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- EMDB-44741: Cryo-EM structure of human Spns1 -

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Basic information

Entry
Database: EMDB / ID: EMD-44741
TitleCryo-EM structure of human Spns1
Map data
Sample
  • Organelle or cellular component: human Spns1 purified in the absence of extra LPC addition
    • Protein or peptide: Protein spinster homolog 1, Spns1
Keywordslysosome / major facilitator superfamily / lysophospholipid transporter / lysophosphatidylcholine / MEMBRANE PROTEIN
Function / homology
Function and homology information


lysophospholipid transport / regulation of lysosomal lumen pH / phospholipid efflux / transmembrane transporter activity / mitochondrial inner membrane / lysosomal membrane / 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
Protein spinster homolog 1
Similarity search - Component
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.49 Å
AuthorsChen H / Li X
Funding support United States, 3 items
OrganizationGrant numberCountry
National Institutes of Health/National Heart, Lung, and Blood Institute (NIH/NHLBI)P01 HL160487 United States
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)R01 GM135343 United States
Welch FoundationI-1957 United States
CitationJournal: Proc Natl Acad Sci U S A / Year: 2025
Title: Molecular basis of Spns1-mediated lysophospholipid transport from the lysosome.
Authors: Hongwen Chen / Hoa T T Ha / Nadia Elghobashi-Meinhardt / Nhung A Le / Philip Schmiege / Long N Nguyen / Xiaochun Li /
Abstract: Spns1 mediates the rate-limiting efflux of lysophospholipids from the lysosome to the cytosol. Deficiency of Spns1 is associated with embryonic senescence, as well as liver and skeletal muscle ...Spns1 mediates the rate-limiting efflux of lysophospholipids from the lysosome to the cytosol. Deficiency of Spns1 is associated with embryonic senescence, as well as liver and skeletal muscle atrophy in animal models. However, the mechanisms by which Spns1 transports lysophospholipid and proton sensing remain unclear. Here, we present a cryogenic electron microscopy structure of human Spns1 in lysophosphatidylcholine (LPC)-bound lumen-facing conformation. Notably, LPC snugly binds within the luminal-open cavity, where the molecular dynamics simulations reveal that LPC presents a propensity to enter between transmembrane-helices (TM) 5 and 8. Structural comparisons and cell-based transport assays uncover several pivotal residues at TM 5/8 that orchestrate the transport cycle, which are unique to Spns1. Furthermore, we identify a five-residue network that is crucial for proton-sensing by Spns1. Transference of these network residues to Spns2, a sphingosine-1-phosphate uniporter, causes the chimeric Spns2 to be low pH dependent. Our results reveal molecular insights into lysosomal LPC transport and the proton-sensing mechanism by Spns1.
History
DepositionMay 3, 2024-
Header (metadata) releaseJan 1, 2025-
Map releaseJan 1, 2025-
UpdateJan 22, 2025-
Current statusJan 22, 2025Processing site: RCSB / Status: Released

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Structure visualization

Supplemental images

emd_44741.png

Downloads & links

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Map

FileDownload / File: emd_44741.map.gz / Format: CCP4 / Size: 103 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
0.83 Å/pix.
x 300 pix.
= 249. Å		0.83 Å/pix.
x 300 pix.
= 249. Å		0.83 Å/pix.
x 300 pix.
= 249. Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 0.83 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.55
Minimum - Maximum-2.1162002 - 3.261201
Average (Standard dev.)0.00326994 (±0.049060337)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions300300300
Spacing300300300
CellA=B=C: 249.0 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: #2

Fileemd_44741_half_map_1.map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: #1

Fileemd_44741_half_map_2.map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Sample components

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Entire : human Spns1 purified in the absence of extra LPC addition

EntireName: human Spns1 purified in the absence of extra LPC addition
Components
  • Organelle or cellular component: human Spns1 purified in the absence of extra LPC addition
    • Protein or peptide: Protein spinster homolog 1, Spns1

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Supramolecule #1: human Spns1 purified in the absence of extra LPC addition

SupramoleculeName: human Spns1 purified in the absence of extra LPC addition
type: organelle_or_cellular_component / ID: 1 / Parent: 0 / Macromolecule list: all
Source (natural)Organism: Homo sapiens (human)

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Macromolecule #1: Protein spinster homolog 1, Spns1

MacromoleculeName: Protein spinster homolog 1, Spns1 / type: protein_or_peptide / ID: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: GRSALIVAVL CYINLLNYMD RFTVAGVLPD IEQFFNIGDS SSGLIQTVFI SSYMVLAPVF GYLGDRYNRK YLMCGGIAFW SLVTLGSSFI PGEHFWLLLL TRGLVGVGEA SYSTIAPTLI ADLFVADQRS RMLSIFYFAI PVGSGLGYIA GSKVKDMAGD WHWALRVTPG ...String:
GRSALIVAVL CYINLLNYMD RFTVAGVLPD IEQFFNIGDS SSGLIQTVFI SSYMVLAPVF GYLGDRYNRK YLMCGGIAFW SLVTLGSSFI PGEHFWLLLL TRGLVGVGEA SYSTIAPTLI ADLFVADQRS RMLSIFYFAI PVGSGLGYIA GSKVKDMAGD WHWALRVTPG LGVVAVLLLF LVVREPPRGA VERHSDLPPL NPTSWWADLR ALARNPSFVL SSLGFTAVAF VTGSLALWAP AFLLRSRVVL GETPPCLPGD SCSSSDSLIF GLITCLTGVL GVGLGVEISR RLRHSNPRAD PLVCATGLLG SAPFLFLSLA CARGSIVATY IFIFIGETLL SMNWAIVADI LLYVVIPTRR STAEAFQIVL SHLLGDAGSP YLIGLISDRL RRNWPPSFLS EFRALQFSLM LCAFVGALGG AAFLGTAIFI EADRRRAQLH VQGLLHEAGS TDDRIVVPQR GRSTRVPVAS VLI

UniProtKB: Protein spinster homolog 1

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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

Concentration15 mg/mL
BufferpH: 5.5
Component:
ConcentrationFormulaName
20.0 mMC6H13NO4SMES
150.0 mMNaClsodium chloride
0.005 % (w/v)C56H92O25GDN
GridModel: Quantifoil R1.2/1.3 / Material: GOLD / Mesh: 400 / Support film - Material: CARBON / Support film - topology: HOLEY / Pretreatment - Type: GLOW DISCHARGE
VitrificationCryogen name: ETHANE / Chamber humidity: 100 % / Chamber temperature: 293 K / Instrument: FEI VITROBOT MARK IV

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Image recordingFilm or detector model: GATAN K3 (6k x 4k) / Average electron dose: 60.0 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Nominal defocus max: 2.0 µm / Nominal defocus min: 1.0 µm
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Startup modelType of model: NONE
Final reconstructionResolution.type: BY AUTHOR / Resolution: 3.49 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 554684
Initial angle assignmentType: NOT APPLICABLE
Final angle assignmentType: NOT APPLICABLE
FSC plot (resolution estimation)

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