A strategy for generating polyglutamine 'length libraries' in model host proteins.

Huntington's disease is one of nine known neurodegenerative diseases in which a disease-specific protein contains an unusually long polyglutamine (polyQ) stretch. The proteins associated with each disease are unrelated in sequence, size, structure, function or location of the mutation. In all cases, there is an apparent critical number of glutamines below which individuals do not develop disease. Expansion of the polyQ domain is closely associated with misfolding and aggregation of the protein. It is not yet well understood how the length of the polyQ tract, and its location within a given protein, is related to misfolding and to disease. In this work we developed a strategy for generating length libraries of polyQ-containing proteins, with the polyQ inserted at an arbitrary location. This strategy facilitates systematic, detailed study of the relationship among polyQ length, context and misfolding.