The DOI matches its Crossref record; 1 of the 1 references it cites were found in a registry or an index.
Transport and inhibition of the sphingosine-1-phosphate exporter SPNS2
Open accessPreprint — published as 10.1038/s41467-025-55942-7
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 dynamic 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 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.
Overview
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Verification
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Citations
Cites
Highly accurate protein structure prediction with AlphaFold
Jumper, J., Evans, R., Pritzel, A., Green, T., Figurnov, M., Ronneberger, O., Tunyasuvunakool, K., Bates, R., Žídek, A., Potapenko, A., et al. (2021) · Nature · doi:10.1038/s41586-021-03819-2 · Cited by 43,764
Flagged first, then by citations
Metadata
- Authors
- Sauer, D., Li, H., Pike, A., Chang, Y.-N., Prakaash, D., Gelova, Z., Stanka, J., Moreau, C., Scott, H., Wunder, F., Wolf, G., Scacioc, A., McKinley, G., Batoulis, H., Mukhopadhyay, S., Garofoli, A., Pinto-Fernandez, A., Kessler, B., Burgess-Brown, N., Štefanic, S., Wiedmer, T., Dürr, K., Puetter, V., Ehrmann, A., Khalid, S., Ingles-Prieto, A., & Superti-Furga, G.
- Affiliations
- University of Oxford (GB)
- Nuvisan
- CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences
- Bayer (Germany) (DE)
- Austrian Academy of Sciences (AT)
- TDI Mass Spectrometry Laboratory, Target Discovery Institute, Nuffield Department of Medicine, University of Oxford, Oxford, Roosevelt Drive, Oxford OX3 7FZ, UK
- University of Zurich
- University of Oxford
- Bayer AG
- Corresponding author
- Sauer, David
- Puetter, Vera
- Ehrmann, Alexander
- Khalid, Syma
- ORCID
- Sauer, David
- Li, Huanyu
- Pike, Ashley
- Chang, Yung-Ning
- Prakaash, Dheeraj
- Stanka, Josefina
- Moreau, Christophe
- Scott, Hannah
- Wunder, Frank
- Wolf, Gernot
- Scacioc, Andreea
- McKinley, Gavin
- Mukhopadhyay, Shubhashish
- Garofoli, Andrea
- Kessler, Benedikt
- Burgess-Brown, Nicola
- Štefanic, Saša
- Wiedmer, Tabea
- Khalid, Syma
- Superti-Furga, Giulio
- Venue
- Nature Communications
- Published
- 2023-11-21
- Volume
- 16
- Issue
- 1
- Pages
- 721-721
- ISSN
- 2041-1723 (ISSN-L)
- PMC
- PMC11739509
- OpenAlex
- W4406471973
- Cited by
- 15
- References
- 1
- Citations by year
- 2026: 8 · 2025: 4 · 2024: 3
- FWCI
- 3.61
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Nature Communications (publishedVersion, cc-by)
- Research Square (acceptedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- McGill University
- Wellcome Trust (060208/Z/00/Z, 093305/Z/10/Z)
- Diamond Light Source
- European Federation of Pharmaceutical Industries and Associations (875510)
- European Commission (777372, HORIZON2020, 101034439, 875510)
- Universität Wien
- Medizinische Universität Wien
- Innovative Medicines Initiative (101034439, 875510, 777372)
- Engineering and Physical Sciences Research Council (EP/X035603, EP/X035603/1)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Sphingolipid Metabolism and Signaling
- Health Sciences › Medicine › Oncology › Drug Transport and Resistance Mechanisms
- Health Sciences › Medicine › Genetics (clinical) › Lysosomal Storage Disorders Research
- Keywords
- SPNS2, sphingosine-1-phosphate, fingolimod, transporter structure, substrate binding, pathogenic variants, hearing loss
- MeSH terms
- Fingolimod Hydrochloride, Animals, Biological Transport, Humans, Lysophospholipids, Mutation, Sphingosine, Cryoelectron Microscopy, Anion Transport Proteins, Hearing Loss, Mice, Molecular Dynamics Simulation, HEK293 Cells
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
