2018
DOI: 10.1016/j.cell.2018.03.003
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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 karyophe… Show more

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Cited by 275 publications
(366 citation statements)
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References 75 publications
(125 reference statements)
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“…Recent work, for example, supports that Nup188 and its paralog Nup205 have atomic structures that resemble the karyopherin/importin β-family of NTRs (Andersen et al, 2013;Flemming et al, 2012;Sampathkumar et al, 2013;Stuwe et al, 2014). In fact, evidence indicates that these interactions might be critical for helping to hold the NPC structure together (Onischenko et al, 2017) perhaps by "ordering" the inherently disordered FG-repeats, which themselves have been shown to display a spectrum of collective behaviors and "phases" (Lemke, 2016) some of which are impacted by NTR-binding (Hofweber et al, 2018;Yoshizawa et al, 2018). Could an NTR-like Nup188 also contribute to an ordering or disordering of centrosome organization?…”
Section: Discussionmentioning
confidence: 99%
See 1 more Smart Citation
“…Recent work, for example, supports that Nup188 and its paralog Nup205 have atomic structures that resemble the karyopherin/importin β-family of NTRs (Andersen et al, 2013;Flemming et al, 2012;Sampathkumar et al, 2013;Stuwe et al, 2014). In fact, evidence indicates that these interactions might be critical for helping to hold the NPC structure together (Onischenko et al, 2017) perhaps by "ordering" the inherently disordered FG-repeats, which themselves have been shown to display a spectrum of collective behaviors and "phases" (Lemke, 2016) some of which are impacted by NTR-binding (Hofweber et al, 2018;Yoshizawa et al, 2018). Could an NTR-like Nup188 also contribute to an ordering or disordering of centrosome organization?…”
Section: Discussionmentioning
confidence: 99%
“…There are ~30 nucleoporins or "nups" that, alongside nup binding partners, construct modular subcomplex building blocks that come together in multiples of eight to assemble ~100 MD transport channels (Hampoelz et al, 2019). The major architectural units of the NPC scaffold consist of the Nup107-160, "Y" or "outer ring" complex in addition to the Nup93 or "inner ring complex" (Amlacher et al, 2011;Bui et al, 2013;Kim et al, 2018;Kosinski et al, 2016;Siniossoglou et al, 2000;von Appen et al, 2015). The latter consists of Nup93, Nup155, Nup35 (Nup53), Nup205 and Nup188 (Amlacher et al, 2011;Vollmer and Antonin, 2014).…”
Section: Introductionmentioning
confidence: 99%
“…The interaction between FUS and its import receptor, karyopherin‐ß2 (Karβ2)/importin‐ß2, significantly diminishes FUS aggregation in vitro . The proline/tyrosine‐nuclear localization signal of FUS is frequently mutated in ALS, precluding the FUS/Karβ2 interaction and accelerating FUS aggregation (Figure C). Inhibition of the molecular chaperone, HSP70, also slows the internal dynamics of cellular SGs .…”
Section: Biomolecular Condensates In Neurodegenerationmentioning
confidence: 99%
“…MPPSkd3, PARLSkd3, ANKSkd3, and NBD2Skd3 were cloned into the pMAL C2 plasmid with TEV site (Yoshizawa et al, 2018) using Gibson assembly (Gibson et al, 2009). Site-directed mutagenesis was performed using QuikChange site-directed mutagenesis (Agilent) and confirmed by DNA sequencing.…”
Section: Cloning Mbp-skd3 Plasmidsmentioning
confidence: 99%
“…Metazoa may partially compensate for the absence of Hsp104 activity in the cytoplasm and nucleus with alternative general protein-disaggregase systems, such as Hsp110, Hsp70, Hsp40, and small heat-shock proteins (Mattoo et al, 2013;Nillegoda et al, 2015;Shorter, 2011) as well as client-specific disaggregases in the cytoplasm such as nuclear-import receptors (Guo et al, 2019;Guo et al, 2018;Niaki et al, 2020;Yoshizawa et al, 2018). However, Hsp110 is not found in mitochondria .…”
Section: Introductionmentioning
confidence: 99%