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...
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doaj-92b17fe7d3254ec8923aa17b5c7f2f0a2020-11-25T03:46:06ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672020-08-01216233623310.3390/ijms21176233N-Terminal Regions of Prion Protein: Functions and Roles in Prion DiseasesHideyuki Hara0Suehiro Sakaguchi1Division of Molecular Neurobiology, The Institute for Enzyme Research (KOSOKEN), Tokushima University, 3-18-15 Kuramoto, Tokushima 770-8503, JapanDivision of Molecular Neurobiology, The Institute for Enzyme Research (KOSOKEN), Tokushima University, 3-18-15 Kuramoto, Tokushima 770-8503, JapanThe 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.https://www.mdpi.com/1422-0067/21/17/6233prion proteinprionprion diseaseneurodegenerationprotein conformation |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Hideyuki Hara Suehiro Sakaguchi |
spellingShingle |
Hideyuki Hara Suehiro Sakaguchi N-Terminal Regions of Prion Protein: Functions and Roles in Prion Diseases International Journal of Molecular Sciences prion protein prion prion disease neurodegeneration protein conformation |
author_facet |
Hideyuki Hara Suehiro Sakaguchi |
author_sort |
Hideyuki Hara |
title |
N-Terminal Regions of Prion Protein: Functions and Roles in Prion Diseases |
title_short |
N-Terminal Regions of Prion Protein: Functions and Roles in Prion Diseases |
title_full |
N-Terminal Regions of Prion Protein: Functions and Roles in Prion Diseases |
title_fullStr |
N-Terminal Regions of Prion Protein: Functions and Roles in Prion Diseases |
title_full_unstemmed |
N-Terminal Regions of Prion Protein: Functions and Roles in Prion Diseases |
title_sort |
n-terminal regions of prion protein: functions and roles in prion diseases |
publisher |
MDPI AG |
series |
International Journal of Molecular Sciences |
issn |
1661-6596 1422-0067 |
publishDate |
2020-08-01 |
description |
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. |
topic |
prion protein prion prion disease neurodegeneration protein conformation |
url |
https://www.mdpi.com/1422-0067/21/17/6233 |
work_keys_str_mv |
AT hideyukihara nterminalregionsofprionproteinfunctionsandrolesinpriondiseases AT suehirosakaguchi nterminalregionsofprionproteinfunctionsandrolesinpriondiseases |
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1724507859322929152 |