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The nuclear localization sequence mediates hnRNPA1 amyloid fibril formation revealed by cryoEM structure

Human heterogeneous nuclear ribonucleoprotein A1 (hnRNPA1) serves as a key regulating protein in RNA metabolism. Malfunction of hnRNPA1 in nucleo-cytoplasmic transport or dynamic phase separation leads to abnormal amyloid aggregation and neurodegeneration. The low complexity (LC) domain of hnRNPA1 d...

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Autores principales: Sun, Yunpeng, Zhao, Kun, Xia, Wencheng, Feng, Guoqin, Gu, Jinge, Ma, Yeyang, Gui, Xinrui, Zhang, Xia, Fang, Yanshan, Sun, Bo, Wang, Renxiao, Liu, Cong, Li, Dan
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7733464/
https://www.ncbi.nlm.nih.gov/pubmed/33311513
http://dx.doi.org/10.1038/s41467-020-20227-8
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author Sun, Yunpeng
Zhao, Kun
Xia, Wencheng
Feng, Guoqin
Gu, Jinge
Ma, Yeyang
Gui, Xinrui
Zhang, Xia
Fang, Yanshan
Sun, Bo
Wang, Renxiao
Liu, Cong
Li, Dan
author_facet Sun, Yunpeng
Zhao, Kun
Xia, Wencheng
Feng, Guoqin
Gu, Jinge
Ma, Yeyang
Gui, Xinrui
Zhang, Xia
Fang, Yanshan
Sun, Bo
Wang, Renxiao
Liu, Cong
Li, Dan
author_sort Sun, Yunpeng
collection PubMed
description Human heterogeneous nuclear ribonucleoprotein A1 (hnRNPA1) serves as a key regulating protein in RNA metabolism. Malfunction of hnRNPA1 in nucleo-cytoplasmic transport or dynamic phase separation leads to abnormal amyloid aggregation and neurodegeneration. The low complexity (LC) domain of hnRNPA1 drives both dynamic phase separation and amyloid aggregation. Here, we use cryo-electron microscopy to determine the amyloid fibril structure formed by hnRNPA1 LC domain. Remarkably, the structure reveals that the nuclear localization sequence of hnRNPA1 (termed PY-NLS), which is initially known to mediate the nucleo-cytoplamic transport of hnRNPA1 through binding with karyopherin-β2 (Kapβ2), represents the major component of the fibril core. The residues that contribute to the binding of PY-NLS with Kapβ2 also exert key molecular interactions to stabilize the fibril structure. Notably, hnRNPA1 mutations found in familial amyotrophic lateral sclerosis (ALS) and multisystem proteinopathoy (MSP) are all involved in the fibril core and contribute to fibril stability. Our work illuminates structural understandings of the pathological amyloid aggregation of hnRNPA1 and the amyloid disaggregase activity of Kapβ2, and highlights the multiple roles of PY-NLS in hnRNPA1 homeostasis.
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spelling pubmed-77334642020-12-17 The nuclear localization sequence mediates hnRNPA1 amyloid fibril formation revealed by cryoEM structure Sun, Yunpeng Zhao, Kun Xia, Wencheng Feng, Guoqin Gu, Jinge Ma, Yeyang Gui, Xinrui Zhang, Xia Fang, Yanshan Sun, Bo Wang, Renxiao Liu, Cong Li, Dan Nat Commun Article Human heterogeneous nuclear ribonucleoprotein A1 (hnRNPA1) serves as a key regulating protein in RNA metabolism. Malfunction of hnRNPA1 in nucleo-cytoplasmic transport or dynamic phase separation leads to abnormal amyloid aggregation and neurodegeneration. The low complexity (LC) domain of hnRNPA1 drives both dynamic phase separation and amyloid aggregation. Here, we use cryo-electron microscopy to determine the amyloid fibril structure formed by hnRNPA1 LC domain. Remarkably, the structure reveals that the nuclear localization sequence of hnRNPA1 (termed PY-NLS), which is initially known to mediate the nucleo-cytoplamic transport of hnRNPA1 through binding with karyopherin-β2 (Kapβ2), represents the major component of the fibril core. The residues that contribute to the binding of PY-NLS with Kapβ2 also exert key molecular interactions to stabilize the fibril structure. Notably, hnRNPA1 mutations found in familial amyotrophic lateral sclerosis (ALS) and multisystem proteinopathoy (MSP) are all involved in the fibril core and contribute to fibril stability. Our work illuminates structural understandings of the pathological amyloid aggregation of hnRNPA1 and the amyloid disaggregase activity of Kapβ2, and highlights the multiple roles of PY-NLS in hnRNPA1 homeostasis. Nature Publishing Group UK 2020-12-11 /pmc/articles/PMC7733464/ /pubmed/33311513 http://dx.doi.org/10.1038/s41467-020-20227-8 Text en © The Author(s) 2020 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
spellingShingle Article
Sun, Yunpeng
Zhao, Kun
Xia, Wencheng
Feng, Guoqin
Gu, Jinge
Ma, Yeyang
Gui, Xinrui
Zhang, Xia
Fang, Yanshan
Sun, Bo
Wang, Renxiao
Liu, Cong
Li, Dan
The nuclear localization sequence mediates hnRNPA1 amyloid fibril formation revealed by cryoEM structure
title The nuclear localization sequence mediates hnRNPA1 amyloid fibril formation revealed by cryoEM structure
title_full The nuclear localization sequence mediates hnRNPA1 amyloid fibril formation revealed by cryoEM structure
title_fullStr The nuclear localization sequence mediates hnRNPA1 amyloid fibril formation revealed by cryoEM structure
title_full_unstemmed The nuclear localization sequence mediates hnRNPA1 amyloid fibril formation revealed by cryoEM structure
title_short The nuclear localization sequence mediates hnRNPA1 amyloid fibril formation revealed by cryoEM structure
title_sort nuclear localization sequence mediates hnrnpa1 amyloid fibril formation revealed by cryoem structure
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7733464/
https://www.ncbi.nlm.nih.gov/pubmed/33311513
http://dx.doi.org/10.1038/s41467-020-20227-8
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