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Structural basis of phosphorylation-independent nuclear import of CIRBP by TNPO3

Author

Listed:
  • Qishun Zhou

    (Medical University of Graz
    Institut Pasteur, Université Paris Cité, CNRS UMR3528, Bacterial Transmembrane Systems Unit)

  • Theo Sagmeister

    (University of Graz)

  • Saskia Hutten

    (Institute of Molecular Physiology)

  • Benjamin Bourgeois

    (Medical University of Graz)

  • Tea Pavkov-Keller

    (University of Graz
    University of Graz
    BioTechMed-Graz)

  • Dorothee Dormann

    (Institute of Molecular Physiology
    Institute of Molecular Biology (IMB) Mainz)

  • Tobias Madl

    (Medical University of Graz
    BioTechMed-Graz)

Abstract

Transportin 3 (TNPO3) is a nuclear import receptor known for its broad substrate specificity, often recognizing arginine-serine (SR/RS) repeat-rich nuclear localization signals (NLS) in SRSF proteins. While serine phosphorylation or glutamate presence has been associated with these NLSs, recent proteomic studies identified TNPO3 cargoes lacking SR/RS repeats. One such example is the cold-inducible RNA-binding protein (CIRBP), which contains a non-classical RSY-NLS. Using X-ray crystallography, here we investigate the TNPO3-CIRBP interaction and find that tyrosines within the RSY-NLS play a key role in binding, independent of phosphorylation. Surprisingly, serine and tyrosine phosphorylation in CIRBP’s NLS inhibits TNPO3 binding, suggesting a regulatory mechanism for nuclear import. Our study reveals a non-conventional nuclear import mechanism mediated by TNPO3, which may extend to other known or yet undiscovered TNPO3 cargoes.

Suggested Citation

  • Qishun Zhou & Theo Sagmeister & Saskia Hutten & Benjamin Bourgeois & Tea Pavkov-Keller & Dorothee Dormann & Tobias Madl, 2025. "Structural basis of phosphorylation-independent nuclear import of CIRBP by TNPO3," Nature Communications, Nature, vol. 16(1), pages 1-14, December.
    • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-59802-2
    DOI: 10.1038/s41467-025-59802-2
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