Instability of familial spongiform encephalopathy-related prion mutants.
We examined the influence of D177N (D178N in humans) mutation on the conformational stability of the S2 region of moPrP(C) with varying pHs by using the SDSL-ESR technique. The ESR spectrum of D177N at pH 7.5 was narrower than that of Y161R1, referred to as WT( *). The ESR spectrum of D177N did not change when pH in the solution decreased to pH 4.0. Our results suggested that the disappearance of a salt bridge (D177-R163) induced the increase in the instability of S2 region. Moreover, the line shape of the ESR spectrum obtained from H176S neighboring the salt bridge linked to the S2 region was similar to D177N. These results indicate that the protonation of H176 is strongly associated with the stability of S2 region. These findings are important for understanding the mechanism by which the disruption of the salt bridge in the S2 region forms the pathogenic PrP(Sc) structure in hereditary prion disease.
Watanabe
Yasuko
Y
Laboratory of Radiation Biology, Graduate School of Veterinary Medicine, Hokkaido University, Sapporo 060-0818, Japan.
Hiraoka
Wakako
W
Shimoyama
Yuhei
Y
Horiuchi
Motohiro
M
Kuwabara
Mikinori
M
Inanami
Osamu
O
D016297:Mutagenesis, Site-Directed; D018621:PrPC Proteins / Q000737:chemistry* / Q000235:genetics / Q000648:ultrastructure*; D011487:Protein Conformation; D017510:Protein Folding; D013329:Structure-Activity Relationship
D018621:PrPC Proteins