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    Interactions between FUS and the C-terminal Domain of Nup62 are Sufficient for their Co-phase Separation into Amorphous Assemblies

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    Authors
    Kumar, Meenakshi Sundaram
    Stallworth, Karly M
    Murthy, Anastasia C
    Lim, Su Min
    Li, Nan
    Jain, Aastha
    Munro, James B
    Fawzi, Nicolas L
    Lagier-Tourenne, Clotilde
    Bosco, Daryl A
    Academic Program
    Biochemistry and Molecular Biotechnology
    UMass Chan Affiliations
    Biochemistry and Molecular Biotechnology
    Microbiology and Physiological Systems
    Morningside Graduate School of Biomedical Sciences
    Neurology
    Document Type
    Journal Article
    Publication Date
    2023-01-21
    Keywords
    amyotrophic lateral sclerosis (ALS) (Lou Gehrig disease)
    fused in sarcoma (FUS)
    nucleocytoplasmic transport
    nucleoporin 62 (Nup62)
    phase separation
    
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    Link to Full Text
    https://doi.org/10.1016/j.jmb.2023.167972
    Abstract
    Deficient 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.
    Source
    Kumar 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.
    DOI
    10.1016/j.jmb.2023.167972
    Permanent Link to this Item
    http://hdl.handle.net/20.500.14038/51736
    PubMed ID
    36690069
    Rights
    Copyright © 2023 Elsevier Ltd. All rights reserved.
    ae974a485f413a2113503eed53cd6c53
    10.1016/j.jmb.2023.167972
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    Morningside Graduate School of Biomedical Sciences Scholarly Publications
    UMass Chan Faculty and Researcher Publications

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