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dc.contributor.authorKumar, Meenakshi Sundaram
dc.contributor.authorStallworth, Karly M
dc.contributor.authorMurthy, Anastasia C
dc.contributor.authorLim, Su Min
dc.contributor.authorLi, Nan
dc.contributor.authorJain, Aastha
dc.contributor.authorMunro, James B
dc.contributor.authorFawzi, Nicolas L
dc.contributor.authorLagier-Tourenne, Clotilde
dc.contributor.authorBosco, Daryl A
dc.date.accessioned2023-03-02T19:50:41Z
dc.date.available2023-03-02T19:50:41Z
dc.date.issued2023-01-21
dc.identifier.citationKumar MS, Stallworth KM, Murthy AC, Lim SM, Li N, Jain A, Munro JB, Fawzi NL, Lagier-Tourenne C, Bosco DA. Interactions between FUS and the C-terminal Domain of Nup62 are Sufficient for their Co-phase Separation into Amorphous Assemblies. J Mol Biol. 2023 Jan 21;435(6):167972. doi: 10.1016/j.jmb.2023.167972. Epub ahead of print. PMID: 36690069.en_US
dc.identifier.eissn1089-8638
dc.identifier.doi10.1016/j.jmb.2023.167972en_US
dc.identifier.pmid36690069
dc.identifier.urihttp://hdl.handle.net/20.500.14038/51736
dc.description.abstractDeficient nucleocytoplasmic transport is emerging as a pathogenic feature of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), including in ALS caused by mutations in Fused in Sarcoma (FUS). Recently, both wild-type and ALS-linked mutant FUS were shown to directly interact with the phenylalanine-glycine (FG)-rich nucleoporin 62 (Nup62) protein, where FUS WT/ Nup62 interactions were enriched within the nucleus but ALS-linked mutant FUS/ Nup62 interactions were enriched within the cytoplasm of cells. Nup62 is a central channel Nup that has a prominent role in forming the selectivity filter within the nuclear pore complex and in regulating effective nucleocytoplasmic transport. Under conditions where FUS phase separates into liquid droplets in vitro, the addition of Nup62 caused the synergistic formation of amorphous assemblies containing both FUS and Nup62. Here, we examined the molecular determinants of this process using recombinant FUS and Nup62 proteins and biochemical approaches. We demonstrate that the structured C-terminal domain of Nup62 containing an alpha-helical coiled-coil region plays a dominant role in binding FUS and is sufficient for inducing the formation of FUS/Nup62 amorphous assemblies. In contrast, the natively unstructured, F/G repeat-rich N-terminal domain of Nup62 modestly contributed to FUS/Nup62 phase separation behavior. Expression of individual Nup62 domain constructs in human cells confirmed that the Nup62 C-terminal domain is essential for localization of the protein to the nuclear envelope. Our results raise the possibility that interactions between FUS and the C-terminal domain of Nup62 can influence the function of Nup62 under physiological and/or pathological conditions.en_US
dc.language.isoenen_US
dc.relation.ispartofJournal of Molecular Biologyen_US
dc.relation.urlhttps://doi.org/10.1016/j.jmb.2023.167972en_US
dc.rightsCopyright © 2023 Elsevier Ltd. All rights reserved.en_US
dc.subjectamyotrophic lateral sclerosis (ALS) (Lou Gehrig disease)en_US
dc.subjectfused in sarcoma (FUS)en_US
dc.subjectnucleocytoplasmic transporten_US
dc.subjectnucleoporin 62 (Nup62)en_US
dc.subjectphase separationen_US
dc.titleInteractions between FUS and the C-terminal Domain of Nup62 are Sufficient for their Co-phase Separation into Amorphous Assembliesen_US
dc.typeJournal Articleen_US
dc.source.journaltitleJournal of molecular biology
dc.source.volume435
dc.source.issue6
dc.source.beginpage167972
dc.source.endpage
dc.source.countryNetherlands
dc.identifier.journalJournal of molecular biology
dc.contributor.departmentBiochemistry and Molecular Biotechnologyen_US
dc.contributor.departmentMicrobiology and Physiological Systemsen_US
dc.contributor.departmentMorningside Graduate School of Biomedical Sciencesen_US
dc.contributor.departmentNeurologyen_US
dc.contributor.studentMeenakshi Sundaram Kumar
dc.description.thesisprogramBiochemistry and Molecular Biotechnology


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