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Structure paper

TitleStructural and functional insights into Spns2-mediated transport of sphingosine-1-phosphate.
Journal, issue, pagesCell, Vol. 186, Issue 12, Page 2644-2655.e16, Year 2023
Publish dateJun 8, 2023
AuthorsHongwen Chen / Shahbaz Ahmed / Hongtu Zhao / Nadia Elghobashi-Meinhardt / Yaxin Dai / Jae Hun Kim / Jeffrey G McDonald / Xiaochun Li / Chia-Hsueh Lee /
PubMed AbstractSphingosine-1-phosphate (S1P) is an important signaling sphingolipid that regulates the immune system, angiogenesis, auditory function, and epithelial and endothelial barrier integrity. Spinster ...Sphingosine-1-phosphate (S1P) is an important signaling sphingolipid that regulates the immune system, angiogenesis, auditory function, and epithelial and endothelial barrier integrity. Spinster homolog 2 (Spns2) is an S1P transporter that exports S1P to initiate lipid signaling cascades. Modulating Spns2 activity can be beneficial in treatments of cancer, inflammation, and immune diseases. However, the transport mechanism of Spns2 and its inhibition remain unclear. Here, we present six cryo-EM structures of human Spns2 in lipid nanodiscs, including two functionally relevant intermediate conformations that link the inward- and outward-facing states, to reveal the structural basis of the S1P transport cycle. Functional analyses suggest that Spns2 exports S1P via facilitated diffusion, a mechanism distinct from other MFS lipid transporters. Finally, we show that the Spns2 inhibitor 16d attenuates the transport activity by locking Spns2 in the inward-facing state. Our work sheds light on Spns2-mediated S1P transport and aids the development of advanced Spns2 inhibitors.
External linksCell / PubMed:37224812 / PubMed Central
MethodsEM (single particle)
Resolution2.93 - 4.17 Å
Structure data

28650

8ex4

EMDB-28650, PDB-8ex4:
Human S1P transporter Spns2 in an inward-facing open conformation (state 1)
Method: EM (single particle) / Resolution: 2.93 Å

28651

8ex5

EMDB-28651, PDB-8ex5:
Human S1P transporter Spns2 in an outward-facing open conformation (state 4)
Method: EM (single particle) / Resolution: 3.47 Å

28652

8ex6

EMDB-28652, PDB-8ex6:
Human S1P transporter Spns2 in an inward-facing open conformation (state 1*)
Method: EM (single particle) / Resolution: 3.54 Å

28653

8ex7

EMDB-28653, PDB-8ex7:
Human S1P transporter Spns2 in an outward-facing partially occluded conformation (state 3)
Method: EM (single particle) / Resolution: 3.53 Å

28654

8ex8

EMDB-28654, PDB-8ex8:
Human S1P transporter Spns2 in an outward-facing partially occluded conformation (state 2)
Method: EM (single particle) / Resolution: 4.17 Å

29860

8g92

EMDB-29860, PDB-8g92:
Structure of inhibitor 16d-bound SPNS2
Method: EM (single particle) / Resolution: 3.6 Å

Chemicals

ChemComp-S1P:
(2S,3R,4E)-2-amino-3-hydroxyoctadec-4-en-1-yl dihydrogen phosphate / Sphingosine-1-phosphate

ChemComp-YUX:
3-[3-(4-decylphenyl)-1,2,4-oxadiazol-5-yl]propan-1-amine

Source
  • homo sapiens (human)
KeywordsMEMBRANE PROTEIN / transporter / IMMUNE SYSTEM / SPNS2 / Sphingosine-1-phosphate / major facilitator superfamily

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