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Molecular structure of an amyloid fibril formed by FUS low-complexity domain
FUS is a multifunctional nuclear protein which undergoes liquid–liquid phase separation in response to stress and DNA damage. Dysregulation of FUS dynamic phase separation leads to formation of pathological fibril closely associated with neurodegenerative diseases such as amyotrophic lateral scleros...
Autores principales: | , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Elsevier
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8749265/ https://www.ncbi.nlm.nih.gov/pubmed/35036880 http://dx.doi.org/10.1016/j.isci.2021.103701 |
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author | Sun, Yunpeng Zhang, Shenqing Hu, Jiaojiao Tao, Youqi Xia, Wencheng Gu, Jinge Li, Yichen Cao, Qin Li, Dan Liu, Cong |
author_facet | Sun, Yunpeng Zhang, Shenqing Hu, Jiaojiao Tao, Youqi Xia, Wencheng Gu, Jinge Li, Yichen Cao, Qin Li, Dan Liu, Cong |
author_sort | Sun, Yunpeng |
collection | PubMed |
description | FUS is a multifunctional nuclear protein which undergoes liquid–liquid phase separation in response to stress and DNA damage. Dysregulation of FUS dynamic phase separation leads to formation of pathological fibril closely associated with neurodegenerative diseases such as amyotrophic lateral sclerosis and frontotemporal dementia. In this study, we determined the cryo-EM structure of a cytotoxic fibril formed by the low-complexity (LC) domain of FUS at 2.9 Å resolution. The fibril structure exhibits a new and extensive serpentine fold consisting of three motifs incorporating together via a Tyr triad. FUS LC employs 91 residues to form an enlarged and stable fibril core via hydrophilic interaction and hydrogen bonds, which is distinct from most of previously determined fibrils commonly stabilized by hydrophobic interaction. Our work reveals the structural basis underlying formation of a cytotoxic and thermostable fibril of FUS LC and sheds light on understanding the liquid-to-solid phase transition of FUS in disease. |
format | Online Article Text |
id | pubmed-8749265 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | Elsevier |
record_format | MEDLINE/PubMed |
spelling | pubmed-87492652022-01-13 Molecular structure of an amyloid fibril formed by FUS low-complexity domain Sun, Yunpeng Zhang, Shenqing Hu, Jiaojiao Tao, Youqi Xia, Wencheng Gu, Jinge Li, Yichen Cao, Qin Li, Dan Liu, Cong iScience Article FUS is a multifunctional nuclear protein which undergoes liquid–liquid phase separation in response to stress and DNA damage. Dysregulation of FUS dynamic phase separation leads to formation of pathological fibril closely associated with neurodegenerative diseases such as amyotrophic lateral sclerosis and frontotemporal dementia. In this study, we determined the cryo-EM structure of a cytotoxic fibril formed by the low-complexity (LC) domain of FUS at 2.9 Å resolution. The fibril structure exhibits a new and extensive serpentine fold consisting of three motifs incorporating together via a Tyr triad. FUS LC employs 91 residues to form an enlarged and stable fibril core via hydrophilic interaction and hydrogen bonds, which is distinct from most of previously determined fibrils commonly stabilized by hydrophobic interaction. Our work reveals the structural basis underlying formation of a cytotoxic and thermostable fibril of FUS LC and sheds light on understanding the liquid-to-solid phase transition of FUS in disease. Elsevier 2021-12-27 /pmc/articles/PMC8749265/ /pubmed/35036880 http://dx.doi.org/10.1016/j.isci.2021.103701 Text en © 2021 The Author(s) https://creativecommons.org/licenses/by-nc-nd/4.0/This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). |
spellingShingle | Article Sun, Yunpeng Zhang, Shenqing Hu, Jiaojiao Tao, Youqi Xia, Wencheng Gu, Jinge Li, Yichen Cao, Qin Li, Dan Liu, Cong Molecular structure of an amyloid fibril formed by FUS low-complexity domain |
title | Molecular structure of an amyloid fibril formed by FUS low-complexity domain |
title_full | Molecular structure of an amyloid fibril formed by FUS low-complexity domain |
title_fullStr | Molecular structure of an amyloid fibril formed by FUS low-complexity domain |
title_full_unstemmed | Molecular structure of an amyloid fibril formed by FUS low-complexity domain |
title_short | Molecular structure of an amyloid fibril formed by FUS low-complexity domain |
title_sort | molecular structure of an amyloid fibril formed by fus low-complexity domain |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8749265/ https://www.ncbi.nlm.nih.gov/pubmed/35036880 http://dx.doi.org/10.1016/j.isci.2021.103701 |
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