Structural basis of phosphorylation-independent nuclear import of CIRBP by TNPO3
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, re...
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| Format: | Article |
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Nature Portfolio
2025-05-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-025-59802-2 |
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| author | Qishun Zhou Theo Sagmeister Saskia Hutten Benjamin Bourgeois Tea Pavkov-Keller Dorothee Dormann Tobias Madl |
| author_facet | Qishun Zhou Theo Sagmeister Saskia Hutten Benjamin Bourgeois Tea Pavkov-Keller Dorothee Dormann Tobias Madl |
| author_sort | Qishun Zhou |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-b28c4176150d401cb98e9f2abbc87ae5 |
| institution | OA Journals |
| issn | 2041-1723 |
| language | English |
| publishDate | 2025-05-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj-art-b28c4176150d401cb98e9f2abbc87ae52025-08-20T01:51:28ZengNature PortfolioNature Communications2041-17232025-05-0116111410.1038/s41467-025-59802-2Structural basis of phosphorylation-independent nuclear import of CIRBP by TNPO3Qishun Zhou0Theo Sagmeister1Saskia Hutten2Benjamin Bourgeois3Tea Pavkov-Keller4Dorothee Dormann5Tobias Madl6Research Unit Integrative Structural Biology, Medicinal Chemistry, Otto Loewi Research Center, Medical University of GrazInstitute of Molecular Biosciences, University of GrazJohannes Gutenberg Universität Mainz, Institute of Molecular PhysiologyResearch Unit Integrative Structural Biology, Medicinal Chemistry, Otto Loewi Research Center, Medical University of GrazInstitute of Molecular Biosciences, University of GrazJohannes Gutenberg Universität Mainz, Institute of Molecular PhysiologyResearch Unit Integrative Structural Biology, Medicinal Chemistry, Otto Loewi Research Center, Medical University of GrazAbstract 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.https://doi.org/10.1038/s41467-025-59802-2 |
| spellingShingle | Qishun Zhou Theo Sagmeister Saskia Hutten Benjamin Bourgeois Tea Pavkov-Keller Dorothee Dormann Tobias Madl Structural basis of phosphorylation-independent nuclear import of CIRBP by TNPO3 Nature Communications |
| title | Structural basis of phosphorylation-independent nuclear import of CIRBP by TNPO3 |
| title_full | Structural basis of phosphorylation-independent nuclear import of CIRBP by TNPO3 |
| title_fullStr | Structural basis of phosphorylation-independent nuclear import of CIRBP by TNPO3 |
| title_full_unstemmed | Structural basis of phosphorylation-independent nuclear import of CIRBP by TNPO3 |
| title_short | Structural basis of phosphorylation-independent nuclear import of CIRBP by TNPO3 |
| title_sort | structural basis of phosphorylation independent nuclear import of cirbp by tnpo3 |
| url | https://doi.org/10.1038/s41467-025-59802-2 |
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