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PEDS Advance Access published online on July 9, 2009
Protein Engineering Design and Selection, doi:10.1093/protein/gzp033
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© The Author 2009. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oxfordjournals.org

Review

Multi-domain misfolding: understanding the aggregation pathway of polyglutamine proteins

Helen M. Saunders and Stephen P. Bottomley1

Department of Biochemistry and Molecular Biology, Monash University, Clayton, VIC 3800, Australia

1 To whom correspondence should be addressed. E-mail: steve.bottomley{at}med.monash.edu.au

The polyglutamine (polyQ) diseases consist of nine neurodegenerative diseases in which a polyQ tract expansion leads to protein misfolding and subsequent aggregation. Even when the causative proteins have the same length polyQ tract, there are differences in the severity and age of disease onset which implicate the polyQ flanking sequences as modulators of disease. Recent studies on the polyQ proteins ataxin-1, ataxin-3 and huntingtin exon-1 have shown that the flanking domains have an intrinsic ability to aggregate. This complex behavior leads to a multi-stage aggregation mechanism which we have termed multi-domain misfolding. In multi-domain misfolding, a flanking domain to the polyQ tract plays an early role in aggregation, before the contribution of the polyQ tract. A number of factors including the stability, dynamics and amyloidogenicity of the flanking domain modulate the impact on polyQ tract aggregation as well as any protein–protein interactions it undertakes. In this review, we examine the recent data in support of this novel mechanism of protein aggregation.

Keywords: aggregation/ataxin-3/polyglutamine repeat/protein misfolding

Received June 4, 2009; revised June 4, 2009; accepted June 7, 2009.


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