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Genetic prion disease–related mutation E196K displays a novel amyloid fibril structure revealed by cryo-EM
Prion diseases are caused by the conformational conversion of prion protein (PrP). Forty-two different mutations were identified in human PrP, leading to genetic prion diseases with distinct clinical syndromes. Here, we report the cryo–electron microscopy structure of an amyloid fibril formed by ful...
Autores principales: | , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
American Association for the Advancement of Science
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8442898/ https://www.ncbi.nlm.nih.gov/pubmed/34516876 http://dx.doi.org/10.1126/sciadv.abg9676 |
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author | Wang, Li-Qiang Zhao, Kun Yuan, Han-Ye Li, Xiang-Ning Dang, Hai-Bin Ma, Yeyang Wang, Qiang Wang, Chen Sun, Yunpeng Chen, Jie Li, Dan Zhang, Delin Yin, Ping Liu, Cong Liang, Yi |
author_facet | Wang, Li-Qiang Zhao, Kun Yuan, Han-Ye Li, Xiang-Ning Dang, Hai-Bin Ma, Yeyang Wang, Qiang Wang, Chen Sun, Yunpeng Chen, Jie Li, Dan Zhang, Delin Yin, Ping Liu, Cong Liang, Yi |
author_sort | Wang, Li-Qiang |
collection | PubMed |
description | Prion diseases are caused by the conformational conversion of prion protein (PrP). Forty-two different mutations were identified in human PrP, leading to genetic prion diseases with distinct clinical syndromes. Here, we report the cryo–electron microscopy structure of an amyloid fibril formed by full-length human PrP with E196K mutation, a genetic Creutzfeldt-Jakob disease–related mutation. This mutation disrupts key interactions in the wild-type PrP fibril, forming an amyloid fibril with a conformation distinct from the wild-type PrP fibril and hamster brain–derived prion fibril. The E196K fibril consists of two protofibrils. Each subunit forms five β strands stabilized by a disulfide bond and an unusual hydrophilic cavity stabilized by a salt bridge. Four pairs of amino acids from opposing subunits form four salt bridges to stabilize the zigzag interface of the two protofibrils. Our results provide structural evidences of the diverse prion strains and highlight the importance of familial mutations in inducing different strains. |
format | Online Article Text |
id | pubmed-8442898 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | American Association for the Advancement of Science |
record_format | MEDLINE/PubMed |
spelling | pubmed-84428982021-09-24 Genetic prion disease–related mutation E196K displays a novel amyloid fibril structure revealed by cryo-EM Wang, Li-Qiang Zhao, Kun Yuan, Han-Ye Li, Xiang-Ning Dang, Hai-Bin Ma, Yeyang Wang, Qiang Wang, Chen Sun, Yunpeng Chen, Jie Li, Dan Zhang, Delin Yin, Ping Liu, Cong Liang, Yi Sci Adv Biomedicine and Life Sciences Prion diseases are caused by the conformational conversion of prion protein (PrP). Forty-two different mutations were identified in human PrP, leading to genetic prion diseases with distinct clinical syndromes. Here, we report the cryo–electron microscopy structure of an amyloid fibril formed by full-length human PrP with E196K mutation, a genetic Creutzfeldt-Jakob disease–related mutation. This mutation disrupts key interactions in the wild-type PrP fibril, forming an amyloid fibril with a conformation distinct from the wild-type PrP fibril and hamster brain–derived prion fibril. The E196K fibril consists of two protofibrils. Each subunit forms five β strands stabilized by a disulfide bond and an unusual hydrophilic cavity stabilized by a salt bridge. Four pairs of amino acids from opposing subunits form four salt bridges to stabilize the zigzag interface of the two protofibrils. Our results provide structural evidences of the diverse prion strains and highlight the importance of familial mutations in inducing different strains. American Association for the Advancement of Science 2021-09-08 /pmc/articles/PMC8442898/ /pubmed/34516876 http://dx.doi.org/10.1126/sciadv.abg9676 Text en Copyright © 2021 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution License 4.0 (CC BY). https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution license (https://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. |
spellingShingle | Biomedicine and Life Sciences Wang, Li-Qiang Zhao, Kun Yuan, Han-Ye Li, Xiang-Ning Dang, Hai-Bin Ma, Yeyang Wang, Qiang Wang, Chen Sun, Yunpeng Chen, Jie Li, Dan Zhang, Delin Yin, Ping Liu, Cong Liang, Yi Genetic prion disease–related mutation E196K displays a novel amyloid fibril structure revealed by cryo-EM |
title | Genetic prion disease–related mutation E196K displays a novel amyloid fibril structure revealed by cryo-EM |
title_full | Genetic prion disease–related mutation E196K displays a novel amyloid fibril structure revealed by cryo-EM |
title_fullStr | Genetic prion disease–related mutation E196K displays a novel amyloid fibril structure revealed by cryo-EM |
title_full_unstemmed | Genetic prion disease–related mutation E196K displays a novel amyloid fibril structure revealed by cryo-EM |
title_short | Genetic prion disease–related mutation E196K displays a novel amyloid fibril structure revealed by cryo-EM |
title_sort | genetic prion disease–related mutation e196k displays a novel amyloid fibril structure revealed by cryo-em |
topic | Biomedicine and Life Sciences |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8442898/ https://www.ncbi.nlm.nih.gov/pubmed/34516876 http://dx.doi.org/10.1126/sciadv.abg9676 |
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