Ordered Structure in Monomeric Polyglutamine

Huntington's disease is associated with the protein huntingtin, which contains a polyglutamine stretch that is normally 10-35 residues long. This polyglutamine tract is expanded to >40 glutamines in affected individuals. Expanded .polyglutamine tracts result in aggregation of huntingtin, which occurs in the nuclei of neurons in the brain. It is commonly believed that monomeric polyglutamine fOIms random coils in solution. However, recent work in our laboratory suggests that polyglutamine may in fact exist as an dynamic ensemble of short stretches of left-handed polyproline II helices interspersed with turns. In this proposal, we propose to study the confonnational properties of monomeric polyglutamine peptides. We will use NMR spectrometry and circular dichroism spectroscopy to determine the various structures adopted by monomeric polyglutamine peptides. Computer simulations will be used to elucidate the physical determinants of these structures. These studies will lead to a more complete model of the aggregation process, which in turn williea.d to the development of drugs for use against Huntington's disease.