%0 Journal Article
%T Phosphorylation of the Nt17 Domain of Htt Influences its Interaction with Model Lipid Membranes
%J -
%D 2019
%R https://doi.org/10.1016/j.bpj.2018.11.2009
%X Huntington disease (HD) is an autosomal dominant genetic neurodegenerative disease caused by abnormally long (>35) CAG-repeats in the huntingtin gene. This mutation encodes an expanded polyglutamine (polyQ) domain in the N-terminus of the huntingtin protein (htt) which directly facilitates its aggregation. The first 17 amino acids (Nt17) of htt can form an amphipathic ¦Á-helix that facilitates lipid binding. In addition to lipid binding, Nt17 self-associates as an initial step in htt aggregation. Phosphorylation of Nt17 modulates htt's toxicity, sub-cellular localization, trafficking, and propensity to aggregate. To determine how phosphorylation alters htt aggregation on lipid membranes, phosphomimetic mutations (T3D, S13D, and S16D) were introduced into a htt-exon1 construct with 46Q. The impact of these mutations on htt aggregation in the presence and absence of model lipid bilayers were evaluated through atomic force microscopy (AFM), thioflavin T (ThT), and polydiacteylene (PDA) lipid binding assays. N-terminal htt phosphorylation retarded fibril formation, promoting formation of larger globular aggregates in the absence of lipid. Phosphomimetic mutations increased the affinity of htt for lipid membranes compared to wild type, and influenced the morphological features of htt aggregation on supported bilayers. These results suggest that phosphorylation modulates the aggregation of htt at lipid interfaces with potential implications for HD
%U https://www.cell.com/biophysj/fulltext/S0006-3495(18)33274-0