Biochemical Studies Of Interactions Between Prion Protein And Lipids
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The Ohio State University / OhioLINK
2008
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ndltd-OhioLink-oai-etd.ohiolink.edu-osu12277250622021-08-03T05:54:49Z Biochemical Studies Of Interactions Between Prion Protein And Lipids Wang, Fei Biochemistry Prion PrP Phospholipids Protein K Conformation <p>Prion diseases, also know as Transmissible Spongiform Encephalopathies (TSEs), are a group of invariably fatal neurodegenerative disorders that occur in a wide variety of mammals including humans. According to the “Protein-Only” hypothesis, prion is the transmissible agent, which is mainly composed of the abnormal isoform (PrPSc) of the normal cellular prion protein (PrPC). PrPSc converts PrPC into likeness of itself, resulting in neurodegeneration. Despite extensive research, the precise mechanism underlying the PrP conversion process in prion diseases still remains unclear. Previous studies using biophysical methods revealed that PrP interacts with lipids, which leads to a conformational change of PrP. Yet, whether Proteinase K (PK) resistance, a classic biochemical feature of PrPSc, is associated with those altered PrP conformations induced by lipid interaction remains unclear. Main parts of this thesis were dedicated to elucidate how PrP and lipid interacts with each other and whether PrP-lipid interaction is sufficient to convert PrP to the classic PK-resistant conformation in the absence of denaturing treatments. Recombinant PrP expressed in E. Coli, which is considered structurally equivalent to PrPC, is monitored for lipid-induced conformational change in this study. In this thesis, I, by virtue of biochemical techniques, found that full-length recombinant PrP (rPrP) preferentially binds to anionic lipids. Under an environment reminiscent of physiological conditions, the lipid interaction causes rPrP conformational change, converting from a mainly α-helical structure to a high β-sheet conformation featuring PrPSc-like PK resistance. In the subsequent study on characterization of rPrP-lipid interaction, I found that the lipid induced rPrP conversion requires both hydrophobic rPrP-lipid interaction and the localization of anionic charges on the surface of lipid vesicles, suggesting the involvement of highly conserved middle region of PrP that consists of a cluster of positively charged lysine residues followed by a hydrophobic domain. To determine the relevance of rPrP-lipid interaction to prion biology, I characterized rPrP-lipid interaction using rPrP with pathogenic mutations and factors known to alter PrPSc propagation or stability. I found that, besides phospholipids, arachidonic acid also supports the generation of C-terminal PK-resistant rPrP. In addition, lipid oxidation, metal ions and RNA affect lipid-induced rPrP conversion in a manner similar to their effects on the pathogenic PrPSc.</p><p>Collectively, these findings of lipid-induced PrP conversion under physiological conditions provide strong support for the relevance of lipid-PrP interaction to the pathogenic changes in prion disease. Further investigation of this process together with the relationship between lipid-induced PrPSc-like conformation and prion infectivity may help us to elucidate the pathogenic mechanism of prion disease.</p> 2008-12-24 English text The Ohio State University / OhioLINK http://rave.ohiolink.edu/etdc/view?acc_num=osu1227725062 http://rave.ohiolink.edu/etdc/view?acc_num=osu1227725062 unrestricted This thesis or dissertation is protected by copyright: all rights reserved. It may not be copied or redistributed beyond the terms of applicable copyright laws. |
| collection |
NDLTD |
| language |
English |
| sources |
NDLTD |
| topic |
Biochemistry Prion PrP Phospholipids Protein K Conformation |
| spellingShingle |
Biochemistry Prion PrP Phospholipids Protein K Conformation Wang, Fei Biochemical Studies Of Interactions Between Prion Protein And Lipids |
| author |
Wang, Fei |
| author_facet |
Wang, Fei |
| author_sort |
Wang, Fei |
| title |
Biochemical Studies Of Interactions Between Prion Protein And Lipids |
| title_short |
Biochemical Studies Of Interactions Between Prion Protein And Lipids |
| title_full |
Biochemical Studies Of Interactions Between Prion Protein And Lipids |
| title_fullStr |
Biochemical Studies Of Interactions Between Prion Protein And Lipids |
| title_full_unstemmed |
Biochemical Studies Of Interactions Between Prion Protein And Lipids |
| title_sort |
biochemical studies of interactions between prion protein and lipids |
| publisher |
The Ohio State University / OhioLINK |
| publishDate |
2008 |
| url |
http://rave.ohiolink.edu/etdc/view?acc_num=osu1227725062 |
| work_keys_str_mv |
AT wangfei biochemicalstudiesofinteractionsbetweenprionproteinandlipids |
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1719427667332169728 |