huntingtin protein along with pathogenic (35 residues) and non-pathogenic poly-glutamine repeats (15 residues) to understand the influence of polyglutamine repeats on the conformational preferences of the N17 fragment and viceversa.