Transport and inhibition of the sphingosine-1-phosphate exporter SPNS2
Abstract Sphingosine-1-phosphate (S1P) is a signaling lysolipid critical to heart development, immunity, and hearing. Accordingly, mutations in the S1P transporter SPNS2 are associated with reduced white cell count and hearing defects. SPNS2 also exports the S1P-mimicking FTY720-P (Fingolimod) and t...
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Nature Portfolio
2025-01-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-025-55942-7 |
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| author | Huanyu Z. Li Ashley C. W. Pike Yung-Ning Chang Dheeraj Prakaash Zuzana Gelova Josefina Stanka Christophe Moreau Hannah C. Scott Frank Wunder Gernot Wolf Andreea Scacioc Gavin McKinley Helena Batoulis Shubhashish Mukhopadhyay Andrea Garofoli Adán Pinto-Fernández Benedikt M. Kessler Nicola A. Burgess-Brown Saša Štefanić Tabea Wiedmer Katharina L. Dürr Vera Puetter Alexander Ehrmann Syma Khalid Alvaro Ingles-Prieto Giulio Superti-Furga David B. Sauer |
| author_facet | Huanyu Z. Li Ashley C. W. Pike Yung-Ning Chang Dheeraj Prakaash Zuzana Gelova Josefina Stanka Christophe Moreau Hannah C. Scott Frank Wunder Gernot Wolf Andreea Scacioc Gavin McKinley Helena Batoulis Shubhashish Mukhopadhyay Andrea Garofoli Adán Pinto-Fernández Benedikt M. Kessler Nicola A. Burgess-Brown Saša Štefanić Tabea Wiedmer Katharina L. Dürr Vera Puetter Alexander Ehrmann Syma Khalid Alvaro Ingles-Prieto Giulio Superti-Furga David B. Sauer |
| author_sort | Huanyu Z. Li |
| collection | DOAJ |
| description | Abstract Sphingosine-1-phosphate (S1P) is a signaling lysolipid critical to heart development, immunity, and hearing. Accordingly, mutations in the S1P transporter SPNS2 are associated with reduced white cell count and hearing defects. SPNS2 also exports the S1P-mimicking FTY720-P (Fingolimod) and thereby is central to the pharmacokinetics of this drug when treating multiple sclerosis. Here, we use a combination of cryo-electron microscopy, immunofluorescence, in vitro binding and in vivo S1P export assays, and molecular dynamics simulations to probe SPNS2’s substrate binding and transport. These results reveal the transporter’s binding mode to its native substrate S1P, the therapeutic FTY720-P, and the reported SPNS2-targeting inhibitor 33p. Further capturing an inward-facing apo state, our structures illuminate the protein’s mechanism for exchange between inward-facing and outward-facing conformations. Finally, using these structural, localization, and S1P transport results, we identify how pathogenic mutations ablate the protein’s export activity and thereby lead to hearing loss. |
| format | Article |
| id | doaj-art-958a9053d8d54652bca2feb39560186c |
| institution | Kabale University |
| issn | 2041-1723 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj-art-958a9053d8d54652bca2feb39560186c2025-01-19T12:32:07ZengNature PortfolioNature Communications2041-17232025-01-0116111410.1038/s41467-025-55942-7Transport and inhibition of the sphingosine-1-phosphate exporter SPNS2Huanyu Z. Li0Ashley C. W. Pike1Yung-Ning Chang2Dheeraj Prakaash3Zuzana Gelova4Josefina Stanka5Christophe Moreau6Hannah C. Scott7Frank Wunder8Gernot Wolf9Andreea Scacioc10Gavin McKinley11Helena Batoulis12Shubhashish Mukhopadhyay13Andrea Garofoli14Adán Pinto-Fernández15Benedikt M. Kessler16Nicola A. Burgess-Brown17Saša Štefanić18Tabea Wiedmer19Katharina L. Dürr20Vera Puetter21Alexander Ehrmann22Syma Khalid23Alvaro Ingles-Prieto24Giulio Superti-Furga25David B. Sauer26Centre for Medicines Discovery, Nuffield Department of Medicine, University of OxfordCentre for Medicines Discovery, Nuffield Department of Medicine, University of OxfordNuvisan ICB GmbHDepartment of Biochemistry, University of OxfordCeMM Research Center for Molecular Medicine of the Austrian Academy of SciencesBayer AGCentre for Medicines Discovery, Nuffield Department of Medicine, University of OxfordCentre for Medicines Discovery, Nuffield Department of Medicine, University of OxfordBayer AGCeMM Research Center for Molecular Medicine of the Austrian Academy of SciencesCentre for Medicines Discovery, Nuffield Department of Medicine, University of OxfordCentre for Medicines Discovery, Nuffield Department of Medicine, University of OxfordBayer AGCentre for Medicines Discovery, Nuffield Department of Medicine, University of OxfordCeMM Research Center for Molecular Medicine of the Austrian Academy of SciencesCentre for Medicines Discovery, Nuffield Department of Medicine, University of OxfordCentre for Medicines Discovery, Nuffield Department of Medicine, University of OxfordCentre for Medicines Discovery, Nuffield Department of Medicine, University of OxfordNanobody Service Facility, University of Zurich, AgroVet-StrickhofCeMM Research Center for Molecular Medicine of the Austrian Academy of SciencesCentre for Medicines Discovery, Nuffield Department of Medicine, University of OxfordNuvisan ICB GmbHBayer AGDepartment of Biochemistry, University of OxfordCeMM Research Center for Molecular Medicine of the Austrian Academy of SciencesCeMM Research Center for Molecular Medicine of the Austrian Academy of SciencesCentre for Medicines Discovery, Nuffield Department of Medicine, University of OxfordAbstract Sphingosine-1-phosphate (S1P) is a signaling lysolipid critical to heart development, immunity, and hearing. Accordingly, mutations in the S1P transporter SPNS2 are associated with reduced white cell count and hearing defects. SPNS2 also exports the S1P-mimicking FTY720-P (Fingolimod) and thereby is central to the pharmacokinetics of this drug when treating multiple sclerosis. Here, we use a combination of cryo-electron microscopy, immunofluorescence, in vitro binding and in vivo S1P export assays, and molecular dynamics simulations to probe SPNS2’s substrate binding and transport. These results reveal the transporter’s binding mode to its native substrate S1P, the therapeutic FTY720-P, and the reported SPNS2-targeting inhibitor 33p. Further capturing an inward-facing apo state, our structures illuminate the protein’s mechanism for exchange between inward-facing and outward-facing conformations. Finally, using these structural, localization, and S1P transport results, we identify how pathogenic mutations ablate the protein’s export activity and thereby lead to hearing loss.https://doi.org/10.1038/s41467-025-55942-7 |
| spellingShingle | Huanyu Z. Li Ashley C. W. Pike Yung-Ning Chang Dheeraj Prakaash Zuzana Gelova Josefina Stanka Christophe Moreau Hannah C. Scott Frank Wunder Gernot Wolf Andreea Scacioc Gavin McKinley Helena Batoulis Shubhashish Mukhopadhyay Andrea Garofoli Adán Pinto-Fernández Benedikt M. Kessler Nicola A. Burgess-Brown Saša Štefanić Tabea Wiedmer Katharina L. Dürr Vera Puetter Alexander Ehrmann Syma Khalid Alvaro Ingles-Prieto Giulio Superti-Furga David B. Sauer Transport and inhibition of the sphingosine-1-phosphate exporter SPNS2 Nature Communications |
| title | Transport and inhibition of the sphingosine-1-phosphate exporter SPNS2 |
| title_full | Transport and inhibition of the sphingosine-1-phosphate exporter SPNS2 |
| title_fullStr | Transport and inhibition of the sphingosine-1-phosphate exporter SPNS2 |
| title_full_unstemmed | Transport and inhibition of the sphingosine-1-phosphate exporter SPNS2 |
| title_short | Transport and inhibition of the sphingosine-1-phosphate exporter SPNS2 |
| title_sort | transport and inhibition of the sphingosine 1 phosphate exporter spns2 |
| url | https://doi.org/10.1038/s41467-025-55942-7 |
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