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

Qishun Zhou, Theo Sagmeister, Saskia Hutten, Benjamin Bourgeois, Tea Pavkov-Keller, Dorothee Dormann and Tobias Madl ()
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Qishun Zhou: Medical University of Graz
Theo Sagmeister: University of Graz
Saskia Hutten: Institute of Molecular Physiology
Benjamin Bourgeois: Medical University of Graz
Tea Pavkov-Keller: University of Graz
Dorothee Dormann: Institute of Molecular Physiology
Tobias Madl: Medical University of Graz

Nature Communications, 2025, vol. 16, issue 1, 1-14

Abstract: 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.

Date: 2025
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DOI: 10.1038/s41467-025-59802-2

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