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TitleTransport and inhibition of the sphingosine-1-phosphate exporter SPNS2.
Journal, issue, pagesNat Commun, Vol. 16, Issue 1, Page 721, Year 2025
Publish dateJan 16, 2025
AuthorsHuanyu 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 /
PubMed AbstractSphingosine-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 ...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.
External linksNat Commun / PubMed:39820269 / PubMed Central
MethodsEM (single particle)
Resolution3.68 - 3.69 Å
Structure data

18667

8qv5

EMDB-18667, PDB-8qv5:
Structure of human SPNS2 in LMNG
Method: EM (single particle) / Resolution: 3.69 Å

18668

8qv6

EMDB-18668, PDB-8qv6:
Structure of human SPNS2 in DDM
Method: EM (single particle) / Resolution: 3.68 Å

Chemicals

ChemComp-LMT:
DODECYL-BETA-D-MALTOSIDE / detergent*YM

Source
  • homo sapiens (human)
  • vicugna pacos (alpaca)
KeywordsLIPID TRANSPORT / SLC TRANSPORTER / MEMBRANE PROTEIN / S1P / EXPORTER

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