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- EMDB-28651: Human S1P transporter Spns2 in an outward-facing open conformatio... -

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Basic information

Entry
Database: EMDB / ID: EMD-28651
TitleHuman S1P transporter Spns2 in an outward-facing open conformation (state 4)
Map data
Sample
  • Complex: Human S1P transporter Spns2 in an outward-facing open conformation (state 4)
    • Protein or peptide: Sphingosine-1-phosphate transporter SPNS2
Keywordstransporter / MEMBRANE PROTEIN
Function / homology
Function and homology information


regulation of eye pigmentation / regulation of humoral immune response / regulation of T cell migration / sphingolipid transporter activity / lymphocyte migration / sphingolipid biosynthetic process / Sphingolipid de novo biosynthesis / sphingosine-1-phosphate receptor signaling pathway / lipid transport / T cell homeostasis ...regulation of eye pigmentation / regulation of humoral immune response / regulation of T cell migration / sphingolipid transporter activity / lymphocyte migration / sphingolipid biosynthetic process / Sphingolipid de novo biosynthesis / sphingosine-1-phosphate receptor signaling pathway / lipid transport / T cell homeostasis / B cell homeostasis / transmembrane transporter activity / lymph node development / sensory perception of sound / bone development / endosome membrane / membrane / plasma membrane
Similarity search - Function
Protein spinster-like / Major facilitator superfamily / Major Facilitator Superfamily / Major facilitator superfamily domain / Major facilitator superfamily (MFS) profile. / MFS transporter superfamily
Similarity search - Domain/homology
Sphingosine-1-phosphate transporter SPNS2
Similarity search - Component
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.47 Å
AuthorsAhmed S / Zhao H / Dai Y / Lee CH
Funding support United States, 1 items
OrganizationGrant numberCountry
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)GM143282 United States
CitationJournal: Cell / Year: 2023
Title: Structural and functional insights into Spns2-mediated transport of sphingosine-1-phosphate.
Authors: Hongwen Chen / Shahbaz Ahmed / Hongtu Zhao / Nadia Elghobashi-Meinhardt / Yaxin Dai / Jae Hun Kim / Jeffrey G McDonald / Xiaochun Li / Chia-Hsueh Lee /
Abstract: Sphingosine-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.
History
DepositionOct 24, 2022-
Header (metadata) releaseMay 31, 2023-
Map releaseMay 31, 2023-
UpdateJun 19, 2024-
Current statusJun 19, 2024Processing site: RCSB / Status: Released

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Structure visualization

Supplemental images

emd_28651.png

Downloads & links

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Map

FileDownload / File: emd_28651.map.gz / Format: CCP4 / Size: 216 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Voxel sizeX=Y=Z: 0.649 Å
Density
Contour LevelBy AUTHOR: 0.2
Minimum - Maximum-1.1761386 - 1.3668884
Average (Standard dev.)0.00053589605 (±0.018060405)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions384384384
Spacing384384384
CellA=B=C: 249.216 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: #1

Fileemd_28651_half_map_1.map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: #2

Fileemd_28651_half_map_2.map
Projections & Slices
AxesZYX

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Slices (1/2)
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Histogram

Histogram (log scale)

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Sample components

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Entire : Human S1P transporter Spns2 in an outward-facing open conformatio...

EntireName: Human S1P transporter Spns2 in an outward-facing open conformation (state 4)
Components
  • Complex: Human S1P transporter Spns2 in an outward-facing open conformation (state 4)
    • Protein or peptide: Sphingosine-1-phosphate transporter SPNS2

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Supramolecule #1: Human S1P transporter Spns2 in an outward-facing open conformatio...

SupramoleculeName: Human S1P transporter Spns2 in an outward-facing open conformation (state 4)
type: complex / ID: 1 / Parent: 0 / Macromolecule list: all
Source (natural)Organism: Homo sapiens (human)

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Macromolecule #1: Sphingosine-1-phosphate transporter SPNS2

MacromoleculeName: Sphingosine-1-phosphate transporter SPNS2 / type: protein_or_peptide / ID: 1 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 48.896184 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: EKRKAAAAIL SLGNVLNYLD RYTVAGVLLD IQQHFGVKDR GAGLLQSVFI CSFMVAAPIF GYLGDRFNRK VILSCGIFFW SAVTFSSSF IPQQYFWLLV LSRGLVGIGE ASYSTIAPTI IGDLFTKNTR TLMLSVFYFA IPLGSGLGYI TGSSVKQAAG D WHWALRVS ...String:
EKRKAAAAIL SLGNVLNYLD RYTVAGVLLD IQQHFGVKDR GAGLLQSVFI CSFMVAAPIF GYLGDRFNRK VILSCGIFFW SAVTFSSSF IPQQYFWLLV LSRGLVGIGE ASYSTIAPTI IGDLFTKNTR TLMLSVFYFA IPLGSGLGYI TGSSVKQAAG D WHWALRVS PVLGMITGTL ILILVPATKR GHADQLGDQL KARTSWLRDM KALIRNRSYV FSSLATSAVS FATGALGMWI PL YLHRAQV VQKTAETCNS PPCGAKDSLI FGAITCFTGF LGVVTGAGAT RWCRLKTQRA DPLVCAVGML GSAIFICLIF VAA KSSIVG AYICIFVGET LLFSNWAITA DILMYVVIPT RRATAVALQS FTSHLLGDAG SPYLIGFISD LIRQSTKDSP LWEF LSLGY ALMLCPFVVV LGGMFFLATA LFFVSDRARA EQQVNQLAMP PASVKV

UniProtKB: Sphingosine-1-phosphate transporter SPNS2

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Experimental details

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Structure determination

Methodcryo EM
Processingsingle particle reconstruction
Aggregation stateparticle

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Sample preparation

BufferpH: 7
VitrificationCryogen name: ETHANE

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Image recordingFilm or detector model: GATAN K3 (6k x 4k) / Average electron dose: 65.0 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: OTHER / Imaging mode: BRIGHT FIELD / Nominal defocus max: 1.6 µm / Nominal defocus min: 0.6 µm
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Startup modelType of model: OTHER
Final reconstructionResolution.type: BY AUTHOR / Resolution: 3.47 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 422542
Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD

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