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Title: Nuclear Import Receptor Inhibits Phase Separation of FUS through Binding to Multiple Sites

Abstract

Liquid-liquid phase separation (LLPS) is believed to underlie formation of biomolecular condensates, cellular compartments that concentrate macromolecules without surrounding membranes. Physical mechanisms that control condensate formation/dissolution are poorly understood. The RNA-binding protein fused in sarcoma (FUS) undergoes LLPS in vitro and associates with condensates in cells. We show that the importin karyopherin-β2/transportin-1 inhibits LLPS of FUS. This activity depends on tight binding of karyopherin-β2 to the C-terminal proline-tyrosine nuclear localization signal (PY-NLS) of FUS. Nuclear magnetic resonance (NMR) analyses reveal weak interactions of karyopherin-β2 with sequence elements and structural domains distributed throughout the entirety of FUS. Biochemical analyses demonstrate that most of these same regions also contribute to LLPS of FUS. Here, the data lead to a model where high-affinity binding of karyopherin-β2 to the FUS PY-NLS tethers the proteins together, allowing multiple, distributed weak intermolecular contacts to disrupt FUS self-association, blocking LLPS. Karyopherin-β2 may act analogously to control condensates in diverse cellular contexts.

Authors:
; ; ; ; ; ; ; ; ; ; ; ; ; ; ;
Publication Date:
Research Org.:
Argonne National Lab. (ANL), Argonne, IL (United States)
Sponsoring Org.:
USDOE Office of Science (SC), Biological and Environmental Research (BER); National Institutes of Health (NIH); NIGMS; Howard Hughes Medical Institute HCIA; Welch Foundation
OSTI Identifier:
1548416
Alternate Identifier(s):
OSTI ID: 1440606
Grant/Contract Number:  
AC02-06CH11357; 1S10RR26461-1; 1S10OD018027-01; R01GM069909; U01GM98256-01; R01GM56322; R01GM118530; R01GM083960; P41GM109824; R01GM112108; R01GM114274; T32GM008203; T32GM008297
Resource Type:
Published Article
Journal Name:
Cell
Additional Journal Information:
Journal Name: Cell Journal Volume: 173 Journal Issue: 3; Journal ID: ISSN 0092-8674
Publisher:
Elsevier
Country of Publication:
United States
Language:
English
Subject:
59 BASIC BIOLOGICAL SCIENCES; karyopherin-β2; transportin-1; PY-NLS; FUS; amyotrophic lateral sclerosis; liquid-liquid phase separation; biomolecular condensate; low-complexity sequences; intrinsically disordered protein; RNA granule

Citation Formats

Yoshizawa, Takuya, Ali, Rustam, Jiou, Jenny, Fung, Ho Yee Joyce, Burke, Kathleen A., Kim, Seung Joong, Lin, Yuan, Peeples, William B., Saltzberg, Daniel, Soniat, Michael, Baumhardt, Jordan M., Oldenbourg, Rudolf, Sali, Andrej, Fawzi, Nicolas L., Rosen, Michael K., and Chook, Yuh Min. Nuclear Import Receptor Inhibits Phase Separation of FUS through Binding to Multiple Sites. United States: N. p., 2018. Web. doi:10.1016/j.cell.2018.03.003.
Yoshizawa, Takuya, Ali, Rustam, Jiou, Jenny, Fung, Ho Yee Joyce, Burke, Kathleen A., Kim, Seung Joong, Lin, Yuan, Peeples, William B., Saltzberg, Daniel, Soniat, Michael, Baumhardt, Jordan M., Oldenbourg, Rudolf, Sali, Andrej, Fawzi, Nicolas L., Rosen, Michael K., & Chook, Yuh Min. Nuclear Import Receptor Inhibits Phase Separation of FUS through Binding to Multiple Sites. United States. doi:10.1016/j.cell.2018.03.003.
Yoshizawa, Takuya, Ali, Rustam, Jiou, Jenny, Fung, Ho Yee Joyce, Burke, Kathleen A., Kim, Seung Joong, Lin, Yuan, Peeples, William B., Saltzberg, Daniel, Soniat, Michael, Baumhardt, Jordan M., Oldenbourg, Rudolf, Sali, Andrej, Fawzi, Nicolas L., Rosen, Michael K., and Chook, Yuh Min. Sun . "Nuclear Import Receptor Inhibits Phase Separation of FUS through Binding to Multiple Sites". United States. doi:10.1016/j.cell.2018.03.003.
@article{osti_1548416,
title = {Nuclear Import Receptor Inhibits Phase Separation of FUS through Binding to Multiple Sites},
author = {Yoshizawa, Takuya and Ali, Rustam and Jiou, Jenny and Fung, Ho Yee Joyce and Burke, Kathleen A. and Kim, Seung Joong and Lin, Yuan and Peeples, William B. and Saltzberg, Daniel and Soniat, Michael and Baumhardt, Jordan M. and Oldenbourg, Rudolf and Sali, Andrej and Fawzi, Nicolas L. and Rosen, Michael K. and Chook, Yuh Min},
abstractNote = {Liquid-liquid phase separation (LLPS) is believed to underlie formation of biomolecular condensates, cellular compartments that concentrate macromolecules without surrounding membranes. Physical mechanisms that control condensate formation/dissolution are poorly understood. The RNA-binding protein fused in sarcoma (FUS) undergoes LLPS in vitro and associates with condensates in cells. We show that the importin karyopherin-β2/transportin-1 inhibits LLPS of FUS. This activity depends on tight binding of karyopherin-β2 to the C-terminal proline-tyrosine nuclear localization signal (PY-NLS) of FUS. Nuclear magnetic resonance (NMR) analyses reveal weak interactions of karyopherin-β2 with sequence elements and structural domains distributed throughout the entirety of FUS. Biochemical analyses demonstrate that most of these same regions also contribute to LLPS of FUS. Here, the data lead to a model where high-affinity binding of karyopherin-β2 to the FUS PY-NLS tethers the proteins together, allowing multiple, distributed weak intermolecular contacts to disrupt FUS self-association, blocking LLPS. Karyopherin-β2 may act analogously to control condensates in diverse cellular contexts.},
doi = {10.1016/j.cell.2018.03.003},
journal = {Cell},
number = 3,
volume = 173,
place = {United States},
year = {2018},
month = {4}
}

Journal Article:
Free Publicly Available Full Text
Publisher's Version of Record
DOI: 10.1016/j.cell.2018.03.003

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Works referencing / citing this record:

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