Polyglutamine disruption of the huntingtin exon 1 N terminus triggers a complex aggregation mechanism.
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.
Thakur
Ashwani K
AK
Department of Structural Biology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15260, USA.
Jayaraman
Murali
M
Mishra
Rakesh
R
Thakur
Monika
M
Chellgren
Veronique M
VM
Byeon
In-Ja L
IJ
Anjum
Dalaver H
DH
Kodali
Ravindra
R
Creamer
Trevor P
TP
Conway
James F
JF
Gronenborn
Angela M
AM
Wetzel
Ronald
R
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
C086055:HTT protein, human; D000071058:Huntingtin Protein; D046911:Macromolecular Substances; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D010455:Peptides; C097188:polyglutamine