title: Polyglutamine disruption of the huntingtin exon 1 N terminus triggers a complex aggregation mechanism.
abstract: Simple polyglutamine (polyQ) peptides aggregate in vitro via a nucleated growth pathway directly yielding amyloid-like aggregates. We show here that the 17-amino-acid flanking sequence (HTT(NT)) N-terminal to the polyQ in the toxic huntingtin exon 1 fragment imparts onto this peptide a complex alternative aggregation mechanism. In isolation, the HTT(NT) peptide is a compact coil that resists aggregation. When polyQ is fused to this sequence, it induces in HTT(NT), in a repeat-length dependent fashion, a more extended conformation that greatly enhances its aggregation into globular oligomers with HTT(NT) cores and exposed polyQ. In a second step, a new, amyloid-like aggregate is formed with a core composed of both HTT(NT) and polyQ. The results indicate unprecedented complexity in how primary sequence controls aggregation within a substantially disordered peptide and have implications for the molecular mechanism of Huntington's disease.
authors.affiliation: Department of Structural Biology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15260, USA.
authors.forename: Ashwani K
authors.initials: AK
authors.lastname: Thakur
authors.forename: Murali
authors.initials: M
authors.lastname: Jayaraman
authors.forename: Rakesh
authors.initials: R
authors.lastname: Mishra
authors.forename: Monika
authors.initials: M
authors.lastname: Thakur
authors.forename: Veronique M
authors.initials: VM
authors.lastname: Chellgren
authors.forename: In-Ja L
authors.initials: IJ
authors.lastname: Byeon
authors.forename: Dalaver H
authors.initials: DH
authors.lastname: Anjum
authors.forename: Ravindra
authors.initials: R
authors.lastname: Kodali
authors.forename: Trevor P
authors.initials: TP
authors.lastname: Creamer
authors.forename: James F
authors.initials: JF
authors.lastname: Conway
authors.forename: Angela M
authors.initials: AM
authors.lastname: Gronenborn
authors.forename: Ronald
authors.initials: R
authors.lastname: Wetzel
mesh_terms: D002942:Circular Dichroism; D006801:Humans; D000071058:Huntingtin Protein; D007700:Kinetics; D046911:Macromolecular Substances / Q000378:metabolism; D009682:Magnetic Resonance Spectroscopy; D046529:Microscopy, Electron, Transmission; D008954:Models, Biological; D009419:Nerve Tissue Proteins / Q000737:chemistry / Q000378:metabolism* / Q000648:ultrastructure; D009687:Nuclear Proteins / Q000737:chemistry / Q000378:metabolism* / Q000648:ultrastructure; D010455:Peptides / Q000138:chemical synthesis / Q000378:metabolism*; D011485:Protein Binding; D011487:Protein Conformation; D055503:Protein Multimerization
chemical_list: C086055:HTT protein, human; D000071058:Huntingtin Protein; D046911:Macromolecular Substances; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D010455:Peptides; C097188:polyglutamine