The Effect of Octapeptide Repeats on Prion Folding and Misfolding
Misfolding of prion protein (PrP) into amyloid aggregates is the central feature of prion diseases. PrP has an amyloidogenic C-terminal domain with three α-helices and a flexible tail in the N-terminal domain in which multiple octapeptide repeats are present in most mammals. The role of the octapept...
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MDPI AG
2021-02-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/22/4/1800 |
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| author | Kun-Hua Yu Mei-Yu Huang Yi-Ru Lee Yu-Kie Lin Hau-Ren Chen Cheng-I Lee |
| author_facet | Kun-Hua Yu Mei-Yu Huang Yi-Ru Lee Yu-Kie Lin Hau-Ren Chen Cheng-I Lee |
| author_sort | Kun-Hua Yu |
| collection | DOAJ |
| description | Misfolding of prion protein (PrP) into amyloid aggregates is the central feature of prion diseases. PrP has an amyloidogenic C-terminal domain with three α-helices and a flexible tail in the N-terminal domain in which multiple octapeptide repeats are present in most mammals. The role of the octapeptides in prion diseases has previously been underestimated because the octapeptides are not located in the amyloidogenic domain. Correlation between the number of octapeptide repeats and age of onset suggests the critical role of octapeptide repeats in prion diseases. In this study, we have investigated four PrP variants without any octapeptides and with 1, 5 and 8 octapeptide repeats. From the comparison of the protein structure and the thermal stability of these proteins, as well as the characterization of amyloids converted from these PrP variants, we found that octapeptide repeats affect both folding and misfolding of PrP creating amyloid fibrils with distinct structures. Deletion of octapeptides forms fewer twisted fibrils and weakens the cytotoxicity. Insertion of octapeptides enhances the formation of typical silk-like fibrils but it does not increase the cytotoxicity. There might be some threshold effect and increasing the number of peptides beyond a certain limit has no further effect on the cell viability, though the reasons are unclear at this stage. Overall, the results of this study elucidate the molecular mechanism of octapeptides at the onset of prion diseases. |
| first_indexed | 2024-03-09T00:57:23Z |
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| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-09T00:57:23Z |
| publishDate | 2021-02-01 |
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| series | International Journal of Molecular Sciences |
| spelling | doaj.art-2cbc1eef76dd44fd81c7322a836054aa2023-12-11T16:46:14ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672021-02-01224180010.3390/ijms22041800The Effect of Octapeptide Repeats on Prion Folding and MisfoldingKun-Hua Yu0Mei-Yu Huang1Yi-Ru Lee2Yu-Kie Lin3Hau-Ren Chen4Cheng-I Lee5Department of Biomedical Sciences, National Chung Cheng University, 168 University Road, Min-Hsiung Chia-Yi 62102, TaiwanDepartment of Biomedical Sciences, National Chung Cheng University, 168 University Road, Min-Hsiung Chia-Yi 62102, TaiwanDepartment of Biomedical Sciences, National Chung Cheng University, 168 University Road, Min-Hsiung Chia-Yi 62102, TaiwanDepartment of Biomedical Sciences, National Chung Cheng University, 168 University Road, Min-Hsiung Chia-Yi 62102, TaiwanDepartment of Biomedical Sciences, National Chung Cheng University, 168 University Road, Min-Hsiung Chia-Yi 62102, TaiwanDepartment of Biomedical Sciences, National Chung Cheng University, 168 University Road, Min-Hsiung Chia-Yi 62102, TaiwanMisfolding of prion protein (PrP) into amyloid aggregates is the central feature of prion diseases. PrP has an amyloidogenic C-terminal domain with three α-helices and a flexible tail in the N-terminal domain in which multiple octapeptide repeats are present in most mammals. The role of the octapeptides in prion diseases has previously been underestimated because the octapeptides are not located in the amyloidogenic domain. Correlation between the number of octapeptide repeats and age of onset suggests the critical role of octapeptide repeats in prion diseases. In this study, we have investigated four PrP variants without any octapeptides and with 1, 5 and 8 octapeptide repeats. From the comparison of the protein structure and the thermal stability of these proteins, as well as the characterization of amyloids converted from these PrP variants, we found that octapeptide repeats affect both folding and misfolding of PrP creating amyloid fibrils with distinct structures. Deletion of octapeptides forms fewer twisted fibrils and weakens the cytotoxicity. Insertion of octapeptides enhances the formation of typical silk-like fibrils but it does not increase the cytotoxicity. There might be some threshold effect and increasing the number of peptides beyond a certain limit has no further effect on the cell viability, though the reasons are unclear at this stage. Overall, the results of this study elucidate the molecular mechanism of octapeptides at the onset of prion diseases.https://www.mdpi.com/1422-0067/22/4/1800prionoctapeptidefoldingmisfoldingfibril |
| spellingShingle | Kun-Hua Yu Mei-Yu Huang Yi-Ru Lee Yu-Kie Lin Hau-Ren Chen Cheng-I Lee The Effect of Octapeptide Repeats on Prion Folding and Misfolding International Journal of Molecular Sciences prion octapeptide folding misfolding fibril |
| title | The Effect of Octapeptide Repeats on Prion Folding and Misfolding |
| title_full | The Effect of Octapeptide Repeats on Prion Folding and Misfolding |
| title_fullStr | The Effect of Octapeptide Repeats on Prion Folding and Misfolding |
| title_full_unstemmed | The Effect of Octapeptide Repeats on Prion Folding and Misfolding |
| title_short | The Effect of Octapeptide Repeats on Prion Folding and Misfolding |
| title_sort | effect of octapeptide repeats on prion folding and misfolding |
| topic | prion octapeptide folding misfolding fibril |
| url | https://www.mdpi.com/1422-0067/22/4/1800 |
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