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This Article Accepted manuscript (PDF) All Versions of this Article: JME-08-0042v1 41/5/301    most recent Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Google Scholar Articles by Davies, P. Articles by McEwan, I. PubMed PubMed Citation Articles by Davies, P. Articles by McEwan, I.

P Davies, School of Medical Sciences, University of Aberdeen, Aberdeen, United Kingdom
K Watt, School of Medical Sciences, University of Aberdeen, Aberdeen, United Kingdom
S Kelly, Division of Biochemistry and Molecular Biology, University of Glasgow, Glasgow, United Kingdom
C Clark, School of Medicine, University of Aberdeen, Aberdeen, United Kingdom
N Price, Glasgow, United Kingdom
I McEwan, School of Medical Sciences, University of Aberdeen, Aberdeen, AB25 2ZD, United Kingdom

Correspondence: Iain McEwan, Email: iain.mcewan{at}abdn.ac.uk

Abstract

Poly-amino acid repeats, especially long stretches of glutamine (Q), are common features of transcription factors and cell-signalling proteins and are prone to expansion, resulting in neurodegenerative diseases. The amino terminal domain of the androgen receptor (AR-NTD) has a poly-Q repeat of between 9 and 36 residues, which when it expands above 40 residues results in spinal bulbar muscular atrophy (SBMA). We have used spectroscopy and biochemical analysis to investigate the structural consequences of an expanded repeat (Q45) or removal of the repeat (Q) on the folding of the AR-NTD. Circular dichroism spectroscopy revealed that in aqueous solution the AR-NTD has a relatively limited amount of stable secondary structure. Expansion of the poly-Q repeat resulted in a modest increase in -helix structure, while deletion of the repeat resulted in a small loss of -helix structure. These effects were more pronounced in the presence of the structure-promoting solvent trifluoroethanol or the natural osmolyte TMAO. Fluorescence spectroscopy showed that the microenvironments of four tryptophan residues were also altered after deletion of the Q stretch. Other structural changes were observed for the AR-NTDQ45 polypeptide after limited proteolysis; in addition this polypeptide not only showed enhanced binding of the hydrophobic probe ANS but was more sensitive to urea-induced unfolding. Taken together these findings support the view that the presence and length of the poly-Q repeat modulates the folding and structure of the AR-NTD