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Journal of Virology, November 2001, p. 10024-10032, Vol. 75, No. 21
0022-538X/01/$04.00+0   DOI: 10.1128/JVI.75.21.10024-10032.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.

Deletion of beta -Strand and alpha -Helix Secondary Structure in Normal Prion Protein Inhibits Formation of Its Protease-Resistant Isoform

Ina Vorberg,1 Kaman Chan,2 and Suzette A. Priola1,*

Laboratory of Persistent Viral Diseases, Rocky Mountain Laboratories, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Hamilton, Montana 59840,1 and Department of Microbiology and Immunology, Stanford University School of Medicine, Stanford, California 943052

Received 24 April 2001/Accepted 19 July 2001

A fundamental event in the pathogenesis of transmissible spongiform encephalopathies (TSE) is the conversion of a normal, proteinase K-sensitive, host-encoded protein, PrP-sen, into its protease-resistant isoform, PrP-res. During the formation of PrP-res, PrP-sen undergoes conformational changes that involve an increase of beta -sheet secondary structure. While previous studies in which PrP-sen deletion mutants were expressed in transgenic mice or scrapie-infected cell cultures have identified regions in PrP-sen that are important in the formation of PrP-res, the exact role of PrP-sen secondary structures in the conformational transition of PrP-sen to PrP-res has not yet been defined. We constructed PrP-sen mutants with deletions of the first beta -strand, the second beta -strand, or the first alpha -helix and tested whether these mutants could be converted to PrP-res in both scrapie-infected neuroblastoma cells (Sc+-MNB cells) and a cell-free conversion assay. Removal of the second beta -strand or the first alpha -helix significantly altered both processing and the cellular localization of PrP-sen, while deletion of the first beta -strand had no effect on these events. However, all of the mutants significantly inhibited the formation of PrP-res in Sc+-MNB cells and had a greatly reduced ability to form protease-resistant PrP in a cell-free assay system. Thus, our results demonstrate that deletion of the beta -strands and the first alpha -helix of PrP-sen can fundamentally affect PrP-res formation and/or PrP-sen processing.

* Corresponding author. Mailing address: Laboratory of Persistent Viral Diseases, Rocky Mountain Laboratories, National Institute of Allergy and Infectious Diseases, National Institutes of Health, 903 S. 4th St., Hamilton, MT 59840. Phone: (406) 363-9319. Fax: (406) 363-9286. E-mail: spriola{at}nih.gov.

Journal of Virology, November 2001, p. 10024-10032, Vol. 75, No. 21
0022-538X/01/$04.00+0   DOI: 10.1128/JVI.75.21.10024-10032.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.


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