STRAIN-DEPENDENT DIFFERENCES IN BETA-SHEET CONFORMATIONS OF ABNORMAL PRION PROTEIN

Strain diversity in the transmissible spongiform encephalopathies (TSE s) has been proposed to be determined by variations in the conformatio n of the abnormal, protease-resistant form of prion protein (PrP-res). me have investigated whether infection of hamsters with three TSE str ains resulted in the formation of PrP-res with different conformations using limited proteinase K (PK) digestion and infrared spectroscopy. PrP-res isolated from the brains of hamsters infected with the hyper ( HY), drowsy (DY), and 263K TSE strains yielded similar SDS-polyacrylam ide gel electrophoresis profiles prior to PK treatment. However, after limited digestion with PK, the PrP-res from the DY strain exhibited a fragmentation pattern that was distinct from that of the other two st rains. Infrared spectra of HY and 263K PrP-res each had major absorpti on bands in the amide I region at 1626 and 1636 cm(-1) both prior to a nd after digestion with PK. These bands were not evident in the DY PrP -res spectra, which had a unique band at 1629-1630 cm(-1) and stronger band intensity at both 1616 and 1694-1695 cm(-1). Because absorbances from 1616 to 1636 cm(-1) of protein infrared spectra are attributed p rimarily to beta-sheet structures, these findings indicate that the co nformations of HY and 263K PrP-res differ hom DY PrP-res at least in s tructural regions with beta-sheet secondary structure. These results s upport the hypothesis that strain-specific PrP-res conformers can self -propagate by converting the normal prion protein to the abnormal conf ormers that induce phenotypically distinct TSE diseases.