University of Montana, Maureen and Mike Mansfield Library
Abstract
Conversion of prion protein (PrP) from its normal, cellular isoform, PrPC, to an infectious, misfolded, fibrillar isoform, PrPSc, is responsible for various neurodegenerative diseases in a variety of mammalian hosts. Although the structure of PrPC is well studied, the structure of PrPSc is not known. Obtaining structural information on the misfolded isoform of prion may lead to preventative therapies and treatments of prion diseases. In this study, six single-tryptophan mutants of recombinant PrP were expressed, purified, and refolded into PrPC or two misfolded isoforms of prion, PrPb and PrPF. Solvent accessibilities of the six tryptophan residues were probed among the three isoforms using various tryptophan fluorescence techniques. For all six mutants, solvent accessibility was shown to decrease following conversion to the misfolded isoforms. Tryptophan accessibility data was used to evaluate two computational models of PrPSc, the beta-helix model and the-beta spiral model, and was also compared with experimental data in literature. Although neither computational model entirely fit the data, the Surewicz model of parallel, in-register beta-strands comprising residues ~160-220 was in agreement with tryptophan accessibilities of residues within this area. However, more structural detail of this experimentally-based model is needed before the two data sets can be fully compared
