N-Terminal Regions of Prion Protein: Functions and Roles in Prion Diseases
The normal cellular isoform of prion protein, designated PrP<sup>C</sup>, is constitutively converted to the abnormally folded, amyloidogenic isoform, PrP<sup>Sc</sup>, in prion diseases, which include Creutzfeldt-Jakob disease in humans and scrapie and bovine spongiform ence...
Main Authors: | , |
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Format: | Article |
Language: | English |
Published: |
MDPI AG
2020-08-01
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Series: | International Journal of Molecular Sciences |
Subjects: | |
Online Access: | https://www.mdpi.com/1422-0067/21/17/6233 |
Summary: | The normal cellular isoform of prion protein, designated PrP<sup>C</sup>, is constitutively converted to the abnormally folded, amyloidogenic isoform, PrP<sup>Sc</sup>, in prion diseases, which include Creutzfeldt-Jakob disease in humans and scrapie and bovine spongiform encephalopathy in animals. PrP<sup>C</sup> is a membrane glycoprotein consisting of the non-structural <i>N</i>-terminal domain and the globular C-terminal domain. During conversion of PrP<sup>C</sup> to PrP<sup>Sc</sup>, its 2/3 C-terminal region undergoes marked structural changes, forming a protease-resistant structure. In contrast, the N-terminal region remains protease-sensitive in PrP<sup>Sc</sup>. Reverse genetic studies using reconstituted PrP<sup>C</sup>-knockout mice with various mutant PrP molecules have revealed that the N-terminal domain has an important role in the normal function of PrP<sup>C</sup> and the conversion of PrP<sup>C</sup> to PrP<sup>Sc</sup>. The N-terminal domain includes various characteristic regions, such as the positively charged residue-rich polybasic region, the octapeptide repeat (OR) region consisting of five repeats of an octapeptide sequence, and the post-OR region with another positively charged residue-rich polybasic region followed by a stretch of hydrophobic residues. We discuss the normal functions of PrP<sup>C</sup>, the conversion of PrP<sup>C</sup> to PrP<sup>Sc</sup>, and the neurotoxicity of PrP<sup>Sc</sup> by focusing on the roles of the N-terminal regions in these topics. |
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ISSN: | 1661-6596 1422-0067 |