Abstract
Until now it is still not clear which structural elements of the prion protein (PrP) are involved in its conversion process. Characterisation of these essential regions would help to understand the conversion process itself and might help to develop specific therapeutic approaches to inhibit PrPres formation by dominant inhibitory mutations. To address this important question 33 evenly spaced insertion mutants were generated spanning the entire sequence of the murine 3F4- tagged PrP. The mutants were expressed by retroviral transduction in three different scrapie infected cell lines (ScN2a; SMB[RC040]; SMB[22F]). The convertibility was affected not only by introducing the insertion in the putatively refolded region (aa100-170), but also in the C-terminus of PrP (up to aa214). Moreover, dominant inhibitory effects on conversion were observed for PrP-mutants at four distinguished regions (aa100-112; aa130-154; aa166-172, aa196-200). Computer based structural analysis revealed that these segments were organized in two structurally clearly separated regions supporting the idea that they could function as protein-protein interaction sites which are necessary during seed formation.
Keywords: PrP mutants, PrP conversion, Glycosylation and cellular trafficking, PrP seed formation
Infectious Disorders - Drug Targets
Title: Inhibition of Prion Amplification by Expression of Dominant Inhibitory Mutants - A Systematic Insertion Mutagenesis Study
Volume: 9 Issue: 1
Author(s): Markus Geissen, Harriet Mella, Armin Saalmuller, Martin Eiden, Juliane Proft, Eberhard Pfaff, Hermann M. Schatzl and Martin H. Groschup
Affiliation:
Keywords: PrP mutants, PrP conversion, Glycosylation and cellular trafficking, PrP seed formation
Abstract: Until now it is still not clear which structural elements of the prion protein (PrP) are involved in its conversion process. Characterisation of these essential regions would help to understand the conversion process itself and might help to develop specific therapeutic approaches to inhibit PrPres formation by dominant inhibitory mutations. To address this important question 33 evenly spaced insertion mutants were generated spanning the entire sequence of the murine 3F4- tagged PrP. The mutants were expressed by retroviral transduction in three different scrapie infected cell lines (ScN2a; SMB[RC040]; SMB[22F]). The convertibility was affected not only by introducing the insertion in the putatively refolded region (aa100-170), but also in the C-terminus of PrP (up to aa214). Moreover, dominant inhibitory effects on conversion were observed for PrP-mutants at four distinguished regions (aa100-112; aa130-154; aa166-172, aa196-200). Computer based structural analysis revealed that these segments were organized in two structurally clearly separated regions supporting the idea that they could function as protein-protein interaction sites which are necessary during seed formation.
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Cite this article as:
Geissen Markus, Mella Harriet, Saalmuller Armin, Eiden Martin, Proft Juliane, Pfaff Eberhard, Schatzl M. Hermann and Groschup H. Martin, Inhibition of Prion Amplification by Expression of Dominant Inhibitory Mutants - A Systematic Insertion Mutagenesis Study, Infectious Disorders - Drug Targets 2009; 9 (1) . https://dx.doi.org/10.2174/1871526510909010040
DOI https://dx.doi.org/10.2174/1871526510909010040 |
Print ISSN 1871-5265 |
Publisher Name Bentham Science Publisher |
Online ISSN 2212-3989 |
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