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Journal of Virology, August 2006, p. 7854-7862, Vol. 80, No. 16
0022-538X/06/$08.00+0     doi:10.1128/JVI.00424-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

Prion Strain-Dependent Differences in Conversion of Mutant Prion Proteins in Cell Culture

Ryuichiro Atarashi,1,2* Valerie L. Sim,2 Noriyuki Nishida,1 Byron Caughey,2 and Shigeru Katamine1

Department of Molecular Microbiology and Immunology, Nagasaki University Graduate School of Biomedical Sciences, 1-12-4 Sakamoto, Nagasaki 853-8523, Japan,1 Laboratory of Persistent Viral Diseases, Rocky Mountain Laboratories, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Hamilton, Montana 598402

Received 28 February 2006/ Accepted 19 May 2006

Although the protein-only hypothesis proposes that it is the conformation of abnormal prion protein (PrPSc) that determines strain diversity, the molecular basis of strains remains to be elucidated. In the present study, we generated a series of mutations in the normal prion protein (PrPC) in which a single glutamine residue was replaced with a basic amino acid and compared their abilities to convert to PrPSc in cultured neuronal N2a58 cells infected with either the Chandler or 22L mouse-adapted scrapie strain. In mice, these strains generate PrPSc of the same sequence but different conformations, as judged by infrared spectroscopy. Substitutions at codons 97, 167, 171, and 216 generated PrPC that resisted conversion and inhibited the conversion of coexpressed wild-type PrP in both Chandler-infected and 22L-infected cells. Interestingly, substitutions at codons 185 and 218 gave strain-dependent effects. The Q185R and Q185K PrP were efficiently converted to PrPSc in Chandler-infected but not 22L-infected cells. Conversely, Q218R and Q218H PrP were converted only in 22L-infected cells. Moreover, the Q218K PrP exerted a potent inhibitory effect on the conversion of coexpressed wild-type PrP in Chandler-infected cells but had little effect on 22L-infected cells. These results show that two strains with the same PrP sequence but different conformations have differing abilities to convert the same mutated PrPC.

* Corresponding author. Mailing address: Laboratory of Persistent Viral Diseases, Rocky Mountain Laboratories, NIAID, NIH, 903 South 4th Street, Hamilton, MT 59840. Phone: (406) 363-9341. Fax: (406) 363-9286. E-mail: atarashir{at}niaid.nih.gov.

Journal of Virology, August 2006, p. 7854-7862, Vol. 80, No. 16
0022-538X/06/$08.00+0     doi:10.1128/JVI.00424-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • Ott, D., Taraborrelli, C., Aguzzi, A. (2008). Novel dominant-negative prion protein mutants identified from a randomized library. Protein Eng Des Sel 21: 623-629 [Abstract] [Full Text]  
  • Maas, E., Geissen, M., Groschup, M. H., Rost, R., Onodera, T., Schatzl, H., Vorberg, I. M. (2007). Scrapie Infection of Prion Protein-deficient Cell Line upon Ectopic Expression of Mutant Prion Proteins. J. Biol. Chem. 282: 18702-18710 [Abstract] [Full Text]  


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