Charge within Nt17 peptides modulates huntingtin aggregation and initial lipid binding events

Biophys Chem. 2023 Oct 12;303:107123. doi: 10.1016/j.bpc.2023.107123. Online ahead of print.ABSTRACTToxic aggregation of pathogenic huntingtin protein (htt) is implicated in Huntington's disease and influenced by various factors, including the first seventeen amino acids at the N-terminus (Nt17) and the presence of lipid membranes. Nt17 has a propensity to form an amphipathic α-helix in the presence of binding partners, which promotes α-helix rich oligomer formation and facilitates htt/lipid interactions. Within Nt17 are multiple sites that are subject to post-translational modification, including acetylation and phosphorylation. Acetylation can occur at lysine 6, 9, and/or 15 while phosphorylation can occur at threonine 3, serine 13, and/or serine 16. Such modifications impact aggregation and lipid binding through the alteration of various intra- and intermolecular interactions. When incubated with htt-exon1(46Q), free Nt17 peptides containing point mutations mimicking acetylation or phosphorylation reduced fibril formation and altered oligomer morphologies. Upon exposure to lipid vesicles, changes to peptide/lipid complexation were observed and peptide-containing oligomers demonstrated reduced lipid interactions.PMID:37852163 | DOI:10.1016/j.bpc.2023.107123
Source: Biophysical Chemistry - Category: Chemistry Authors: Source Type: research