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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...

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Detalles Bibliográficos
Autores principales: Sun, Yunpeng, Zhang, Shenqing, Hu, Jiaojiao, Tao, Youqi, Xia, Wencheng, Gu, Jinge, Li, Yichen, Cao, Qin, Li, Dan, Liu, Cong
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Elsevier 2021
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.
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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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