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- EMDB-42110: Choline-bound FLVCR1 -

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Basic information

Entry
Database: EMDB / ID: EMD-42110
TitleCholine-bound FLVCR1
Map dataCholine-bound FLVCR1 from 1 mM Ethanolamine data set
Sample
  • Complex: Human FLVCR1
    • Protein or peptide: Heme transporter FLVCR1
  • Ligand: CHOLESTEROL HEMISUCCINATE
  • Ligand: CHOLINE ION
  • Ligand: water
KeywordsCholine / ethanolamine / membrane transport / TRANSPORT PROTEIN
Function / homology
Function and homology information


heme export / ethanolamine transmembrane transporter activity / choline transmembrane transporter activity / heme transport / heme transmembrane transporter activity / embryonic skeletal system morphogenesis / choline transport / phospholipid biosynthetic process / head morphogenesis / regulation of organ growth ...heme export / ethanolamine transmembrane transporter activity / choline transmembrane transporter activity / heme transport / heme transmembrane transporter activity / embryonic skeletal system morphogenesis / choline transport / phospholipid biosynthetic process / head morphogenesis / regulation of organ growth / Heme biosynthesis / heme biosynthetic process / embryonic digit morphogenesis / mitochondrial transport / blood vessel development / erythrocyte maturation / spleen development / erythrocyte differentiation / Iron uptake and transport / multicellular organism growth / intracellular iron ion homeostasis / in utero embryonic development / mitochondrial inner membrane / heme binding / mitochondrion / membrane / plasma membrane
Similarity search - Function
: / Major facilitator superfamily / Major Facilitator Superfamily / Major facilitator superfamily domain / Major facilitator superfamily (MFS) profile. / MFS transporter superfamily
Similarity search - Domain/homology
Choline/ethanolamine transporter FLVCR1
Similarity search - Component
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.02 Å
AuthorsHite RK / Son Y
Funding support1 items
OrganizationGrant numberCountry
Not funded
CitationJournal: Nature / Year: 2024
Title: Structural basis of lipid head group entry to the Kennedy pathway by FLVCR1.
Authors: Yeeun Son / Timothy C Kenny / Artem Khan / Kıvanç Birsoy / Richard K Hite /
Abstract: Phosphatidylcholine and phosphatidylethanolamine, the two most abundant phospholipids in mammalian cells, are synthesized de novo by the Kennedy pathway from choline and ethanolamine, respectively. ...Phosphatidylcholine and phosphatidylethanolamine, the two most abundant phospholipids in mammalian cells, are synthesized de novo by the Kennedy pathway from choline and ethanolamine, respectively. Despite the essential roles of these lipids, the mechanisms that enable the cellular uptake of choline and ethanolamine remain unknown. Here we show that the protein encoded by FLVCR1, whose mutation leads to the neurodegenerative syndrome posterior column ataxia and retinitis pigmentosa, transports extracellular choline and ethanolamine into cells for phosphorylation by downstream kinases to initiate the Kennedy pathway. Structures of FLVCR1 in the presence of choline and ethanolamine reveal that both metabolites bind to a common binding site comprising aromatic and polar residues. Despite binding to a common site, FLVCR1 interacts in different ways with the larger quaternary amine of choline in and with the primary amine of ethanolamine. Structure-guided mutagenesis identified residues that are crucial for the transport of ethanolamine, but dispensable for choline transport, enabling functional separation of the entry points into the two branches of the Kennedy pathway. Altogether, these studies reveal how FLVCR1 is a high-affinity metabolite transporter that serves as the common origin for phospholipid biosynthesis by two branches of the Kennedy pathway.
History
DepositionSep 25, 2023-
Header (metadata) releaseMar 27, 2024-
Map releaseMar 27, 2024-
UpdateMay 29, 2024-
Current statusMay 29, 2024Processing site: RCSB / Status: Released

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Structure visualization

Supplemental images

emd_42110.png

Downloads & links

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Map

FileDownload / File: emd_42110.map.gz / Format: CCP4 / Size: 216 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
AnnotationCholine-bound FLVCR1 from 1 mM Ethanolamine data set
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
0.83 Å/pix.
x 384 pix.
= 317.184 Å		0.83 Å/pix.
x 384 pix.
= 317.184 Å		0.83 Å/pix.
x 384 pix.
= 317.184 Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 0.826 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy EMDB: 0.33
Minimum - Maximum-0.9200715 - 1.6000309
Average (Standard dev.)0.00037645324 (±0.026845414)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions384384384
Spacing384384384
CellA=B=C: 317.184 Å
α=β=γ: 90.0 °

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Supplemental data

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Additional map: Density modified map

Fileemd_42110_additional_1.map
AnnotationDensity modified map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: Half map B

Fileemd_42110_half_map_1.map
AnnotationHalf map B
Projections & Slices
AxesZYX

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Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: Half map A

Fileemd_42110_half_map_2.map
AnnotationHalf map A
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 FLVCR1

EntireName: Human FLVCR1
Components
  • Complex: Human FLVCR1
    • Protein or peptide: Heme transporter FLVCR1
  • Ligand: CHOLESTEROL HEMISUCCINATE
  • Ligand: CHOLINE ION
  • Ligand: water

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Supramolecule #1: Human FLVCR1

SupramoleculeName: Human FLVCR1 / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1
Source (natural)Organism: Homo sapiens (human)

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Macromolecule #1: Heme transporter FLVCR1

MacromoleculeName: Heme transporter FLVCR1 / type: protein_or_peptide / ID: 1 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 59.899352 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: MARPDDEEGA AVAPGHPLAK GYLPLPRGAP VGKESVELQN GPKAGTFPVN GAPRDSLAAA SGVLGGPQTP LAPEEETQAR LLPAGAGAE TPGAESSPLP LTALSPRRFV VLLIFSLYSL VNAFQWIQYS IISNVFEGFY GVTLLHIDWL SMVYMLAYVP L IFPATWLL ...String:
MARPDDEEGA AVAPGHPLAK GYLPLPRGAP VGKESVELQN GPKAGTFPVN GAPRDSLAAA SGVLGGPQTP LAPEEETQAR LLPAGAGAE TPGAESSPLP LTALSPRRFV VLLIFSLYSL VNAFQWIQYS IISNVFEGFY GVTLLHIDWL SMVYMLAYVP L IFPATWLL DTRGLRLTAL LGSGLNCLGA WIKCGSVQQH LFWVTMLGQC LCSVAQVFIL GLPSRIASVW FGPKEVSTAC AT AVLGNQL GTAVGFLLPP VLVPNTQNDT NLLACNISTM FYGTSAVATL LFILTAIAFK EKPRYPPSQA QAALQDSPPE EYS YKKSIR NLFKNIPFVL LLITYGIMTG AFYSVSTLLN QMILTYYEGE EVNAGRIGLT LVVAGMVGSI LCGLWLDYTK TYKQ TTLIV YILSFIGMVI FTFTLDLRYI IIVFVTGGVL GFFMTGYLPL GFEFAVEITY PESEGTSSGL LNASAQIFGI LFTLA QGKL TSDYGPKAGN IFLCVWMFIG IILTALIKSD LRRHNINIGI TNVDVKAIPA DSPTDQEPKT VMLSKQSESA I

UniProtKB: Choline/ethanolamine transporter FLVCR1

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Macromolecule #2: CHOLESTEROL HEMISUCCINATE

MacromoleculeName: CHOLESTEROL HEMISUCCINATE / type: ligand / ID: 2 / Number of copies: 3 / Formula: Y01
Molecular weightTheoretical: 486.726 Da
Chemical component information

ChemComp-Y01:
CHOLESTEROL HEMISUCCINATE

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Macromolecule #3: CHOLINE ION

MacromoleculeName: CHOLINE ION / type: ligand / ID: 3 / Number of copies: 1 / Formula: CHT
Molecular weightTheoretical: 104.171 Da
Chemical component information

ChemComp-CHT:
CHOLINE ION

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Macromolecule #4: water

MacromoleculeName: water / type: ligand / ID: 4 / Number of copies: 26 / Formula: HOH
Molecular weightTheoretical: 18.015 Da
Chemical component information

ChemComp-HOH:
WATER

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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

Concentration6.0 mg/mL
BufferpH: 7.5
Component:
ConcentrationNameFormula
0.01 %Lauryl Maltose Neopentyl Glycol
0.001 %Cholesterol hemi succinate
20.0 mMHEPES
150.0 mMKCl
1.0 mMethanolamine

Details: 0.01 % LMNG, 0.001 % CHS, 20 mM HEPES (pHed with KOH, pH 7.5), 150 mM KCl, 1 mM ethanol amine
GridModel: Quantifoil R1.2/1.3 / Material: GOLD / Mesh: 400 / Support film - Material: CARBON / Support film - topology: HOLEY
VitrificationCryogen name: ETHANE / Chamber humidity: 100 % / Chamber temperature: 297 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: 66.0 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Nominal defocus max: 1.5 µm / Nominal defocus min: 0.5 µm
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Particle selectionNumber selected: 5046088
Startup modelType of model: OTHER / Details: cryosparc ab-initio
Final reconstructionApplied symmetry - Point group: C1 (asymmetric) / Resolution.type: BY AUTHOR / Resolution: 3.02 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: cryoSPARC / Number images used: 36781
Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD / Software - Name: cryoSPARC
FSC plot (resolution estimation)

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Atomic model buiding 1

RefinementSpace: REAL / Protocol: BACKBONE TRACE / Target criteria: FSC 0.5
Output model

PDB-8ubz:
Choline-bound FLVCR1

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