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Article

The Effect of Octapeptide Repeats on Prion Folding and Misfolding

Department of Biomedical Sciences, National Chung Cheng University, 168 University Road, Min-Hsiung Chia-Yi 62102, Taiwan
*
Author to whom correspondence should be addressed.
These authors contributed equally.
Academic Editors: Jya-Wei Cheng, Shih-Che Sue, Kuen-Phon Wu, Hui-Chun Cheng and Shang-Te Hsu
Int. J. Mol. Sci. 2021, 22(4), 1800; https://doi.org/10.3390/ijms22041800
Received: 31 December 2020 / Revised: 6 February 2021 / Accepted: 8 February 2021 / Published: 11 February 2021
(This article belongs to the Special Issue Structural Biology of Proteins and Peptides)
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. View Full-Text
Keywords: prion; octapeptide; folding; misfolding; fibril prion; octapeptide; folding; misfolding; fibril
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MDPI and ACS Style

Yu, K.-H.; Huang, M.-Y.; Lee, Y.-R.; Lin, Y.-K.; Chen, H.-R.; Lee, C.-I. The Effect of Octapeptide Repeats on Prion Folding and Misfolding. Int. J. Mol. Sci. 2021, 22, 1800. https://doi.org/10.3390/ijms22041800

AMA Style

Yu K-H, Huang M-Y, Lee Y-R, Lin Y-K, Chen H-R, Lee C-I. The Effect of Octapeptide Repeats on Prion Folding and Misfolding. International Journal of Molecular Sciences. 2021; 22(4):1800. https://doi.org/10.3390/ijms22041800

Chicago/Turabian Style

Yu, Kun-Hua, Mei-Yu Huang, Yi-Ru Lee, Yu-Kie Lin, Hau-Ren Chen, and Cheng-I Lee. 2021. "The Effect of Octapeptide Repeats on Prion Folding and Misfolding" International Journal of Molecular Sciences 22, no. 4: 1800. https://doi.org/10.3390/ijms22041800

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