Amyloid fibril formation is associated with a range of neurodegenerative 
diseases in humans, including Alzheimer's, Parkinson's, and prion diseases. In 
yeast, amyloid underlies several non-Mendelian phenotypes referred to as yeast 
prions. Mechanism of amyloid formation is critical for a complete understanding 
of the yeast prion phenomenon and human amyloid-related diseases. Ure2 protein 
is the basis of yeast prion [URE3]. The Ure2p prion domain is largely 
disordered. Residual structures, if any, in the disordered region may play an 
important role in the aggregation process. Studies of Ure2p prion domain are 
complicated by its high aggregation propensity, which results in a mixture of 
monomer and aggregates in solution. Previously we have developed a solid-support 
electron paramagnetic resonance (EPR) approach to address this problem and have 
identified a structured state for the Alzheimer's amyloid-β monomer. Here we use 
solid-support EPR to study the structure of Ure2p prion domain. EPR spectra of 
Ure2p prion domain with spin labels at every fifth residue from position 10 to 
position 75 show similar residue mobility profile for denaturing and native 
buffers after accounting for the effect of solution viscosity. These results 
suggest that Ure2p prion domain adopts a completely disordered structure in the 
native buffer. A completely disordered Ure2p prion domain implies that the 
amyloid formation of Ure2p, and likely other Q/N-rich yeast prion proteins, is 
primarily driven by inter-molecular interactions.