8QV6

Structure of human SPNS2 in DDM

Summary for 8QV6

• Entry DOI: 10.2210/pdb8qv6/pdb
• EMDB information: 18668
• Descriptor: Sphingosine-1-phosphate transporter SPNS2, Nanobody D12, DODECYL-BETA-D-MALTOSIDE (3 entities in total)
• Functional Keywords: slc transporter, membrane protein, s1p, exporter, lipid transport
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 2
• Total formula weight: 75147.30

Authors

Li, H.Z.,Pike, A.C.W.,McKinley, G.,Mukhopadhyay, S.M.M.,Moreau, C.,Scacioc, A.,Abrusci, P.,Borkowska, O.,Chalk, R.,Stefanic, S.,Burgess-Brown, N.,Duerr, K.L.,Sauer, D.B. (deposition date: 2023-10-17, release date: 2025-02-19)

Primary citation

Li, H.Z.,Pike, A.C.W.,Chang, Y.N.,Prakaash, D.,Gelova, Z.,Stanka, J.,Moreau, C.,Scott, H.C.,Wunder, F.,Wolf, G.,Scacioc, A.,McKinley, G.,Batoulis, H.,Mukhopadhyay, S.,Garofoli, A.,Pinto-Fernandez, A.,Kessler, B.M.,Burgess-Brown, N.A.,Stefanic, S.,Wiedmer, T.,Durr, K.L.,Puetter, V.,Ehrmann, A.,Khalid, S.,Ingles-Prieto, A.,Superti-Furga, G.,Sauer, D.B.
Transport and inhibition of the sphingosine-1-phosphate exporter SPNS2.
Nat Commun, 16:721-721, 2025

PubMed 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.

PubMed: 39820269
DOI: 10.1038/s41467-025-55942-7

Experimental method

ELECTRON MICROSCOPY (3.68 Å)