eCite Digital Repository

The structural impact of a polyglutamine tract is location dependent


Robertson, AJ and Horne, HJ and Ellisdon, AM and Thomas, B and Scanlon, MJ and Bottomley, SP, The structural impact of a polyglutamine tract is location dependent, Biophysical Journal, 95, (1) pp. 5922-5930 . ISSN 0006-3495 (2008) [Refereed Article]

DOI: doi:10.1529/biophysj.108.138487


Polyglutamine (polyQ) expansion leads to protein aggregation and neurodegeneration in Huntington's disease and eight other inherited neurological conditions. Expansion of the polyQ tract beyond a threshold of 37 glutamines leads to the formation of toxic nuclear aggregates, therefore suggesting that polyQ expansion causes a conformational change within the protein the nature of which is unclear. There is a trend in the disease proteins that the polyQ tract is located external to, but not within a structured domain. We have created a model polyQ protein, in which the repeat location mimics the flexible environment of the polyQ tract in the disease proteins. Our model protein recapitulates the aggregation features observed with the clinical proteins, and allows structural characterization. Using NMR spectroscopy and a range of biophysical techniques we demonstrate that polyQ expansion into the pathological range has no effect on the structure, dynamics and stability of a domain adjacent to the polyQ tract. To explore the clinical significance of repeat location we engineered a variant of the model protein with a polyQ tract within the domain, a location that does not mimic physiological context, demonstrating significant destabilization and structural perturbation. These different effects highlight the importance of repeat location. We conclude that protein misfolding within the polyQ tract itself is the driving force behind the key characteristics of polyQ disease and that structural perturbation of flanking domains is not required.

Item Details

Item Type:Refereed Article
Keywords:polyglutamine tract nmr
Research Division:Biological Sciences
Research Group:Biochemistry and cell biology
Research Field:Structural biology (incl. macromolecular modelling)
Objective Division:Expanding Knowledge
Objective Group:Expanding knowledge
Objective Field:Expanding knowledge in the biological sciences
UTAS Author:Horne, HJ (Dr James Horne)
ID Code:53550
Year Published:2008
Web of Science® Times Cited:28
Deposited By:Central Science Laboratory
Deposited On:2008-12-11
Last Modified:2008-12-11

Repository Staff Only: item control page