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  1. Article ; Online: A simple thermodynamic description of phase separation of Nup98 FG domains.

    Ng, Sheung Chun / Görlich, Dirk

    Nature communications

    2022  Volume 13, Issue 1, Page(s) 6172

    Abstract: The permeability barrier of nuclear pore complexes (NPCs) controls nucleocytoplasmic transport. It retains inert macromolecules but allows facilitated passage of nuclear transport receptors that shuttle cargoes into or out of nuclei. The barrier can be ... ...

    Abstract The permeability barrier of nuclear pore complexes (NPCs) controls nucleocytoplasmic transport. It retains inert macromolecules but allows facilitated passage of nuclear transport receptors that shuttle cargoes into or out of nuclei. The barrier can be described as a condensed phase assembled from cohesive FG repeat domains, including foremost the charge-depleted FG domain of Nup98. We found that Nup98 FG domains show an LCST-type phase separation, and we provide comprehensive and orthogonal experimental datasets for a quantitative description of this behaviour. A derived thermodynamic model correlates saturation concentration with repeat number, temperature, and ionic strength. It allows estimating the enthalpy, entropy, and ΔG (0.2 kJ/mol, 0.1 k
    MeSH term(s) Nuclear Pore Complex Proteins/metabolism ; Nuclear Pore/metabolism ; Active Transport, Cell Nucleus ; Cell Nucleus/metabolism ; Permeability ; Thermodynamics
    Chemical Substances Nuclear Pore Complex Proteins
    Language English
    Publishing date 2022-10-18
    Publishing country England
    Document type Journal Article
    ZDB-ID 2553671-0
    ISSN 2041-1723 ; 2041-1723
    ISSN (online) 2041-1723
    ISSN 2041-1723
    DOI 10.1038/s41467-022-33697-9
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article ; Online: Recapitulation of selective nuclear import and export with a perfectly repeated 12mer GLFG peptide.

    Ng, Sheung Chun / Güttler, Thomas / Görlich, Dirk

    Nature communications

    2021  Volume 12, Issue 1, Page(s) 4047

    Abstract: The permeability barrier of nuclear pore complexes (NPCs) controls nucleocytoplasmic transport. It retains inert macromolecules while allowing facilitated passage of importins and exportins, which in turn shuttle cargo into or out of cell nuclei. The ... ...

    Abstract The permeability barrier of nuclear pore complexes (NPCs) controls nucleocytoplasmic transport. It retains inert macromolecules while allowing facilitated passage of importins and exportins, which in turn shuttle cargo into or out of cell nuclei. The barrier can be described as a condensed phase assembled from cohesive FG repeat domains. NPCs contain several distinct FG domains, each comprising variable repeats. Nevertheless, we now found that sequence heterogeneity is no fundamental requirement for barrier function. Instead, we succeeded in engineering a perfectly repeated 12mer GLFG peptide that self-assembles into a barrier of exquisite transport selectivity and fast transport kinetics. This barrier recapitulates RanGTPase-controlled importin- and exportin-mediated cargo transport and thus represents an ultimately simplified experimental model system. An alternative proline-free sequence forms an amyloid FG phase. Finally, we discovered that FG phases stain bright with 'DNA-specific' DAPI/ Hoechst probes, and that such dyes allow for a photo-induced block of nuclear transport.
    MeSH term(s) Active Transport, Cell Nucleus ; Biophysical Phenomena ; Cell Nucleus/metabolism ; Cells, Cultured ; Consensus Sequence ; Humans ; Karyopherins/metabolism ; Kinetics ; Nuclear Pore Complex Proteins/metabolism ; Oligopeptides/chemistry ; Permeability ; Protein Engineering/methods ; Repetitive Sequences, Amino Acid
    Chemical Substances Karyopherins ; Nuclear Pore Complex Proteins ; Oligopeptides
    Language English
    Publishing date 2021-06-30
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2553671-0
    ISSN 2041-1723 ; 2041-1723
    ISSN (online) 2041-1723
    ISSN 2041-1723
    DOI 10.1038/s41467-021-24292-5
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  3. Article ; Online: Barrier properties of Nup98 FG phases ruled by FG motif identity and inter-FG spacer length.

    Ng, Sheung Chun / Biswas, Abin / Huyton, Trevor / Schünemann, Jürgen / Reber, Simone / Görlich, Dirk

    Nature communications

    2023  Volume 14, Issue 1, Page(s) 747

    Abstract: Nup98 FG repeat domains comprise hydrophobic FG motifs linked through uncharged spacers. FG motifs capture nuclear transport receptors (NTRs) during nuclear pore complex (NPC) passage, confer inter-repeat cohesion, and condense the domains into a ... ...

    Abstract Nup98 FG repeat domains comprise hydrophobic FG motifs linked through uncharged spacers. FG motifs capture nuclear transport receptors (NTRs) during nuclear pore complex (NPC) passage, confer inter-repeat cohesion, and condense the domains into a selective phase with NPC-typical barrier properties. We show that shortening inter-FG spacers enhances cohesion, increases phase density, and tightens such barrier - all consistent with a sieve-like phase. Phase separation tolerates mutating the Nup98-typical GLFG motifs, provided domain-hydrophobicity remains preserved. NTR-entry, however, is sensitive to (certain) deviations from canonical FG motifs, suggesting co-evolutionary adaptation. Unexpectedly, we observed that arginines promote FG-phase-entry apparently also by hydrophobic interactions/ hydrogen-bonding and not just through cation-π interactions. Although incompatible with NTR·cargo complexes, a YG phase displays remarkable transport selectivity, particularly for engineered GFP
    MeSH term(s) Nuclear Pore Complex Proteins/genetics ; Nuclear Pore Complex Proteins/chemistry ; Active Transport, Cell Nucleus ; Nuclear Pore/metabolism
    Chemical Substances Nuclear Pore Complex Proteins
    Language English
    Publishing date 2023-02-10
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2553671-0
    ISSN 2041-1723 ; 2041-1723
    ISSN (online) 2041-1723
    ISSN 2041-1723
    DOI 10.1038/s41467-023-36331-4
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  4. Article ; Online: Atomic resolution dynamics of cohesive interactions in phase-separated Nup98 FG domains.

    Najbauer, Eszter E / Ng, Sheung Chun / Griesinger, Christian / Görlich, Dirk / Andreas, Loren B

    Nature communications

    2022  Volume 13, Issue 1, Page(s) 1494

    Abstract: Cohesive FG domains assemble into a condensed phase forming the selective permeability barrier of nuclear pore complexes. Nanoscopic insight into fundamental cohesive interactions has long been hampered by the sequence heterogeneity of native FG domains. ...

    Abstract Cohesive FG domains assemble into a condensed phase forming the selective permeability barrier of nuclear pore complexes. Nanoscopic insight into fundamental cohesive interactions has long been hampered by the sequence heterogeneity of native FG domains. We overcome this challenge by utilizing an engineered perfectly repetitive sequence and a combination of solution and magic angle spinning NMR spectroscopy. We map the dynamics of cohesive interactions in both phase-separated and soluble states at atomic resolution using TROSY for rotational correlation time (TRACT) measurements. We find that FG repeats exhibit nanosecond-range rotational correlation times and remain disordered in both states, although FRAP measurements show slow translation of phase-separated FG domains. NOESY measurements enable the direct detection of contacts involved in cohesive interactions. Finally, increasing salt concentration and temperature enhance phase separation and decrease local mobility of FG repeats. This lower critical solution temperature (LCST) behaviour indicates that cohesive interactions are driven by entropy.
    MeSH term(s) Active Transport, Cell Nucleus ; Nuclear Pore/metabolism ; Nuclear Pore Complex Proteins/metabolism ; Permeability
    Chemical Substances Nuclear Pore Complex Proteins
    Language English
    Publishing date 2022-03-21
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2553671-0
    ISSN 2041-1723 ; 2041-1723
    ISSN (online) 2041-1723
    ISSN 2041-1723
    DOI 10.1038/s41467-022-28821-8
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  5. Article ; Online: Mechanical control of nuclear import by Importin-7 is regulated by its dominant cargo YAP.

    García-García, María / Sánchez-Perales, Sara / Jarabo, Patricia / Calvo, Enrique / Huyton, Trevor / Fu, Liran / Ng, Sheung Chun / Sotodosos-Alonso, Laura / Vázquez, Jesús / Casas-Tintó, Sergio / Görlich, Dirk / Echarri, Asier / Del Pozo, Miguel A

    Nature communications

    2022  Volume 13, Issue 1, Page(s) 1174

    Abstract: Mechanical forces regulate multiple essential pathways in the cell. The nuclear translocation of mechanoresponsive transcriptional regulators is an essential step for mechanotransduction. However, how mechanical forces regulate the nuclear import process ...

    Abstract Mechanical forces regulate multiple essential pathways in the cell. The nuclear translocation of mechanoresponsive transcriptional regulators is an essential step for mechanotransduction. However, how mechanical forces regulate the nuclear import process is not understood. Here, we identify a highly mechanoresponsive nuclear transport receptor (NTR), Importin-7 (Imp7), that drives the nuclear import of YAP, a key regulator of mechanotransduction pathways. Unexpectedly, YAP governs the mechanoresponse of Imp7 by forming a YAP/Imp7 complex that responds to mechanical cues through the Hippo kinases MST1/2. Furthermore, YAP behaves as a dominant cargo of Imp7, restricting the Imp7 binding and the nuclear translocation of other Imp7 cargoes such as Smad3 and Erk2. Thus, the nuclear import process is an additional regulatory layer indirectly regulated by mechanical cues, which activate a preferential Imp7 cargo, YAP, which competes out other cargoes, resulting in signaling crosstalk.
    MeSH term(s) Active Transport, Cell Nucleus ; Cell Nucleus/metabolism ; Karyopherins/genetics ; Karyopherins/metabolism ; Mechanotransduction, Cellular ; Receptors, Cytoplasmic and Nuclear/genetics ; Receptors, Cytoplasmic and Nuclear/metabolism
    Chemical Substances Karyopherins ; Receptors, Cytoplasmic and Nuclear
    Language English
    Publishing date 2022-03-04
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2553671-0
    ISSN 2041-1723 ; 2041-1723
    ISSN (online) 2041-1723
    ISSN 2041-1723
    DOI 10.1038/s41467-022-28693-y
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  6. Article ; Online: Surface Properties Determining Passage Rates of Proteins through Nuclear Pores.

    Frey, Steffen / Rees, Renate / Schünemann, Jürgen / Ng, Sheung Chun / Fünfgeld, Kevser / Huyton, Trevor / Görlich, Dirk

    Cell

    2018  Volume 174, Issue 1, Page(s) 202–217.e9

    Abstract: Nuclear pore complexes (NPCs) conduct nucleocytoplasmic transport through an FG domain-controlled barrier. We now explore how surface-features of a mobile species determine its NPC passage rate. Negative charges and lysines impede passage. Hydrophobic ... ...

    Abstract Nuclear pore complexes (NPCs) conduct nucleocytoplasmic transport through an FG domain-controlled barrier. We now explore how surface-features of a mobile species determine its NPC passage rate. Negative charges and lysines impede passage. Hydrophobic residues, certain polar residues (Cys, His), and, surprisingly, charged arginines have striking translocation-promoting effects. Favorable cation-π interactions between arginines and FG-phenylalanines may explain this apparent paradox. Application of these principles to redesign the surface of GFP resulted in variants that show a wide span of transit rates, ranging from 35-fold slower than wild-type to ∼500 times faster, with the latter outpacing even naturally occurring nuclear transport receptors (NTRs). The structure of a fast and particularly FG-specific GFP
    MeSH term(s) Active Transport, Cell Nucleus/physiology ; Amino Acid Motifs ; Binding Sites ; Green Fluorescent Proteins/genetics ; Green Fluorescent Proteins/metabolism ; HeLa Cells ; Humans ; Hydrophobic and Hydrophilic Interactions ; Microscopy, Confocal ; Mutagenesis, Site-Directed ; Nuclear Pore/metabolism ; Nuclear Pore Complex Proteins/chemistry ; Nuclear Pore Complex Proteins/genetics ; Nuclear Pore Complex Proteins/metabolism ; Protein Domains ; Protein Structure, Quaternary ; Recombinant Proteins/biosynthesis ; Recombinant Proteins/chemistry ; Recombinant Proteins/isolation & purification ; Surface Properties
    Chemical Substances Nuclear Pore Complex Proteins ; Recombinant Proteins ; Green Fluorescent Proteins (147336-22-9)
    Language English
    Publishing date 2018-06-27
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 187009-9
    ISSN 1097-4172 ; 0092-8674
    ISSN (online) 1097-4172
    ISSN 0092-8674
    DOI 10.1016/j.cell.2018.05.045
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  7. Article ; Online: Polycation-π interactions are a driving force for molecular recognition by an intrinsically disordered oncoprotein family.

    Song, Jianhui / Ng, Sheung Chun / Tompa, Peter / Lee, Kevin A W / Chan, Hue Sun

    PLoS computational biology

    2013  Volume 9, Issue 9, Page(s) e1003239

    Abstract: Molecular recognition by intrinsically disordered proteins (IDPs) commonly involves specific localized contacts and target-induced disorder to order transitions. However, some IDPs remain disordered in the bound state, a phenomenon coined "fuzziness", ... ...

    Abstract Molecular recognition by intrinsically disordered proteins (IDPs) commonly involves specific localized contacts and target-induced disorder to order transitions. However, some IDPs remain disordered in the bound state, a phenomenon coined "fuzziness", often characterized by IDP polyvalency, sequence-insensitivity and a dynamic ensemble of disordered bound-state conformations. Besides the above general features, specific biophysical models for fuzzy interactions are mostly lacking. The transcriptional activation domain of the Ewing's Sarcoma oncoprotein family (EAD) is an IDP that exhibits many features of fuzziness, with multiple EAD aromatic side chains driving molecular recognition. Considering the prevalent role of cation-π interactions at various protein-protein interfaces, we hypothesized that EAD-target binding involves polycation- π contacts between a disordered EAD and basic residues on the target. Herein we evaluated the polycation-π hypothesis via functional and theoretical interrogation of EAD variants. The experimental effects of a range of EAD sequence variations, including aromatic number, aromatic density and charge perturbations, all support the cation-π model. Moreover, the activity trends observed are well captured by a coarse-grained EAD chain model and a corresponding analytical model based on interaction between EAD aromatics and surface cations of a generic globular target. EAD-target binding, in the context of pathological Ewing's Sarcoma oncoproteins, is thus seen to be driven by a balance between EAD conformational entropy and favorable EAD-target cation-π contacts. Such a highly versatile mode of molecular recognition offers a general conceptual framework for promiscuous target recognition by polyvalent IDPs.
    MeSH term(s) Intrinsically Disordered Proteins/chemistry ; Models, Chemical ; Oncogene Proteins/chemistry ; Polyamines/chemistry ; Polyelectrolytes ; Sarcoma, Ewing/chemistry
    Chemical Substances Intrinsically Disordered Proteins ; Oncogene Proteins ; Polyamines ; Polyelectrolytes ; polycations
    Language English
    Publishing date 2013-09-26
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2193340-6
    ISSN 1553-7358 ; 1553-734X
    ISSN (online) 1553-7358
    ISSN 1553-734X
    DOI 10.1371/journal.pcbi.1003239
    Database MEDical Literature Analysis and Retrieval System OnLINE

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