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PMID: 19270701 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, Non-P.H.S.

Polyglutamine disruption of the huntingtin exon 1 N terminus triggers a complex aggregation mechanism.

Nature structural & molecular biology ·Vol. 16 ·No. 4 ·2009-04-00 ·Pages 380-9

Thakur AK, Jayaraman M, Mishra R, Thakur M, Chellgren VM, Byeon IJ, Anjum DH, Kodali R, Creamer TP, Conway JF, Gronenborn AM, Wetzel R

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.

MeSH Terms
Circular Dichroism Humans Huntingtin Protein Kinetics Macromolecular Substances/metabolism Magnetic Resonance Spectroscopy Microscopy, Electron, Transmission Models, Biological Nerve Tissue Proteins/chemistry,metabolism,ultrastructure Nuclear Proteins/chemistry,metabolism,ultrastructure Peptides/chemical synthesis,metabolism Protein Binding Protein Conformation Protein Multimerization
Chemicals
HTT protein, human Huntingtin Protein Macromolecular Substances Nerve Tissue Proteins Nuclear Proteins Peptides polyglutamine
Authors & Affiliations
12 authors, click to expand affiliations / ORCID
Thakur Ashwani K
Department of Structural Biology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15260, USA.
Jayaraman Murali
Mishra Rakesh
Thakur Monika
Chellgren Veronique M
Byeon In-Ja L
Anjum Dalaver H
Kodali Ravindra
Creamer Trevor P
Conway James F
Gronenborn Angela M
Wetzel Ronald
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Article Info
Journal
Nature structural & molecular biology
Abbr.
Nat Struct Mol Biol
ISSN
1545-9985
DOI
10.1038/nsmb.1570
Published
2009-04-00
Epub
2009-00-08
Pages
380-9
Language
English
Region
United States
NLM ID
101186374
PMCID
PMC2706102
Subset
IM
Grants
NIA NIH HHS · R01 AG019322 · United States
NIA NIH HHS · R01 AG019322-08 · United States
External Links
PubMed source DOI: 10.1038/nsmb.1570 PMC Full Text View journal details
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