title: Huntingtin disrupts lipid bilayers in a polyQ-length dependent manner.
abstract: Huntington's Disease (HD) is a neurodegenerative disorder that is defined by the accumulation of nanoscale aggregates comprised of the huntingtin (htt) protein. Aggregation is directly caused by an expanded polyglutamine (polyQ) domain in htt, leading to a diverse population of aggregate species, such as oligomers, fibrils, and annular aggregates. Furthermore, the length of this polyQ domain is directly related to onset and severity of disease. The first 17 N-terminal amino acids of htt have been shown to further modulate aggregation. Additionally, these 17 amino acids appear to have lipid binding properties as htt interacts with a variety of membrane-containing structures present in cells, such as organelles, and interactions with these membrane surfaces may further modulate htt aggregation. To investigate the interaction between htt exon1 and lipid bilayers, in situ atomic force microscopy (AFM) was used to directly monitor the aggregation of htt exon1 constructs with varying Q-lengths (35Q, 46Q, 51Q, and myc-53Q) on supported lipid membranes comprised of total brain lipid extract. The exon1 fragments accumulated on the lipid membranes, causing disruption of the membrane, in a polyQ dependent manner. Furthermore, the addition of an N-terminal myc-tag to the htt exon1 fragments impeded the interaction of htt with the bilayer.
authors: The C. Eugene Bennett Department of Chemistry, West Virginia University, Morgantown, WV 26505, USA.
authors: Kathleen A
authors: KA
authors: Burke
authors: Kaitlin M
authors: KM
authors: Hensal
authors: C Samuel
authors: CS
authors: Umbaugh
authors: Maxmore
authors: M
authors: Chaibva
authors: Justin
authors: J
authors: Legleiter
mesh_terms: D005091:Exons / Q000235:genetics; D006801:Humans; D000071058:Huntingtin Protein; D008051:Lipid Bilayers / Q000737:chemistry / Q000378:metabolism*; D008563:Membrane Lipids / Q000737:chemistry / Q000378:metabolism*; D018625:Microscopy, Atomic Force; D008958:Models, Molecular; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D010455:Peptides / Q000378:metabolism*; D011485:Protein Binding; D055503:Protein Multimerization; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: C086055:HTT protein, human; D000071058:Huntingtin Protein; D008051:Lipid Bilayers; D008563:Membrane Lipids; D009419:Nerve Tissue Proteins; D010455:Peptides; D011993:Recombinant Fusion Proteins; C097188:polyglutamine